By: Philip M. Boone, Serkan Erdin, Michael E. Talkowski, et al.

We got a new disease causing gene!

WAPL-related disorder features developmental delay, intellectual differences, and risk of other developmental anomalies. It’s a cohesinopathy, caused by cohesin release factor deficiency.

They also used CRISPR to generate truncating variants in WAPL in human induced pluripotent stem cells (iPSCs) and induced neurons. Mice with 50% Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity.

Occurrence of Infusion Associated Reactions and Antidrug Antibodies in Enzyme Replacement Therapy for Fabry Disease and the Effect of Preventive Measures (Link)

By: Maud Janssens, Sanne J. van der Veen, Laura van Dussen, André B. P. van Kuilenburg, Marion M. M. G. Brands, Mirjam Langeveld

For Fabry disease variants not amenable to the oral medication Galafold, you’ve only got one main way to treat the underlying disease: enzyme replacement therapy (ERT). ERT is fairly decent, though infusion associated reactions (IARs) can be common.

In this study, they successfully figured out, albeit with an n=17, that if you implement a 30 week stepwise dose escalation protocol, your risk of an infusion reaction is MUCH lower. How much lower? In their study of these 17 males with classical Fabry disease considered at high risk of developing iADAs, none of the patients in the intervention group (stepwise dose escalation) experienced IARs (0/8), compared to more than half of the patients in the control group (5/9, p = 0.029).

The hitch: While in this small intervention group they ultimately did prevent IARs, they did not prevent the development of inhibiting anti-drug antibodies (iADAs), which I believe was likely their primary goal with doing this super long dose escalation protocol.

My takeaway: Avoiding infusion reactions is a worthy cause. BUT, in this stepwise protocol, patients must come in every week for the first 30 weeks (instead of the normal every other week). That’s a huge burden on all the patients, physicians, nurses, and care coordinators involved. And given that it ultimately did not prevent iADAs from forming, I think this protocol could likely be sped up.

Prenatal Referrals for Differences of Sex Development: Genetic Diagnoses and Clinical Outcomes at a Tertiary Fetal Care Center (Link)

By: Lylach Haizler-Cohen, Nicole R. Legro, Anne Eckert, Sonja A. Duncan, Tucker L. C. Pyle

A quick nugget from the article:

In this study, there were a total of 255 patients referred: 161 for sex chromosome DSD, 85 for atypical genitalia, and 9 for fetal sex discordance. Among the 64 pregnancies with postnatal data, 22% of the prenatal genital findings were considered false positives.

One more nugget:

Looking at the sub-cohort of 85 fetuses with atypical genitalia and 9 with fetal sex discordance: Of those 94 fetuses, 15 had a cytogenetic diagnosis, including five chromosome aneuploidies, one sex chromosome DSD, and nine copy-number variants. Another six had a single-gene diagnosis, bringing the overall diagnostic yield to 22% or 21/94.

I’m a numbers guy, and I always appreciate knowing the odds of finding a genetic answer in common referrals. Another point to make, it doesn’t appear that all the fetuses/babies without a diagnosis got exome or genome sequencing - and I’m assuming this would increase the yield as well.

Genomics-first association of pharmacogenomic risk phenotypes with adverse drug reactions in a healthcare-based population (Link)

By: Rebecca I. Torene, Ryley Uber, Tracy Brandt, Karyn Meltz Murphy, Eric A. Wright, Kyle Retterer

TLDR: 3.9% of patients in this population (N=226,053) accumulated an electronic health record (EHR)-recorded adverse drug reaction (ADR) to a medication for which they also had a genotype predicted to increase ADR risk.

Much longer version:

I am going to start this one by saying that I remain somewhat skeptical about pharmacogenomics. Not because I don’t think PGx is real. There are some drug and gene combinations where the evidence is incredibly convincing. My hesitation is more about how we translate that information into population-wide clinical care.

The study:

Researchers looked at the health records of 226,053 individuals and evaluated 58 pharmacogenomic drug and gene relationships across 11 genes.

The big findings:

1. 93.7% of people had at least one risk PGx phenotype.

2. 44.4% had both a PGx risk phenotype and had actually been prescribed a medication relevant to that phenotype.

3. 3.9% of the entire cohort had a documented adverse drug reaction associated with a medication for which they had a PGx risk phenotype.

That 3.9% number is what caught my attention, but there is some important context.

The cohort had a median of 18 years of EHR data, so this was not 3.9% developing an adverse reaction over a year or two. The study also did not establish that the PGx phenotype caused each reaction, define the severity of the reaction, or demonstrate that they would have been prevented through genotype-guided prescribing.

There was a trial previously (PREPARE) that found that genotype-guided prescribing reduced clinically relevant adverse drug reactions by approximately 30% among individuals with actionable PGx results. That suggests there is a real clinical benefit, but it still does not tell us whether population-wide implementation is worth the cost.

To me, the economic question depends heavily on how PGx is implemented.

If we need to order a separate $500 pharmacogenomic panel for every person, build the informatics infrastructure, and maintain the results indefinitely, I remain skeptical that preventing an adverse reaction in a relatively small percentage of people would justify the investment.

My Thoughts: What some hospitals are doing now is extracting clinically validated PGx information from peoples existing genomic datasets, putting that information into the EHR, and having systems like Epic (sorry if you have something else) recognize it when a relevant medication is prescribed.

You order clopidogrel. Epic sees that the person is a CYP2C19 poor metabolizer. A recommendation appears suggesting an alternative.

But even if you have this data already, this whole process is not free. You need validated pharmacogenomic pipelines, integration with your EHR, continually updated drug and gene recommendations, clinical decision support, provider education, alert management, pharmacy involvement, and people responsible for maintaining the entire system.

Other big points I didn’t discuss:

1. Standard exome sequencing may be inadequate for some pharmacogenes because it can miss relevant noncoding variants, structural variants, copy-number changes, and complex haplotypes, particularly at loci such as CYP2D6.

2. More often than not, someone with a “high-risk” PGx phenotype will still take the relevant medication without experiencing an adverse reaction. The phenotype increases risk, but it does not make a reaction inevitable.

So now the final question becomes, is preventing some unknown proportion of the PGx-associated adverse reactions observed in 3.9% of a cohort enough to justify building pharmacogenomic infrastructure today?

I genuinely don’t know.

For those of you working in pharmacogenomics, pharmacy, informatics, or health system implementation, I would love to hear your thoughts.

Sincerely,

Max

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Authors: Nikola Reko, Rosanna Weksberg, Sanaa Choufani1 et al

Are you ready for prenatal epigenetic signature testing??

Researchers conducted a proof-of-concept study using Down syndrome to explore the feasibility of developing episignatures capable of informing variant pathogenicity prenatally.

To do this, they first generated a blood-derived T21 episignature using a cohort of 266 samples. Next, they used that episignature and publicly available DNAm data for 850 T21 and control samples across six different pre- and postnatal tissues to train machine-learning models.

The results:

1. Their models trained on postnatal blood-derived signatures as well as other tissues can generate cell-type-agnostic disease-specific patterns.

   1. This method also generated an episignature capable of accurately classifying prenatal samples.

My big takeaway: This proof of concept study provides the framework for the development of epigenetic signatures for many other genetic disorders. I still don’t know that this will be used for diagnostic testing, but it may be helpful for that VUS you got on prenatal exome sequencing.

Neonatal gene therapy with AAV2/8-LSPhGAA improves hypertrophic cardiomyopathy in the Gaa^c.1826dupA knock-in murine model (Link)

Authors: Shih-hsin Kan, Raymond Y. Wang, et al.

TLDR: In a murine infantile onset pompe disease model, gene therapy nearly corrected the cardiac manifestations, though did not seem to have a profound impact on improving muscle weakness.

Longer version:

Researchers created a mouse model carrying the infantile-onset PD (IOPD) pathogenic variant, GAA:c.1826dupA (p.Y609*), causing the mice to have reduced GAA activity, early-onset hypertrophic cardiomyopathy, and impaired grip strength and gait abnormalities.

They then injected the mice (n=18) with a single retro-orbital dose of the gene therapy (AAV2/8-LSPhGAA at 2 × 10⁹ vg/g body weight) at postnatal day 12–14.

Results: Twelve weeks post-treatment, mice exhibited supraphysiological GAA enzymatic activity in the heart (550% of WT) and liver (400% of WT) with a 93% reduction in cardiac glycogen. Echocardiography revealed near complete reversal of cardiac pathology. However, forelimb grip strength remained unchanged and automated gait analysis showed benefit limited to hind paw base of support.

My thoughts: This specific gene therapy has already been used in a phase 1 trial in adults with LOPD. In the trial, some patients were discontinued from ERT because they demonstrated clinical stability. However, I think that before we call this gene therapy a replacement, I want to know that patients can improve the outcomes that matter to their quality of life: strength, mobility, breathing, fatigue and independence. Speaking anecdotally, my patients (older and younger with Infantile and late onset) notice improvement in muscle strength and decreased weakness after ERT. All this to say, if gene therapy protects the heart but does not adequately treat skeletal muscle, then we may need to consider combination treatment with ERT, other medications, or a better gene therapy.

What do you all think?

Prenatal Substance Exposure and Birth Weight: Findings From the HEALthy Brain and Child Development Study (Link)

Authors: Gretchen Bandoli, Catherine Psaras, Christina D. Chambers, et al.

Giving you the takeaway early on: If you are consulted for low birth weight, consider exposure to prenatal cannabis and or opioid exposure.

The paper:

The HEALthy Brain and Child Development (HBCD) Study is the largest US study of brain development from birth into middle childhood. I had never heard of it until now, but glad it exists!

For this paper, they analyzed data from 660 mothers to determine whether alcohol, cannabis, nicotine, or opioids had a significant effect on birth weight.

What i found interesting is that they not only took self-reported exposure data into account, but also took nail clippings to confirm each participants true substance exposure. Which I personally like, as this provides more objective data.

Prenatal substance exposure criteria were met by 17% of participants for cannabis (n = 115), followed by nicotine (15%; n = 102), alcohol (13%; n = 86), and opioids (5%; n = 32); 432 (65%) did not meet the criteria for any of the 4 exposures.

The data:

1. The median gestational age at delivery was 39 (IQR, 38–40) weeks. In unadjusted and adjusted models, point estimates for the 4 exposures signaled a reduction in completed gestational weeks but were not statistically significant.

2. More than minimal levels of prenatal cannabis and opioid exposure were associated with lower newborn birth weight and birth weight for gestational age. Estimates from nicotine and alcohol models were not statistically significant.

3. Although more than 90% of alcohol use in HBCD was captured with self-report, only 66% of cannabis, 62% of nicotine, and 72% of opioids were captured by self-report

4. Individuals who met prenatal substance exposure criteria were more likely to identify as non-Hispanic Black or African American, be insured through Medicaid, receive WIC benefits, screen positive for probable or possible depression on the EPDS, and were less likely to have education beyond a high school diploma.

Last tidbit: These initial findings from the first HBCD data release are based on less than 10% of the anticipated final sample size of the HBCD Study, so we will have more data to come!

With love,

Max

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Points to consider for the reporting of variants of uncertain significance in germline genetic and genomic testing: A statement of the American College of Medical Genetics and Genomics (ACMG) (Link)

By: Chloe Mighton, Heidi L. Rehm, et al.

TLDR: The ACMG and the Laboratory Quality Assurance Committee are saying that not all VUSs deserve the same reporting weight. And I agree.

Earlier in June, ACMG released a new “Points to Consider” statement on the reporting of variants of uncertain significance, or VUSs.

Big takeaways:

1. One of the core recommendations is that VUSs should generally be returned in symptomatic testing when the finding is related to the phenotype.

   1. But in asymptomatic testing, when there are no signs, symptoms, or relevant family history, VUSs generally should not be returned.

2. The second big recommendation: VUS subclasses.

   1. The paper leans into the idea of VUS-low, VUS-mid, and VUS-high.

      1. I personally agree with this. Right now, “VUS” is too broad. A variant barely above likely benign and a variant just shy of likely pathogenic both get labeled the same way, even though clinically, they do not carry the same weight.

3. The paper also recognizes some exceptions, including VUS reporting in partner-based carrier screening when the other partner has a pathogenic or likely pathogenic variant in the same gene.

4. Another notable point: they suggest that VUSs should not generally be returned in asymptomatic prenatal testing if the finding is unrelated to fetal findings or family history.

My takeaway: phenotyping is going to matter. Time to bring back the physical exam! I also think this is ACMG warming us up for the next variant classification update, which I would imagine should be coming sometime in the next year or so.

Overall, I agree with the premise: not all VUSs are the same. Now if only we could get some of these third-party genetic testing companies to follow the same logic…

Molecular Diagnostic Yield of Exome Sequencing and Genome Sequencing in Critical Ill Neonates and Infants: A Systematic Review and Meta-Analysis (Link)

Authors: Jianle Yang, Nan Wu, et al.

In this systematic review and meta-analysis of 26 exome and 22 genome cohorts (n=>4,000) of critically ill neonates and/or critically ill infants (age >28 days up to 1 year, requiring PICU admission), the overall diagnostic yield was 39.4% for ES (95% CI, 32.8%-46.3%) and 39.4% for GS (95% CI, 34.7%-44.1%).

That’s kind of it for this one. They also did a bunch of subgroup analyses on whether exome or genome had higher yields in cardiology vs neurology vs others. Truthfully, I’m not sure how helpful this sub-analysis is as much of it was not statistically significant or only minimally different.

Mapping Clinical Progression to Brain Atrophy in CLN2 Patients Under Cerliponase Alfa Treatment: A Prospective Neuroimaging Study (Link)

Authors: Marvin Petersen, Angela Schulz, et al.

Cerliponase alfa, better known as Brineura, is an intraventricular enzyme replacement therapy for neuronal ceroid lipofuscinosis type 2, or CLN2 disease. CLN2 is a lysosomal storage disorder associated with early childhood psychomotor regression, seizures, progressive motor and language decline, vision loss, and brain atrophy. Even in patients receiving ERT, brain atrophy continues.

The goal for this study was to determine whether patients receiving ERT have slower progression of brain atrophy compared to untreated natural history controls. And the outcome: it did.

More details:

In this prospective neuroimaging study of 27 patients receiving intraventricular enzyme therapy, biannual MRIs showed a significant reduction in mean cortical thickness over time (β = −0.002, p = 0.021). This corresponded to an estimated annual cortical thickness loss of 4.2% in treated patients, compared with 12.5% in natural history controls.

Not surprisingly, they also found that greater brain atrophy was associated with worse clinical outcomes, including changes in motor/language scores and movement disorder measures.

The authors conclude that MRI-based brain morphometric measures may serve as useful CLN2 biomarkers to help support diagnosis, monitor disease progression, and guide therapy.

My takeaway: As we get better disease-modifying therapies for rare neurologic diseases, we are going to need better biomarkers than clinical exam alone to understand who is responding, who is still progressing, and when therapy needs to be adjusted.

Letter to the editor: Newborn screening for low blood citrulline leads to diagnosis of ornithine aminotransferase deficiency (Link)

Author: Me! and the rest of my colleagues at OHSU :)

Programs screening for OTC deficiency using low blood citrulline should be aware that OAT deficiency may be detected. We suggest follow-up genetic testing broader than OTC sequencing for positive screens.

Sincerely,

Max

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The Costs of Genomic Newborn Screening in England: A Micro-Costing Analysis from the Generation Study (Link)

Authors: Martin Vu, James Buchanan, et al.

TLDR: This study assessed the total cost of genome based newborn screening as a service, which is estimated to be $1,625 (£1,208) per newborn, primarily driven by the cost of sequencing (58%).

Little bit longer: Right now in the United States, dried blood spot newborn screening costs about $150 per baby, which typically covers testing, cards/filter paper, shipping/courier, data systems, reporting, follow-up, personnel, and program administration.

Recently, genomic newborn screening (gNBS) has been at the forefront of neonatal medicine because it can detect a broader range of actionable genetic conditions in newborns than standard NBS, including those without detectable biochemical markers. But how much would it cost to implement nationwide?

The objective of this study was to estimate the cost of gNBS to screen newborns in the UK. The study used a micro-costing methodology that calculates the cost of healthcare services by mapping all activities involved, measuring the time and resources required for each, and assigning costs according to the capacity of the personnel and resources engaged.

Big conclusion: The total cost per newborn with no condition suspected findings was ~$1625, whereas the cost per newborn with a condition suspected finding was $2,358.

My takeaway: This wont be feasible until sequencing costs come down. It’s going to be tough to justify and increase from £42 in UK to £1,208, or $150 to $1625 in the US.

How Variants of Uncertain Significance Impact Clinical Decisions: A Systematic Review (Link)

Authors: Shiv Ayappa, Katharine P. Callahan, et al.

Did you know that according to Sue Richards et al. and the ACMG, “A variant of uncertain significance (VUS) should not be used in clinical decision-making”? The National Comprehensive Cancer Network (NCCN) has also issued specific guidance for clinicians against using VUS to guide screening and treatment of hereditary cancer. YET, we all have made decisions where we felt a VUS was actually impactful and used it in care.

Personally, I think these blanket “don’t use a VUS” statements are too broad… and I feel others would agree.

In this paper, they conducted a systematic review of studies that reported the impact of VUS on medical care decisions, encompassing actions of both clinicians and patients.

Their main findings:

1. All studies in non-cancer fields reported that VUS had an impact.

2. Nearly half in cancer-based fields (46%, 15/32) found no impact of VUS.

3. 60% (21/35) of studies in real practice found that VUS altered care.

4. Studies reporting clinician-centered decisions (92%, 11/12) were more often to report an impact of VUS compared to those reporting patient-centered decisions (56%, 17/30).

5. If researchers used surveys or interviews rather than chart review, studies more often found an impact of VUS (80%, 20/25).

6. Studies reporting on screening decisions also documented an impact of VUS (85%, 11/13) more often than those reporting on definitive care (59%, 19/32).

Their three explanations for the variable impact of a VUS:

1. Clinicians and patients may misunderstand the meaning of VUS or associated guidelines for use.

2. Clinicians and patients may feel unable to ignore VUS despite understanding that they ‘should.

   1. Literature supports the idea that people struggle to ignore information once they have it.

3. Physicians may disagree with the guidance to ignore VUS.

What are your all thoughts on this?

2025 Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C (Link)

Authors: Tarekegn Hiwot, Marc C. Patterson, et al.

Probably easier to click the link and read the article, but ill summarize some points I thought were big.

1. Clinical Classifications

   1. Pre/perinatal (< 2 months)

   2. Early infantile (2 months–2 years)

   3. Late infantile (2–6 years)

   4. Juvenile (6–16 years)

   5. Adult (> 16 years)

2. Biomarker assessment should be considered the first-line test to screen for Niemann-Pick Disease Type C (NPC). Three classes of biochemical markers are currently in use: oxysterols, N-palmitoyl-O-phosphocholine-serine (PPCS), and lyso-sphingomyelin (lyso-SM).

3. Disease Modifying Therapy:

   1. All patients with a confirmed diagnosis of NPC should be considered for miglustat therapy.

   2. All patients with a confirmed diagnosis of NPC and neurological symptoms should be considered for levacetylleucine therapy.

   3. All patients with a confirmed diagnosis of NPC and neurological symptoms using background miglustat treatment should be considered for arimoclomol therapy.

      1. Combination treatment should be considered for all patients with a confirmed diagnosis of NPC (though this was a level C recommendation).

Sincerely,

Max

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Authors: Annika Zink, Alessandro Prigione, et al.

While sildenafil (better known as Viagra) may have originally been manufactured to treat high blood pressure, its clinical use has expanded. We use sildenafil to treat erectile dysfunction, pulmonary arterial hypertension, and even some cancers nowadays. Well now we have data to suggest it may be helpful in treating Leigh Syndrome, and potentially other mitochondrial diseases. They believe its mechanism of action is mediated through cyclic GMP (cGMP)-dependent protein kinase 1 (PRKG1).

While this study has numerous IN DEPTH evaluations, I’m mostly going to stick to the clinical aspect.

The study (well, the parts I’m interested in):

They took neural precursor cells (NPCs) from patients with Leigh Syndrome who carry a MT-ATP6 variant, then used a high-throughput drug screen to evaluate a library of 5,632 drug candidates to see which had the greatest positive impact on mitochondrial membrane potential (MMP). Through this screen, they identified phosphodiesterase type 5 (PDE5) inhibitors as lead compounds and prioritized sildenafil given its safety profile.

They also used animal models and found that sildenafil increased the lifespan of two mammalian models of Leigh Syndrome. With one treated pig remaining clinically stable for over 6 months.

Fast forwarding a little bit:

They gave sildenafil to six patients with Leigh Syndrome carrying MT-ATP6 variants. Below is a snippet from their table, but overall there is improved muscle strength and resistance to metabolic crises.

Additionally, they assessed disease progression using the NPMDS or the Newcastle Mitochondrial Disease Adult Scale (NMDAS). NPMDS/NMDAS scores of the six sildenafil-treated patients decreased or showed reduced rates of increase over time.

My takeaway: This seems like it could be a game changer. What’s most shocking to me is the positive gains seen in teenagers and adults with Leigh syndrome. I would love to hear about other peoples experience with this!

Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson’s disease models (Link)

Authors: Shiwei Du, Xingguo Liu, et al.

This is science fiction coming to reality. The article discusses an approach in delivering mitochondria into cells and tissues of mice and monkeys by encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes (see image). While the article addresses both Leigh syndrome and Parkinson’s disease, we will focus solely on Leigh syndrome.

First, they had to make the encapsulated mitochondria. To do this, they took mitochondria isolated from donor cells and mixed them with erythrocyte-derived plasma membrane, generating mitochondrial capsules.

They then treated human fibroblasts which harbor a fragment deletion of mtDNA, with mitochondrial capsules containing mitochondria isolated from normal human fibroblasts. About 86% of cells acquired the donor mitochondria. They then performed mtDNA sequencing, which showed the deletion mutation rate was reduced from 14.4% to 2.67%. They also took human fibroblasts from patients with the m.3243A>G mutation, and treated them with mitochondrial capsules. The mtDNA sequencing revealed a decline in the mutation rate from 92.6% to 73.3%.

Now on to the in vivo models:

In mice, delivery of mitochondrial capsules rescued the mitochondrial DNA depletion syndrome and Leigh syndrome in Dguok^−/− and Ndufs4^−/−, respectively. The mice showed rapid regrowth of their fur coats, prolonged survival, and prevented mobility loss. In Dguok^−/− mice, whole-body energy expenditure was also increased, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum was significantly decreased.

In monkeys, they found that transplanted mitochondria were also detected in brain tissue after direct injection of mitochondrial capsules into the substantia nigra (SN). They could also be identified in brain, intestine, liver, and lung tissues after intravenous injection.

My Takeaways: This is another amazing advancement for the field of mitochondrial medicine. Using erythrocyte membranes to delivery mitochondria: genius. ALSO, they injected these mice and monkeys with these encapsulated mitochondria multiple times per week without a notable immune response, suggesting this could be re-dosed in humans. All i know is, if this becomes available for the general population, I call dibs on Lebron James’ mitochondria.

CRISPR-Cas-based activation of PPARGC1A boosts endogenous mitochondria and enhances cardiac function after myocardial infarction (Link)

Authors: Mario Escobar, Isaac B. Hilton, et al.

TLDR: I’m not sure I agree with this articles extrapolation of its data, but it is interesting that the CRISPR system can be used to increase cardiac mitochondria.

The study: They evaluated CRISPRa-based induction of PPARGC1A as a strategy for transcriptional control of mitochondrial biogenesis and examined the mitochondrial and cardiac function enhancements caused by increased endogenous PPARGC1A.

For background: They state that endogenous generation of mitochondria is primarily regulated by the key upstream master transcription factor PPARGC1A (also called PGC1α).

Methods: They injected their CRISPRa PPARGC1A upregulator into a rat myocardial infarction (MI) model. In this model, MI is induced through permanent ligation of the left anterior descending (LAD) artery, leading to development of heart failure.

What they found: After delivery of CRISPRa targeting PPARGC1A, they measured an increase in mitochondrial function (∼63% increase), as well as an increase in the numbers of mitochondria. (~70-120% depending of cell type). It also resulted in an increase of both PPARGC1A protein levels and the mitochondrial marker TOMM20 in comparison with the control. At 10 days post-MI, ejection fraction (EF) was similar between groups, but at 21 days post-treatment, CRISPRa treatment had a 39% increase in EF compared with control. Treatment did not result in noticeable differences in cardiac fibrosis or inflammation.

My thoughts: I think its great that they were able to show that a CRISPR system can be delivered to adult cardiac cells. I also think its great that the ejection fraction was increased after 21 days. However, post MI there is still dead tissue that can’t be fixed, which could lead to arrhythmias, maladaptive remodeling, or other cardiac concerns. Additionally, you would have to administer this therapy post-MI, which has numerous implications and health risks. On another note, they only evaluated the mice 21 days post-MI, what about months later? Heart failure is a chronic progressive issue and 21 days doesn’t give a reasonable time frame. Lastly, they didn’t look at any other tissues to see what the implications of PPARGC1A upregulation might be.

SIMD 2026 Newborn Screening Position Statement - Points to Consider in changing landscapes of Newborn Screening (Link)

Authors: Shibani Kanungo, Susan Berry, Carol Greene, Sarah Viall

In light of the federal advisory committee termination, the SIMD suggests the following Points to Consider:

1. SIMD members should:

   1. Actively participate in local and state NBS advisory boards in review of conditions

   2. Engage with local legislators to promote understanding of any NBS condition

   3. Engage with parent advocacy groups to understand their perspective

2. When considering addition of a condition to a state’s panel for newborn screening, States should continue to:

   1. Consider and effectively communicate the status of public health preparedness of a proposed condition, in addition to the potential for harm or benefit of screening for that condition.

   2. Use SIMD and other professional societies as a resource for expertise on evidence-based ‘testing’ or ‘research’ or ‘clinical’ info on any condition.

   3. Use APHL (Association of Public Health Laboratories) resources (Link 1) (Link 2)

Sincerely,

Max

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TLDR: The overall positive rate of prenatal Trio-ES among 104 families with a history of DD/ID (whether parents had DD/ID or neurotypical parents with a previous child with DD/ID) was ~21%.

Background: This cohort study enrolled 104 prenatal families with a history of DD/ID from a single center, excluding those with copy number variation abnormalities.

These families were divided into two groups:

1. Those with a history of DD/ID births but phenotypically normal parents (lacking proband samples)

   1. Among 81 families with a history of DD/ID births but phenotypically normal parents, the positive rate was 13.58% (11/81), including 7.41% (6/81) affected fetuses and 6.17% (5/81) only parents as carriers, both primarily exhibiting a recessive inheritance pattern.

   2. Additionally, the positive rate in non-syndromic DD/ID families was 11.54% (6/52), while it reached 17.24% (5/29) in syndromic DD/ID families (associated with epilepsy, dystonia, hearing impairment, abnormal head circumference, etc.).

2. Those without a history of DD/ID births, but with one or both parents having ID.

   1. Among 23 families without a history of DD/ID births but with one or both parents having ID, the positive rate significantly increased to 47.83% (11/23), primarily driven by dominant variants.

Their conclusion: They recommended using Trio-ES for prenatal genetic evaluation in families with a history of DD/ID, particularly those presenting with a syndromic phenotype.

My “hot” take: The future will be prenatal exomes for all, and our current newborn screen will be supplemented by a “preborn” screen.

Pharmacodynamics, Efficacy, and Safety of Intraputaminal Eladocagene Exuparvovec Administered to Pediatric Patients With Aromatic L-Amino Acid Decarboxylase Deficiency Using an MR-Compatible Cannula: 48 Weeks of Follow-Up (Link)

If you ever hear oculogyric crisis (feel free to google it), this is typically pathognomonic on board exams for Aromatic L-amino acid decarboxylase (AADC) deficiency.

As a brief background, Aromatic L-amino acid decarboxylase (AADC) catalyzes the final step in the biosynthesis of the monoamine neurotransmitters serotonin and dopamine (scroll a little lower to see the pathway); dopamine is the precursor for norepinephrine and epinephrine. Most of the clinical manifestations of AADC deficiency can be explained by the deficiency of these four neurotransmitters; essential this leads to severe motor and developmental symptoms.

This paper is reporting the results from 48 weeks of follow-up for this phase 2, multicenter, open-label trial assessing the pharmacodynamics, safety, and efficacy of eladocagene exuparvovec administered to the putamen in children (aged 16 months-129 months) with AADC deficiency.

The pudding:

1. CSF homovanillic acid (HVA), a marker of dopamine production, increased significantly from 22.5 nmol/L at baseline to 55.3 nmol/L at 48 weeks (change +28.3; p=0.0003), with improvements seen as early as 8 weeks and sustained through follow-up.

2. Imaging: 18F-DOPA uptake in the putamen increased by 296% from baseline at 48 weeks (p<0.0001), supporting restored dopaminergic activity.

3. Motor development: At baseline, all patients had severe motor delay. By week 48 (n=12):

   1. 9 achieved full head control

   2. 4 could sit unassisted

   3. 2 could stand with support

   4. 2 could walk independently

4. Hypotonia: Present in 100% at baseline. By week 48, only 16.7% had no hypotonia, but severity improved substantially (severe hypotonia decreased from 69.2% to 8.3%).

5. A very interesting note: The youngest patients (<24 months) showed the fastest and most robust gains, achieving advanced motor milestones (e.g., walking backward) by 48 weeks.

My take: This is one of those therapies that seems to work, and REALLY seems to work the earlier you give it. I imagine a future where AADC deficiency becomes a serious newborn screening candidate.

Early Neonatal Administration of Vosoritide in Achondroplasia: A Report of Two Cases (Link)

TLDR: Vosoritide initiated in the first 1–2 weeks of life in 2 infants with achondroplasia was well tolerated and associated with high early growth velocities, but did not prevent progression of foramen magnum stenosis (FMS), both requiring decompression in infancy.

Background: This report describes 2 infants with achondroplasia (ACH) who started vosoritide on days 8 and 9 of life, with longitudinal clinical and imaging follow-up.

Key points:

1. Both patients tolerated treatment well, with no serious adverse events reported during follow-up.

2. Despite early initiation, both developed progressive FMS on serial MRI prior to symptom onset, requiring decompression surgery at 5 and 9 months of age.

3. Growth velocity (GV) was elevated early in infancy:

   1. Case 1: 20.7 cm/year at 6 months → 15.0 at 1 year → 8.6 at 18 months

   2. Case 2: 17.9 cm/year at 6 months → 15.5 at 1 year → 10.2 at 18 months

      1. Both cases demonstrated the expected age-related decline in GV, though absolute values appeared higher than ACH reference medians ( ~14.4 → 7.4 cm/year in boys from 0.6–1.6 years [case 1] and from 13.0 to 7.8 cm/year in girls [case 2]).

Takeaway: Early neonatal vosoritide appears safe and may enhance growth velocity, but does not appear to prevent the development or progression of FMS.

Sincerely,

Max

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Novel promoters drive therapeutic transgene expression and evade transgene-specific immune responses in a mouse model of Pompe disease (Link)

Were getting closer to a gene therapy for Pompe disease!

TLDR: They created a AAV vector gene therapy, injected it into mice, and found that it increased amounts of GAA and decreased glycogen accumulation in the liver, heart, and skeletal muscles.

The study: In this study, they synthesized a hybrid promoter (MyoG6PC) by combining a high potency human skeletal muscle-specific transcriptional cis-regulatory module (hSk-CRM4) from the human myosin light chain 11 (MYL11 or MYLPF) gene with a human G6PC minimal promoter that has high activity in mouse liver. They then took the G6PC promoter, and the hybrid promoter, and conducted AAV vector-mediated gene therapy in Gaa-KO mice and analyzed those mice at 3 or 12 weeks after therapy. The hope was that it would further boost transgene expression in skeletal muscle.

The results: (Full disclosure, I’m just going to share the results of the longer 12 week study).

1. GAA activities were significantly increased in the liver, heart, and skeletal muscles of AAV9-MyoG6PC.GAA-treated mice.

2. Glycogen contents were significantly decreased by the AAV9-MyoG6PC.GAA treatment in the heart and skeletal muscle of male mice, accompanied by the improvement of muscle functions in the grip strength test.

   1. Female mice had an attenuated response with lower GAA activity and higher glycogen content in comparison with males, which correlated with lower plasma GAA activity.

      1. This sex difference has previously been reported and has been attributed to the effects of androgen hormones

3. No anti-GAA antibody response was detectable at 12 weeks following vector administration, given that antibody formation interferes with the uptake of GAA from blood into the heart and skeletal muscle

My takeaway: I’m excited to see we may have a treatment better than ERT on the horizon.

Pregnancies in Women With Long-Chain Fatty Acid Oxidation Disorders: Results of a European and North American Survey (Link)

Got a patient with a long chain fatty acid oxidation disorder (lcFAOD) who is of child bearing age or pregnant? If so, you should know that they are at about a 20% chance risk of decompensation both during and after pregnancy.

More details:

In this n=39 and 89 pregnancies (see breakdown in graph below), they found several interesting points!

1. 19% of women had at least one metabolic decompensation during pregnancy.

2. Most deliveries were uncomplicated, with preventive IV glucose infusions given in 50%.

   1. In 72 out of 82 pregnancies (87.8%), the women were admitted to hospital for delivery.

3. 21% of mothers developed a metabolic decompensation in the postpartum period

MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy (Link)

You know how we tell our patients with negative testing, “Genetics is rapidly evolving and we find new genes associated with X,Y or Z everyday”? Well this is that!

Its another gene to add to the list of disorders with developmental and epileptic encephalopathy. Briefly, MDGA2 encodes a membrane-associated protein that is regulates glutamatergic synapse development, modulating neuroligins, and maintaining excitatory-inhibitory synaptic balance.

They identified seven distinct homozygous loss-of-function variants in MDGA2 in nine individuals from seven consanguineous families, all presenting with developmental and epileptic encephalopathy (DEE). These individuals exhibited a phenotype including infantile hypotonia, severe neurodevelopmental delay, intractable seizures, along with distinct morphologic features. Neuroimaging findings varied.

My takeaway: I personally enjoy seeing studies like this because this indicates that we are still growing and learning. Additionally, I think it gives families hope that we may find a cause for their child’s undiagnosed condition.

Sincerely,

Max + EveryGene Team

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Over the past two years, we’ve been quietly building something we wish existed when we were studying for boards.

It’s called EveryGene Academy, and it was created to solve a few common frustrations we kept seeing: expensive resources, limited question volume, shallow explanations, and confusing interfaces. Our goal was simple — build a platform that helps users understand why an answer is correct, track progress over time, and study in a way that feels structured but flexible.

The question bank includes over 900 board-style questions with detailed explanations, study and test modes, performance tracking, and broad coverage across clinical genetics topics. Whether you’re preparing for ABGC or ABMGG exams, reviewing material during training, or reinforcing your genetics foundation.

We’ve also been intentional about pricing. Exam prep shouldn’t be financially out of reach, so subscriptions are structured to be affordable, starting at $89 for two months access, with a discounted 6-month option available for those who join our waitlist.

EveryGene Academy officially opens on March 1.
If you join the waitlist, you’ll receive $30 off the 6-month subscription at launch.

Thank you for being part of this community — we’re so excited to finally be able to share this with you!

Prenatal Exposure to Antiseizure Medications and the Risk of Congenital Anomalies (Link)

TLDR: Valproic acid is associated with increased congenital anomalies, but the relative risk was observed to be relatively low.

The Study:

Researchers conducted a retrospective cohort study using the Korean National Health Insurance Service mother-child linkage database from 2013 to 2021. This equates to 2,494,958 pregnancies!

Among those pregnancies, 5,880 (0.24%) were exposed to antiseizure medications (ASMs) during the first trimester, and 637/5,880 (10.8%) resulted in congenital anomalies; whereas 173,861 (7.0%) in the unexposed group resulted in congenital anomalies.

Some notes about the cohort: they excluded mothers with a diagnosed congenital anomaly themselves and children diagnosed with a chromosomal abnormality.

So what did they find?

1. Among monotherapies, valproate had the highest risk (OR 1.46, 95% CI 1.11–1.91), showing a dose-dependent relationship (OR 1.57, 95% CI 1.12–2.19 at ≥500 mg/d).

   1. Polytherapy, including valproate, had a higher risk (OR 2.06, 95% CI 1.32–3.20),

2. Polytherapy without valproate was not significantly associated with an increased risk of congenital anomalies (OR 1.26, 95% CI 0.92–1.71).

3. Specific congenital anomalies associated with individual ASMs included congenital hydrocephalus (carbamazepine), atrial septal defects (oxcarbazepine), cleft palate (valproate), hypospadias (levetiracetam), and tetralogy of Fallot and talipes equinovarus (topiramate).

   1. 6 Antiseizure medications (ethosuximide, lacosamide, perampanel, phenobarbital, phenytoin, and vigabatrin) were excluded because they had fewer than 10 exposure cases.

My takeaway: The increase in relative risk for congenital anomalies while on AEMs is statistically significant, but not largely different. Also, 7% of pregnancies not exposed to AEMs with congenital anomalies seems high! They try to explain this by stating they were unable to sort the heart defects by size of the lesion (could have just been a small PFO); they searched for all “congenital anomalies” instead of “major congenital malformations,” which might encompass minor or clinically insignificant anomalies; they also had a relatively high average maternal age of 32.9 years, with nearly 30% of mothers aged 35 years or older.

Fortify Alabama: Corn Masa Fortification for Spina Bifida Prevention (Link)

While this is more genetics-adjacent, I think its important to our field of genetics!

In the United States, the rate of neural tube defects (NTDs) is higher in the Hispanic population. Specifically, its 2.73 per 10,000 live births for Non-Hispanic black or African Americans, 3.09 for non-Hispanic whites, and 3.8 per 10,000 for Hispanics.

Given these numbers, Alabama researchers (and lobbyists) set out to fortify a staple of the Hispanic diet, corn masa flour, with folic acid. And to sum up years of their work briefly: They did it.

They estimate that if this is taken up on a national scale that it will prevent 40-100 neural tube defects per year, and that the cost saved from preventing NTDs far exceeds the cost of implementation (did you know fortification only costs $0.20-$1 per ton of flour produced!).

My takeaway: Low cost with high potential impact on a national scale. I guess we will have to see the data in 10+ years to see if this actually panned out as predicted or if additional variables are at play.

L-fucose supplementation in a patient with global hypofucosylation and a mono-allelic variant in SLC35C1: Clinical improvement and assessment of biomarkers (Link)

This superstar list of genetic providers provide compelling evidence about how treating a SLC35C1 heterozygous female (yes this is classically thought of as being an autosomal recessive disease) with fucose improved her outcomes.

Background: The SLC35C1 gene encodes a GDP-fucose transmembrane transporter (FucT1) located in the Golgi apparatus. Mutations in this gene are classically associated with an autosomal recessive disease characterized by short stature, facial morphologic features, and moderate-to-severe developmental delay.

The patient: This child was found to only have one variant detected on serum, but her biochemical N-glycan profile fit with a fucose deficiency (they suspect somatic mosaicism was at play). Additionally, I can tell you from first hand experience that she DRAMATICALLY improved when on fucose supplementation. She had “improvements in weight and head circumference, normalization of IgG levels, and remarkable developmental catch-up. Biochemically, there was an increase in abundance of previously decreased fucosylated glycan species in serum”.

I picked this article for two reasons:

1. To highlight the importance of biochemical testing and to question the notion that genome testing is the end-all be-all.

2. To bring to light Fucose, which will be shaping the way we think about medicine in the coming years. As we speak, fucose is being used to treat GLUT1 disorders with vast improvement in seizures reported. Clinical trials will be underway for this soon.

Sincerely,

Max and the EveryGene Team

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Growth charts are available for those with 47,XXY!

These charts were created by prominent figures in the Klinefelter space (including Dr. Tartaglia and Dr. Davis) using a cohort of 1279 males aged younger than 20 years with a diagnosis of Klinefelter syndrome (KS).

This paper includes KS-specific growth charts for stature-for-age, weight-for-age, weight-for-length (0–24 months), and body mass index (BMI)-for-age (2–18 years).

Some notable points:

1. Not all kids with KS are tall! They state that approximately 20% of boys with KS aged younger than 4 years were below the 5th percentile for height.

2. Aligning with the textbook definition of KS, approximately 25% of individuals with KS exceeded the 95th percentile for height by late childhood.

3. Interestingly, height velocity increased in mid-childhood (after age 6 years), but without a distinct pubertal growth spurt.

Sequence Variants in Small CAG Repeat Expansions of the HTT Gene and Disease Onset and Progression in Huntington Disease (Link)

TLDR: While CAG repeat length is the major determinant of disease onset and penetrance, sequence variants within the HTT repeat, not detectable by currently used testing, are HUGE modifiers of disease onset and penetrance in those with CAG_36–42 repeats. This is REALLY important when providing counseling.

While I could go into all the incredible details in the study, I will leave it up to you to read about the specific variants that pertain to you.

My big points would be:

1. They analyzed 328 carriers with uninterrupted CAG_36–42 repeats.

2. Age at motor onset was 8 years earlier in CAG-CCG loss of interruption (LOI) patients than in patients with the canonical sequence (53.5 ± 11.1 years vs 61.8 ± 10.9, p < 0.0001) and approximately 13 years earlier than predicted age at motor onset by the Langbehn formula (12.9 ± 6.6, p < 0.001).

3. Cognitive decline was significantly faster in patients with CAG-CCG loss of interruption compared to those harboring the canonical sequence.

4. All LOI variant carriers had an earlier age of onset ratio than those with the canonical variant.

As they nicely wrote, “Combined with issues of mis-sizing, these findings urgently call for revised guidelines that integrate sequence variants to guarantee more accurate and personalized genetic counseling practices in the future.”

Bonus Nuggets written by YOU!

AI-scending the scope: Perspectives on the integration and utilization of artificial intelligence and machine learning in genetic counseling graduate programs (Link)

Authors: Ofir Feuer, Kyla Holmes, et al.

My key takeaways from the study:

1. “A key observation is the disparity in preparedness and confidence among [genetic counseling] programs. Some GCGPs report actively planning and executing AI/ML integration, while others express feelings of inadequacy and apprehension.”

   1. This statement resonated with me as someone who is actively trying to push genetics into the modern era. AI, along with social media, adaptation will advance our field. If we remain “dusty dinosaurs” (as my work colleague calls us) then we will be left behind.

2. They also provided suggestions on how to integrate AI/ML in genetic counseling education:

   1. Develop practice and ethics guidelines specific to AI/ML applications in genetic counseling,

   2. Create educational training modules for AI/ML in genetic counseling

   3. Establish AI/ML-focused PBCs targeted toward the unique needs of GCs

Overall, while this study is focused on genetic counselors and GC programs, I think what they write is broadly applicable!

Congrats on the publication!

Qatar’s National Expanded Metabolic Newborn Screening Program: Incidence and Outcomes (Link)

Authors: Tala Jamaleddin et al.

For those interested in newborn screening and inborn errors of metabolism outside of their country, I highly suggest you read this paper.

They retrospectively analyzed a total of 351,223 newborn screens from 2010 to 2023 and found:

1. There was a significantly high incidence of 1:1105 for IEMs in Qatar, compared to Italy ( 1 in 3707 live births) and USA (1 in 2500 live births).

   1. Of note, in their study consanguinity was reported at 60.1%.

2. A total of 318 positive cases with IEMs, with Classical Homocystinuria being the most frequently detected condition, with a cumulative incidence of 1:6754 live births.

   1. There is a founder variant p. Arg336Cys in the CBS gene

Again, interesting read for me as someone living in the US. Also, totally didn’t realize EveryGene was reaching the other side of globe! So cool!

Congrats on the publication!

Sincerely,

Max

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TLDR: Cases of clear-cut fetal alcohol syndrome have a specific DNA methylation signature or episignature. Unclear cases have a lower detection rate.

The study: Genomic DNA methylation profiles from 93 individuals with suspected fetal alcohol spectrum disorder (FASD) were analyzed and compared with a large database of control and patient cohorts. These 93 individuals were grouped based on the FASD scoring system.

The scoring system: The accepted standard for FASD diagnosis is the 4-digit diagnostic code, which is based on the scoring of 4 key diagnostic features: (1) prenatal alcohol exposure, (2) growth failure, (3) FAS-specific facial abnormalities, and (4) neurological features, such as cognitive and motor delays. Using these diagnostic criteria, patients may be diagnosed with fetal alcohol syndrome, partial FAS (pFAS), alcohol-related neurodevelopmental disorder, or alcohol-related birth defects. Fetal alcohol syndrome represents the most severe affected patients.

What did they find:

1. Confirmed FAS has a high detection rate, but then again these were the samples used to train the model so the model is supposed to pick them up and it would be very concerning if they didn’t.

2. Sensitivity drops as phenotype becomes milder

Interesting notes:

1. They performed exome sequencing on 22 cases in the cohort and found 1 likely pathogenic variant in 1 case; a BRPF1 variant. This case was also positive for the FAS episignature.

2. They detected a high overlap of probes linked to the DNAm episignature of Sotos syndrome. This suggests that some epigenetic disruptions in FASD may converge on pathways involved in neurodevelopmental regulation.

My takeaways:

1. A test that could help shorten a diagnostic odyssey would be HUGE. While some may see the low sensitivity as a failure, I think potentially helping provide evidence supporting a FASD diagnosis in suspected cases could be very helpful.

2. A positive FAS episignature does not confirm a clinical diagnosis of FAS. Instead, it provides molecular evidence supporting a potential diagnosis when considered alongside clinical criteria.

Evaluating the return of additional findings from the 100,000 Genomes Project: A mixed-methods study exploring participant experiences of receiving secondary findings from genomic sequencing (Link)

A new mixed-methods study looked at how people actually feel about receiving secondary findings. The punchline: participants overwhelmingly want this information, value it, and believe others should have access to it too.

This study involved a cross-sectional survey and interviews with participants who received a positive additional finding (PAF) and interviews with participants who had no additional findings (NAF). It involved 146 surveys followed by 35 interviews with PAF participants and 29 interviews with NAF participants.

Big Takeaways:

1. PAF results were seen as useful and would influence health management (82%). Most (90%) had shared their result with family members.

2. All interviewees (PAF and NAF participants) supported offering AFs routinely, holding the view that people were “better off knowing” and that the “positives outweigh the negatives.”

   1. Positive views were linked to conditions being medically actionable with opportunities for early intervention.

3. Those with an NAF were relieved and reassured, whereas those with a PAF were grateful for the opportunity to be proactive with their health and reported that they would follow health care and lifestyle recommendations.

4. 22% of survey participants with a PAF reported that their health care provider had not made any recommendations to lower the risk associated with their PAF.

   1. Additionally, one-third reported that their PAF would not help to reduce their chances of getting sick.

Should the “mitochondrial cocktail” be a default option? An opinion (Link)

Would love to hear everyone’s thoughts on this paper!

These authors wrote this opinion piece in the hope that we “break free of the routine constraints of the “mitochondrial cocktail” as the default treatment of mitochondrial disorders.”

Briefly, their arguments include:

1. It is clear that the oxidation “debt” in these disorders is substantial. However, the quantity of antioxidants given is likely to be trivial, compared to the “debt”.

   1. “None of these treatments has ever included an estimate of the “debt” or the quantity of antioxidants that might be effective. Above all, there is no evidence that the treatment meets their goals of clinical impact.”

2. The notion that the treatment is harmless is unproven and in part false. Any substance with biological activity can be harmful.

   1. Individuals who are physically and intellectually compromised may not recognize an adverse effect.

3. The cocktail supplements can cost a lot of money.

4. Moral argument. Anything prescribed by a doctor or clinic gives families the hope that this may work.

   1. “We must ask ourselves if it is ethical to give this hope when we ourselves have little or no confidence in its efficacy.”

Notable quotes:

Are we treating ourselves and our sense of impotence at the price of the patient and their family?

Given these facts, why then do so many intelligent and rational people choose to use a therapy that is unproven despite decades of experience?

Sincerely,

Max

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Navigating Complexity: How Abortion Laws Reshaped Genetic Counseling (Link)

When the Supreme Court overturned Roe v. Wade in 2022, it reshaped how healthcare professionals interact with patients every single day. A new study in the Journal of Genetic Counseling zooms in on prenatal genetic counselors in Ohio, Indiana, and Kentucky from 2020 to 2024.

Background on each states guidelines:

• Ohio: Patients were confused after a 2023 constitutional amendment protecting reproductive rights. Many mistakenly believed abortion was unrestricted, though a 22-week limit and a Down syndrome ban remained.

• Indiana: A near-total ban went into effect, but proximity to Michigan and Illinois gave counselors more confidence that patients could still access care.

• Kentucky: With abortion banned in nearly all cases, counselors rarely discuss termination, instead sending patients across state lines.

The study: Twenty-two prenatal genetic counselors took part in focus groups and interviews.

Findings:

1. Documentation became strategic: Counselors used to write clear, detailed notes. Now, many are deliberately vague. While this aims to protect patients (and themselves) from potential legal fallout, it did cause confusion for other providers trying to follow what happened in a counseling session.

2. Referrals turned into resources: Instead of directly referring patients for abortion care, counselors often provide a list of clinics and let patients decide. The urgency of gestational limits meant that counselors sometimes encouraged patients to schedule first, decide later.

3. Counseling conversations shifted: Counselors described being “scared to bring it up and scared not to.” Some leaned more heavily into psychosocial support, while others felt their rapport with patients deepened when they could guide them through confusion and stigma. In Kentucky, where abortion is banned outright, the conversation often doesn’t happen at all.

4. Peer networks strengthened: When institutions fell short, counselors leaned on each other. Group chats, phone calls, and support from maternal-fetal medicine colleagues became lifelines.

5. Education hasn’t kept up: Most genetic counselors said their training programs barely prepared them for this landscape. New graduates felt thrown into the deep end, and some classmates chose to avoid prenatal counseling altogether.

6. Increased motivation: Despite the stress, many counselors reported feeling more motivated in their work. Being the guide through such a confusing, politicized terrain gave them a stronger sense of purpose and advocacy. For some, that reduced burnout.

Why this matters: This study shows how abortion laws reach far beyond the clinic doors of abortion providers. They shape genetic counseling sessions, alter medical records, create urgency in life-changing decisions, and force healthcare workers to become quiet advocates navigating an impossible system.

For patients, this means confusion, delays, and sometimes silence where information should be. For counselors, it means carrying the weight of uncertainty while trying to uphold their ethical duty: ensuring patients make informed, autonomous decisions.

Quantitative muscle ultrasound as a window into disease progression in infantile-onset Pompe disease (Link)

Researchers have published their data on the use of Quantitative Muscle Ultrasound (QMUS) to detect progressive myopathy in patients with infantile-onset Pompe disease (IOPD) that are on enzyme replacement therapy (ERT). While QMUS has been used to identify muscle abnormalities in LOPD, its application in IOPD has been less studied.

By taking measurements of muscle EI in key muscle groups across 2–3 time points (with each time point at least a year apart), they found that muscle echointensity (EI) correlated with functional status in IOPD. In fact, QMUS often revealed subclinical muscle changes before Gross Motor Function Measure or 6-Minute Walk Test decline.

This means we may potentially have a non-invasive way to monitor disease progression in IOPD. This is a win.

Long-Term Safety and Clinical Outcomes With Olipudase Alfa Enzyme Replacement Therapy in Children and Adolescents With Acid Sphingomyelinase Deficiency (Link)

I personally love these updates on how ERTs are doing overtime. The ERT, Olipudase Alfa, is currently FDA approved for the non-central nervous system manifestations in people with Acid Sphingomyelinase Deficiency (ASMD) (also called Niemann-Pick A and B).

For background: The most common presenting symptom in untreated NPD-A is hepatosplenomegaly. Additional symptoms include growth failure, psychomotor stagnation and then regression, a classic cherry-red spot of the macula of the retina, and interstitial lung disease. Most untreated children succumb before the third year of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized in untreated individuals by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system manifestations occur.

With that in mind, we now ask ourselves, “How many of these manifestations will ERT address?”

After following 20 children and adolescents with ASMD (baseline age (years) 1.5–17.5) who have been on ERT for 4 to 8 years they found that:

1. Splenomegaly and hepatomegaly were reduced relative to baseline (mean percent decrease in spleen and liver volumes 78% ± 1.2% and 59.8% ± 1.5%, respectively).

2. Among nine individuals able to perform assessments, diffusing capacity of the lung for carbon monoxide (DL_CO) impairment was severe (< 40%) (n = 1), moderate (40%–60%) (n = 4), or mild (60%–80%) (n = 4) at baseline versus absent (n = 4), mild (n = 4) or moderate (n = 1) at final assessment.

3. At baseline, 10/20 children had clinical short stature (height Z-scores ≤ − 2) at baseline versus 0/20 at the final assessment.

Final answer: Yes the ERT works for decreasing hepatosplenomegaly, increasing growth, and improving lung function. Which is great! Now only if we had an ERT that improved life expectancy or penetrated the CNS…

Sincerely,

Max + EveryGene Team

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Maternal metabolic conditions identified by newborn screening (Link)

TLDR: Save this paper for when you need to rule out a maternal condition on NBS.

While the goal of newborn screening is to test the newborn, abnormal screening results can often pick up metabolic conditions in the mother. I personally see this quite often with 3-MCC deficiency and vitamin B12 deficiency.

In this article, authors conducted a PubMed literature search and identified reports of 14 maternal conditions identified via NBS where the mother has the biochemical or metabolic condition and the child is unaffected or an obligate carrier.

What I think makes this paper great is they also talk about the specific findings you would see on biochemical testing, further testing needed, and treatment options in those mothers suspected or affected with a condition.

Maternal disorders identified and discussed include primary carnitine deficiency, secondary carnitine deficiency (Glutaric acidemia type 1, MCADD, Cobalamin C, 3-MCC deficiency, Holocarboxylase synthetase deficiency, VLCADD), PKU, 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency, hypermethioninemia, Homocystinuria, Vitamin deficiencies (B12, riboflavin nutritional deficiency), and riboflavin transporter deficiency.

Brain Magnetic Resonance Imaging of Children With Molybdenum Cofactor Deficiency (Link)

Super niche condition? Yes. BUT a new therapy is approved (Nulibry) for MoCD type A AND some hospitals are performing screening studies for this condition as early initiation can lead to greatly improved outcomes!

Background: Molybdenum cofactor deficiency (MoCD) mimics hypoxic ischemic encephalopathy (HIE) on brain MRI. Therefore it’s really important to understand what key differentiating factors from HIE are present on the initial Brain MRI, as well as how things change after starting Nulibry (Fosdenopterin).

The study: They evaluated 35 MRI brain scans of 13 patients with neonatal MoCD (7 type A, 6 type B) to characterize brain abnormalities arising from exposure to toxicity related to sulfite accumulation and to evaluate changes in response to cPMP treatment in 6 children with MoCD type A.

Biggest takeaway: White matter edema, as the earliest sign of sulfite-related toxicity, indicates a reversible disease stage. The presence of restricted diffusion in the context of MoCD signifies irreversible brain injury and a poor neurological prognosis, irrespective of subsequent biochemical correction upon cPMP treatment.

Other takeaways:

1. They identified strong evidence of intrauterine chronic toxicity in all 13 patients, consisting of a cranially displaced midbrain, smaller cerebellum than expected for age, with evidence of crossed diaschisis, and enlarged peri-cerebellar CSF spaces in the posterior fossa (see image).

2. Signs of vasogenic edema were consistently found in deep white matter (DWM) on the first available images of all 13 patients (age range 1–42 days).

3. MRI changes indicating brain atrophy were present in all patients with brain imaging in the chronic phase apart from patients A and B who were treated early with cPMP.

Long-Term Outcomes of Chenodeoxycholic Acid Therapy for Cerebrotendinous Xanthomatosis: A Nationwide Study on Prognostic Factors and Treatment Response (Link)

Biggest takeaway: You can change a patient’s life by catching a Cerebrotendinous xanthomatosis (CTX) diagnosis and starting Chenodeoxycholic acid (CDCA) before neurologic symptoms appear and before the age of 28 years.

Background on CTX: It’s an autosomal recessive disease caused by biallelic pathogenic variants in the CYP27A1 gene encoding the enzyme sterol 27-hydroxylase. Its deficiency leads to impaired bile acid production, which primarily affects chenodeoxycholic acid (CDCA) and, to a lesser extent, cholic acid (CA). The clinical phenotype of CTX presents with a spectrum of neurological and extraneurological manifestations. Neurological involvement includes developmental delay, cerebellar, pyramidal, and extrapyramidal impairments as well as dementia, psychiatric symptoms, peripheral neuropathy, and seizures. Extraneurological features often include juvenile cataracts, tendon xanthomas, cholestatic jaundice or liver disease, and persistent diarrhea.

Chenodeoxycholic acid (CDCA) is the first-line treatment for CTX and acts primarily by inhibiting endogenous bile acid synthesis via a negative feedback mechanism, thereby preventing the accumulation of toxic intermediates such as cholestanol and 7α-hydroxy-4-cholesten-3-one (7αC4). Studies have shown that CDCA has the potential to reverse the pathophysiologic process of CTX when used prior to the onset of neurological symptoms. However, the literature indicates an average diagnostic delay of about two decades.

The study: Included 86 CTX patients (44 males, 42 females) from 61 families. The mean age at symptom onset was 9 ± 9 years, and the mean age at diagnosis was 27 ± 14 years. The mean follow-up time was 4.78 ± 3.25 years

What did they find?

1. Patients diagnosed at age ≥ 28 years had significantly higher rates of hyperreflexia (85% vs. 30%), spasticity (78% vs. 20%), dysarthria (85% vs. 30%), dysphagia (25% vs. 0%), anxiety (50% vs. 26%) and mood/affective disorders (68% vs. 39%) than patients diagnosed earlier (p < 0.05).

   1. Those diagnosed at ≥ 28 years of age had lower rates of improvement or stabilization, with anxiety improving in 56% of cases, behavioral disorders in 60%, and mood/affective disorder in 60% of cases. However, psychosis continued to deteriorate in 83% of late-diagnosed patients.

2. In patients diagnosed before 28 years of age, hyperreflexia, spasticity, ataxia, dysarthria, parkinsonism, myoclonus, and myopathy improved or stabilized in 100% of cases, and tremors stabilized in 93%.

   1. In contrast, patients diagnosed at ≥ 28 years of age showed less improvement or stabilization: hyperreflexia (70%), spasticity (66%), ataxia (60%) and tremor (74%)

3. Seizures stabilized or improved in 100% of early-diagnosed patients and 98% of late-diagnosed patients,

4. Diarrhea responded well to CDCA in all patients.

Overall, statistical comparison of all neurological findings (pyramidal, cerebellar, extrapyramidal and myopathic involvement) between V0 and CCC visits showed that patients diagnosed before 28 years had significantly better treatment outcomes (p < 0.05).

Effectiveness of Pyridoxal-5′-Phosphate in PNPO Deficiency: A Systematic Review (Link)

Pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency is a neonatal-onset B6-responsive epileptic encephalopathy. Given it is ultrarare, large data regarding treatment efficacy and alternatives is hard to come by. Luckily for us, a group of researchers has done a meta analysis on 49 patients to assess treatment response to active vitamin B6 or pyridoxal-5′-phosphate (PLP).

Findings:

1. Clinical seizure responsiveness following PLP therapy was observed in 77.6% of patients

2. The majority of PLP-responsive patients responded exclusively to PLP, with pyridoxine being attempted but ineffective in most of them (n = 30/33, 90.9%)

3. The median PLP dosage for PLP-responsive patients was 35.5 mg/kg/day (range: 10–74)

4. Of the patients with reportable data, normal neurodevelopment was documented for 41.7% of these patients, while 25.0% showed a minor to moderate delay, and a severe delay was noted for 30.3% patients.

Sincerely,

Max + EveryGene Team

Long-term enzyme replacement therapy: Findings from the mucopolysaccharidosis VI clinical surveillance program after 15 years follow-up (Link)

Mucopolysaccharidosis (MPS) VI, or Maroteaux–Lamy syndrome is a lysosomal storage disease caused by deficient N-acetylgalactosamine-4-sulfatase or arylsulfatase B. Affected individuals usually present with coarse facial features, normal intelligence, short stature, musculoskeletal abnormalities, poor endurance, compromised respiratory and cardiac function, spinal cord compression, impaired vision, hearing loss, and hepatosplenomegaly.

Galsulfase (Naglazyme) enzyme replacement therapy (ERT) is currently the only disease modifying therapy approved for MPS VI by the FDA and the European Medicines Agency. This study sought to evaluate outcomes after 15 years of follow up.

So what did they find?

1. Improvements in endurance (6MWT) and respiratory function (PFTs) among treated participants.

2. Decreased urinary GAG levels

3. Then they make a “suggestion of additional positive impact on quality of life, joint mobility, hepatosplenomegaly, physical resistance, growth, and survival.”

My problem with the ERT: People with MPSVI have significant short stature that is life limiting and impairing, yet this ERT doesn’t actually directly address growth. The only improvements they actually have statistically significant data for are the 6MWT, PFTs, and GAGS, which yes have somewhat improved but at what cost? We need a better drug.

Exclusion-based exome sequencing in critically ill adults 18–40 years old has a 24% diagnostic rate and finds racial disparities in access to genetic testing (Link)

I picked this article because it had been getting some national attention. It also kept popping up on my LinkedIn feed so figured Id give it a read. Would love to hear your thoughts on this one!

Researchers retrospectively analyzed whole-exome sequencing (WES) data from 365 adults ages 18–40 years with intensive care unit (ICU) admissions at the University of Pennsylvania Health System. Through doing this they found some findings including:

1. Nearly 25% of all UPHS ICU-admitted patients aged 18–40 years have a Mendelian genetic diagnosis related to their ICU admission

   1. About 50% of these diagnoses were already documented in the EHR prior to WES being performed retroactively.

2. They state that for over 75% of these patients that had diagnoses, their genetic diagnosis confers specific care-altering management recommendations.

   1. The article does not discuss to which degree care has changed and whether that diagnosis would have changed care immediately in the ICU.

3. Racial disparities were present: Diagnoses were documented for 63.1% of White patients, 100% of Asian patients, and 50% of patients of other race/ethnicity, but only for 22.7% of Black patients.

4. Certain ICU admission indications were more likely to yield diagnostic results.

   1. The highest rates were observed in pulmonary disease (n = 11, diagnostic rate: 81.8%), vascular disease (n = 46, diagnostic rate: 39.1%), and renal disease (n = 19, diagnostic rate: 36.8%).

   2. The lowest diagnostic rates were observed for infectious diseases (n = 25, diagnostic rate: 12.0%), endocrine disease (n = 14, diagnostic rate: 7.1%), and psychiatric disease with a diagnostic rate of 0% (n = 2).

Overall, I do feel the article poses important questions and points about broadening genetic testing into the adult ICU, but it fails to give the granular detail I seek.

Differentiation of neonatal and infantile onset ECHS1 deficiency using SCEH enzyme activity and plasma acylcarnitine analysis (Link)

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is an autosomal recessive disorder that presents in the neonatal or infantile period with encephalopathy and lactic acidosis, with most neonates passing prior to molecular sequencing results being returned. BUT if ECHS1D had a biomarker, making the diagnosis may be faster.

The study: Short-chain enoyl-CoA hydratase activity testing was performed in six ECHS1D fibroblast samples with neonatal or infantile onset, as well as 11 controls. Using that data they were able to determine SCEH activity reference ranges in neonatal and infantile onset ECHS1D fibroblasts. They also were able to distinguish between ECHS1D and controls on dried blood spots. (meaning this disorder is one step closer to getting on a newborn screen!)

A great additional point they make about ECHS1D : “ We note similarity in the clinical presentation of infantile onset ECHS1D and Glutaric aciduria type 1 (GA1) in early childhood. Identification of presymptomatic individuals with GA1 via newborn screening, followed by early initiation of low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, has improved neurological outcomes in GA1 patients. Similarly, we propose identification of presymptomatic individuals with ECHS1D via newborn screening, with early institution of valine restricted diet, antioxidants, and aggressive management of catabolic illnesses could lead to change in the natural history and improved neurological outcomes in patients with infantile ECHS1D.”

Sincerely,

Max

Triptans are medications commonly prescribed to treat migraines. Given their potential use during pregnancy, it's crucial to understand any potential implications for child development.

A group of researchers investigated whether prenatal exposure to triptans, either alone or in combination with other migraine medications, is associated with neurodevelopmental outcomes in children.

Key Findings:

• Slight Increase in Neurodevelopmental Disorders (NDDs): Children born to mothers who used triptans during pregnancy exhibited a slightly higher risk of NDDs, with weighted hazard ratios (wHRs) ranging from 1.05 to 1.16. However, these increases were not statistically significant.

• No Significant Association with ADHD or Speech/Language Disorders: When comparing children of mothers who discontinued triptan use before pregnancy (low use) to those who continued use, the risks for ADHD and speech/language disorders were negligible (wHRs between 0.82 and 1.14).

• Slightly Elevated Risk for Autism Spectrum Disorders (ASD): Late discontinuers (moderate to high use) showed a modestly increased risk for ASD (wHRs of 1.24 and 1.30), but the confidence intervals crossed the null, indicating no statistically significant association.

Implications for Expectant Mothers:

• These findings suggest that the use of triptans during pregnancy may not substantially elevate the risk of neurodevelopmental disorders in children.

Novel Variants in VARS2 Demonstrate the Phenotypic Variability of a Rare Mitochondriopathy That Responds to Valine Supplementation (Link)

If you dont know about the ARS disorders, you should!

Aminoacyl-tRNA synthetases (ARS) are a family of enzymes that play a role in protein synthesis. They catalyze the esterification reaction that links a transfer RNA (tRNA) with its cognate amino acid, matching the anticodon triplet of the tRNA. This process, known as “charging” the tRNA, is essential for efficient and accurate protein synthesis. Disorders of the ARS genes can lead to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. Recently, there have been lots of discussions regarding treatment of the various ARS conditions with their cognate amino acid.

One such gene, VARS2, encodes a mitochondrial aminoacyl-tRNA synthetase that catalyzes the attachment of valine to its cognate tRNA molecule. In this paper, they sought to test the efficacy of providing valine in those with VARS disorder by creating cell lines in vertebras with the same bi-allelic variants in VARS as their patients.

What did they find:

• Statistically significant improved survival was only achieved with the highest tested dose of supplemented valine.

• Animals that underwent CRISPR editing that led to in-frame editing displayed improved cardiac function when supplemented with valine at all tested concentrations

Big takeaway: Valine supplementation at any dose may improve cardiac function, though higher doses of valine may be required in order to improve survival outcomes in those with VARS related disease.

Novel Treatment Strategy for Patients With Urea Cycle Disorders: Pharmacological Chaperones Enhance Enzyme Stability and Activity in Patient-Derived Liver Disease Models (Link)

Headline: There may be a new treatment in the pipeline for females with OTC deficiency who have unfavorable X-chromosome inactivation.

In this study, they performed a high throughput screening (HTS) using a diversity library with 10,000 chemical compounds to identify pharmacological chaperone (PC) candidates that stabilize purified wild-type OTC. This yielded five potential candidates, which were then further narrowed down based on those that enhanced enzyme activity and ureagenesis (PC4).

The proposed mechanism of action for the candidate that showed promise (PC4) is a direct interaction with the OTC protein, thereby enhancing OTC stability and activity.

• Of note, they also hypothesized that cell lines not expressing OTC protein—for example, due to an early stop mutation causing nonsense-mediated mRNA decay—are probably not suitable patient lines to treat with PCs.

Takeaway: Increasing OTC activity only by a few percent—for example, restoring the residual enzyme activity from 5% to 10%—might be therapeutic in heterozygous female OTCD patients. Thus, females with unfavorable/skewed XCI causing predominant expression of the mutant OTC allele and only little of the wild-type OTC protein might benefit from PC treatment as it may rescue OTC activity in vivo.

Diagnosis of Inherited Metabolic Disease in Older Patients: A Systematic Literature Review (Link)

While inherited metabolic diseases (IMDs) are traditionally diagnosed in infancy or childhood, these conditions are increasingly being recognized in older adults, often after prolonged diagnostic journeys.

In this systematic literature review, researchers analyzed 260 articles encompassing 293 patients, with a median diagnostic age of 69 years

Key Findings:

• The median time from symptom onset to diagnosis was 14.5 years.

• The most frequently reported IMDs in this age group included Fabry disease, alkaptonuria, Gaucher disease, mitochondrial disorders, and glycogen storage disease type V.

  • Fabry disease is the most frequently reported, likely due to widespread industry-sponsored screening programs.

  • In total, 67 different diagnoses were made.

• Musculoskeletal symptoms were the most prevalent, followed by neurological and cardiovascular manifestations.

Takeaway: IMDs in adults and older persons are unrecognized. Understanding the presenting symptoms of older patients would help decrease the diagnostic odyssey.

Have a great summer!

Max

Congrats to you all on the amazing work!!

1. COL9A1-related disorder with pectus carinatum, without epiphyseal dysplasia: case report and review of literature (Link)

Authors: Bukola A Olarewaju, Erin R Alexander, Monica M Crowe, Kristina Dandurand, David Melville, Fadi Shamoun, Mayowa A Osundiji

One of followers helped co-author this interesting case report and literature review of autosomal dominant COL9A1-related disorders!

Classically, COL9A1- related disorders present with multiple epiphyseal dysplasia (MED), a disorder affecting the epiphysis of long bones.

In their paper, they study a 22-year-old male who presented with a chronic history of leg pain and laxity of the knee joint, in the context of a history of pectus carinatum requiring a chest brace, and tall stature with bilateral piezogenic pedal papules. Interestingly, the patient's long bones all appeared slender on a radiograph, but were without epiphyseal dysplasia. These findings together suggest that there is a phenotypic spectrum of COL9A1-related disorders.

2. Obesity Prevalence in DDX3X-Related Neurodevelopmental Disorder (Link)

Authors: Giavanna Verdi, Nathaniel H Robin

The awesome people at UAB analyzed the prevalence of obesity in adulthood in those affected by DDX3X-related neurodevelopmental disorder (DDX3X-NDD).

While individuals with DDX3X-NDD classically have poor weight gain or failure to thrive in early childhood, there is not much published on adult weight trends in this condition.

To investigate this, they developed a survey to be distributed to caregivers of patients with DDX3X-NDD. Approximately 31% of the study population (n = 70) expressed concerns about obesity, and nearly half of this population found obesity to be a concern after the diagnosis of DDX3X-NDD.

Their findings suggest that while poor weight gain due to feeding difficulties in infancy is common, obesity is a common health concern for older DDX3X-NDD patients.

3. Supporting Disclosure: Neurofibromatosis Type 1 Pediatric Diagnosis Disclosure Resources for Caregivers and Children (Link)

Authors: Ryan Brown-Ezell, MS (she/her); Ashley Cannon, PhD, MS, CGC (she/her) ; R. Lynn Holt, MS, CGC (she/her)

Disclosing a diagnosis of Neurofibromatosis Type 1 (NF1) to a child can be a daunting and emotionally challenging process for caregivers. Many report feelings of distress and uncertainty about how to approach the conversation, often compounded by their own limited understanding of the condition.

To address this need, a collaborative effort led by our follower and genetic counseling student Ryan Brown-Ezell, MS, in partnership with genetic counselors, a bibliotherapy expert, the Children’s Tumor Foundation (CTF), a child psychologist, caregivers, and an illustrator, resulted in the creation of two free resources:

1. “Talking to Your Child About NF1," a caregiver guide offering practical strategies for age-appropriate disclosure, grounded in child development theory and designed to help parents feel more confident and prepared.

2. "Super Emerson," a child-friendly storybook that follows a relatable character navigating life with NF1, helping young readers understand their condition through storytelling and activities.

4. New Insights Into the Spectrum of RASopathies: Clinical and Genetic Data in a Cohort of 121 Spanish Patients (Link)

Authors: Ana Isabel Sánchez Barbero, Irene Valenzuela, Paula Fernández-Alvarez, Élida Vazquez, Anna Maria Cueto-Gonzalez, Amaia Lasa-Aranzasti, Laura Trujillano, Bárbara Masotto, Elena García Arumí, Eduardo F Tizzano

In this study, one of our followers retrospectively analyzed the clinical data of 121 patients with a molecularly confirmed diagnosis of RASopathy. They then described the frequencies for clinical features in all organ systems as well as molecular data.

Insights:

1. The most common clinical diagnosis was Noonan Syndrome and the most frequently affected gene was PTPN11 followed by SOS1, RAF1, LZTR1, and RIT1.

2. All patients had distinctive craniofacial features indicative of the RASopathy spectrum

3. They also note uncommon clinical characteristics such as aortic dilation, multivalvular heart disease, abnormalities of the posterior fossa, and uterine congenital anomalies in female patients.

Sincerely,

Max

If you havent heard, EveryGene has developed a FREE Board Question Collective! It will be a large resource for board studying for all future genetic providers. Check it out here! LINK

Newborn screening follow-up for very long-chain acyl-CoA dehydrogenase deficiency in Colorado: Working towards a standardized protocol (Link)

VLCADD is a disorder of fatty acid oxidation that can be lethal in the newborn period if not detected, and thus is present on the newborn screen in the united states. One of the problems the newborn screen runs into is deciphering true positive results from false positive results. To help address this issue the esteemed lead authors Dr. Crenshaw and Dr. D’Annibale have come up with a testing algorithm that showed 96% agreement with the clinical designation.

To determine this algorithm they conducted a retrospective chart review of abnormal NBS for VLCADD in Colorado. They analyzed confirmatory plasma acylcarnitine profiles (P-ACP), genetic sequencing of ACADVL, Collaborative Laboratory Integrated Reports (CLIR) scores, patient enzyme analysis of VLCAD, and cell-based variant expression analysis.

Ultimately, they found that the biomarker with the best discrimination between affected and unaffected individuals was C14:1/C12:1 [chi-squared 10.4 (p = 0.001)]. The highest performing algorithm was (Molecular testing + cell-based expression) + (P-ACP C14:1 OR P-ACP C14:1/C12:1).

Using the findings of this data, they also developed a standardized diagnostic approach to more accurately classify patients that starts with the molecular findings and requires at least one of the P-ACP C14:1 or P-ACP C14:1/C12:1 to agree with molecular findings.

Growth Charts for Children With Beckwith–Wiedemann Spectrum (Link)

Beckwith-Wiedemann syndrome or spectrum has its own growth charts!

Using heights, weights, and head circumference data points from 581 individuals throughout the US and Europe, researchers were able to put together growth charts for BWS children aged 0-18 years. These charts are for height-for-age, weight-for-age, BMI-for-age, and head circumference-for-age for males and females.

Mean height, weight, and head circumference were compared with those of the growth charts generated by the World Health Organization (WHO). Some interesting or noteworthy points in comparing people with BWS to general WHO children include:

1. Children with BWS are generally bigger babies, and also taller at age 18 than the general population.

   

2. The mean adult height for males was highest in the IC1-GOM group, followed by IC2-LOM, CDKN1C, and the lowest in the patUPD11 group.

My takeaway: I think the learning opportunity here is in the counseling you can give families regarding future growth parameter trajectories.

Long-Term Outcomes of Adolescents and Young Adults Identified by Metabolic Newborn Screening (Link)

A center in Germany sought to determine the long term outcomes of those diagnosed by newborn screen. To do this, they enrolled 257 children who were followed until a median age of 13.7 years of age.

They then grouped all diseases on their newborn screen based on risk profiles: Group 1 (PKU, Biotinidase Deficiency, attenuated IVA, and attenuated VLCADD), Group 2 (MCADD and GA1), Group 3 (cVLCADD, cIVA, and Galactosemia), Group 4 (LCHADD/MTPD and CPT1D) and Group 5 (MSUD).

So what did they find?

1. Forty-five percent of children experienced at least 1 metabolic decompensation, with a maximum of 100% in MSUD and LCHADD

   1. In 85% of them, the first decompensations occurred neonatally.

   2. Hospitalization rate decreased with age.

      1. The median duration of the single hospitalizations was higher in younger children

   3. IQ at last test did not differ between individuals with and without a metabolic decompensation.

   4. With decreasing therapy adherence, the frequency of symptoms increased and IQ values declined.

My thoughts: Intuitive this all makes sense. One point the article makes multiple times is that newborn screening (NBS) cannot “reliably protect against metabolic decompensations”. I would argue this is not the entire point of NBS, and the point of NBS is that it protects the vulnerable by enabling early detection and intervention, which can significantly reduce the risk of severe outcomes, even if it cannot completely prevent every crisis.

Sincerely,

Max

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Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy (Link)

This short correspondence to the editor writes about a prenatal diagnosis of Spinal Muscular Atrophy Type 1 confirmed on amniocentesis who was ultimately treated with Risdiplam prenatally.

What is Risdiplam? Risdiplam is a small-molecule drug that modulates splicing of the gene SMN2 and increases the level of the protein SMN (survival motor neuron) in persons with spinal muscular atrophy (SMA). Previous data have shown transplacental passage of risdiplam-related material and supported the feasibility of prenatal treatment.

The n=1 study: Risdiplam was administered orally to the mother at a dose of 5 mg per day between 32 weeks 5 days’ gestation and delivery at 38 weeks 6 days’ gestation. Risdiplam was subsequently administered orally to the infant 8 days after birth and has been continued daily to the present time (30 months of age in February 2025). No features of SMA, such as hypotonia, weakness, areflexia, or fasciculation, have appeared to date. Motor-function, muscle ultrasonographic, and electrophysiological studies have been performed every 6 months and have shown normal peripheral-nerve and muscle development for age.

Potentially adding a point of complexity: The infant appeared normal at birth but was identified postnatally to have a ventricular septal defect, optic-nerve hypoplasia in both eyes, and has mild right hemiparesis associated with left midbrain hypoplasia. The congenital abnormalities were considered by the investigators to have occurred early in fetal development, before exposure to risdiplam. The child also has subsequent global developmental delay. Microarray and long-read genome sequencing did not identify a second genetic disorder.

In summary, when considering the phenotype of SMA type 1, it appears Risdiplam has likely improved this child’s outcome. I do wonder whether there were any abnormalities noted on the mothers’ weekly ultrasounds she was reportedly receiving that would have given further indication that the congenital findings occurred before Risdiplam initiation. Additionally, a fetal MRI would have been helpful as well.

Oral Infigratinib Therapy in Children with Achondroplasia (Link)

An oral treatment option for Achondroplasia may be on its way.

In this phase 2 dose-finding study, they evaluated the safety and efficacy of oral Infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five cohorts with differing drug doses.

How Infigratinib works: Infigratinib is an orally bioavailable FGFR1–3 selective tyrosine kinase inhibitor that directly inhibits the phosphorylation of FGFR and, as a result, attenuates both main downstream signaling pathways that are involved in the condition.

Adverse events: Seven patients (10%) had adverse events that were assessed by the investigator as being related to the study drug, all of which were mild in severity; these events were dyspepsia and flatulence, a decrease in the vitamin D level, decreased appetite, and hyperphosphatemia. No corneal or retinal disorders were reported or identified by ophthalmic examination. No accelerated progression of bone age, changes in bone mineral density, or other bone-related adverse events were reported.

Additional findings: In the highest dosed cohort (n=13), an increased annualized height velocity was observed which persisted throughout the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P=0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was −0.12 (95% CI, −0.18 to −0.06).

My thoughts: An oral medication would be a superior delivery method in comparison to IV. If the safety profile is sound and the efficacy is equal to vosoritide this would be a great option for children with achondroplasia who wish to increase their height and other proportions. The future phase 3 trial at the desired study dose should be telling.

I’ll leave you with this quote: “If I could take a drug to get rid of my spinal stenosis [when the spinal column narrows and starts to compress the spinal cord], I would take it,” says Erin Pritchard, lecturer in disability and education at Liverpool Hope University, who has achondroplasia. “But to get rid of my identity as a person with dwarfism, to make me grow so that I fit in society and I don’t get stared at, pointed out, laughed at, photographed, I think that’s where it gets problematic, because I should not have to change to fit in with a prejudiced society.”

Safety and Efficacy of DTX401, an AAV8-Mediated Liver-Directed Gene Therapy, in Adults with Glycogen Storage Disease Type Ia (GSDIa) (Link)

The results from the Phase 1/2 AAV8-mediated gene therapy trial of DTX401 for GSD1a are in!

Big picture: It works! Is it a cure? No. But it does help increase mean time to hypoglycemia during fasting and reduces cornstarch burden.

What is DTX401? It’s an investigational adeno-associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase.

Who was evaluated and treated? 12 adults with GSDIa

What were the side effects? The most commonly reported adverse events (number of participants, %) were headache (8, 67%), diarrhea (5, 42%), and vomiting (5, 42%). While all participants experienced elevated triglycerides, there were seven episodes of hypertriglyceridemia reported as AEs in three participants (25%). No serious treatment-emergent liver transaminase elevations were reported. The serious adverse events reported were lactic acidosis and nephrolithiasis (both in the same participant), metabolic disorder, cellulitis, and migraine. No participant experienced a dose-limiting toxicity, treatment-emergent adverse event (TEAE) leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE.

What did they find?

1. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%).

2. Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); p < 0.001.

   1. One participant was able to get off cornstarch completely (100% reduction).

3. In nine participants who completed the study survey, five (56%) reported GSDIa was “much improved”, one (11%) reported GSDIa was “moderately improved”, two (22%) reported GSDIa was “minimally improved”, and one (11%) reported “no change” from baseline at Week 52.

   1. No participant reported worsening of GSDIa.

Conclusion: DTX401 was overall safe and demonstrated clinically meaningful reductions in cornstarch intake, improved glycemic stability, and in most cases improved quality of life. I’ll take this as a win!

Maternal health outcomes in ornithine transcarbamylase deficiency: A comparative analysis of pregnancies in symptomatic and asymptomatic heterozygotes (Link)

There is limited existing literature regarding the outcomes for pregnancies in mothers with OTCD (ornithine transcarbamylase deficiency). In the data that is published, there are reports of hyperammonemic coma and death due to metabolic stress of pregnancy in females with OTCD who were asymptomatic prior to pregnancy. There are even worse outcomes in those who were not diagnosed with their OTCD prior to pregnancy (PMID: 31441224).

In comes this new study to try and change the narrative, and in broad strokes: In asymptomatic OTC heterozygotes, pregnancy is safe and well tolerated. In those with symptomatic disease, hyperammonemia may be observed.

Deeper Dive:

This study evaluated maternal morbidity and mortality from 109 pregnancies in 49 OTC heterozygotes.

What the study found:

1. In those with asymptomatic OTCD, pregnancy was well-tolerated and without metabolic decompensations.

2. Among individuals with symptomatic disease, hyperammonemia was observed in 5 of the 21 pregnancies. Three of these episodes were in a single individual across three different pregnancies. One individual required ICU admission.

Additional considerations:

• All participants in this study were connected to a metabolic care center participating in the longitudinal study. This may introduce a sampling bias, as access to metabolic expertise may improve survivorship and therefore limit the generalizability of this study.

  • Additionally, many asymptomatic OTCD heterozygotes in the UCD natural history were previously diagnosed after they delivered an affected male child. This biases the cohort toward heterozygotes with asymptomatic OTCD who tolerated pregnancy and were diagnosed retrospectively as part of cascade testing.

My takeaway: In considering both of the large studies, I will still proceed with caution during the pregnancy of people with OTC, but I will feel a bit more reassured in those who have an established diagnosis prior to pregnancy and who are asymptomatic.

Sincerely,

Max

Researchers have combined proteomics (looking at the proteins) and metabolomics (looking at small molecule metabolites) to help delineate the complex pathological mechanisms underlying Late Onset Pompe Disease (LOPD).

For background: Pompe disease is caused by a deficiency of the enzyme acid α-glucosidase, resulting in glycogen accumulation in lysosomes. This disease has been categorized into two classifications: Infantile onset Pompe disease and Late onset Pompe disease (LOPD). LOPD includes individuals with onset before age 12 months without cardiomyopathy and all individuals with onset after age 12 months.

Back to the study:

It was a single-center retrospective study which included 6 patients diagnosed with LOPD and 4 well-matched controls.

Their findings:

1. They identified that the mTOR signaling pathway, arginine and proline metabolism, and arginine biosynthesis pathways were downregulated.

   1. They also found that L-arginine levels were significantly lower in patients with LOPD.

      1. A previous study reported L-arginine deprivation could induce autophagy by inhibiting mTOR pathway and endoplasmic reticulum stress (Link).

2. Significant changes were observed in Parkin, TOMM20, NDP52, and BNIP3, which play important roles in the mitophagy pathway.

3. They suggested that CALML3 could be a promising biomarker and may play an important role in the progression of LOPD.

   1. CALML3, a calcium sensor protein of the calmodulin-like protein family, takes part in calcium-related pathways, and is predicted to participate in the regulation of contraction, metabolism, and the MAPK signaling pathway

Concluding remarks: With only 6 patients, its tough to draw definitive conclusions from this paper. With that said, I do think the associations they make between arginine depletion and the CALML3 biomarkers could potentially be fruitful avenues for further research.

Newborn screening for common genetic variants associated with permanent hearing loss: Implementation in Ontario and a review of the first 3 years (Link)

With congenital permanent hearing loss (PHL) having an incidence of 1:1000 newborns, it makes perfect sense why it is included on the newborn screen. Additionally, it has been proven that earlier detection of hearing loss means earlier intervention, which could prevent sequelae of undetected hearing loss such as faltering of speech and language development, poor social growth, and decreased academic success.

Researchers in Ontario recognize the clinical importance of early diagnosis of congenital permanent hearing loss and have implemented dried blood spot genetic testing for 22 variants in the GJB2 and SLC26A4 genes (as they are the most frequent determinants of significant early onset PHL).

What did they find?

1. Over 3 years, 412,424 infants were screened with 93 having screen positive results defined as the detection of two or more variants in either GJB2 or SLC26A4.

   1. Of these, 72 had confirmed PHL, 20 had normal hearing and 1 declined follow-up

2. Thirteen infants with PHL (1 in 31,724; 11.8% of screen positives) were not identified through audiometric testing as they passed (3) or missed (10) screening.

3. They found that PHL genetic screening has a detection rate of 1 in 4,435 infants

4. Mean ages at time of initial Auditory Brainstem Response (ABR), imaging, and cochlear implantation all occurred at significantly younger ages for the children with positive genetic screens than children with negative genetic screens.

5. Additional qualitative outcomes researchers noted include accelerating parental acceptance, alleviating parental guilt, facilitating medical referral to otolaryngology, providing a better understanding of likely clinical outcome, and expediting the path to intervention.

My thoughts: At a broader level, this paper further fuels the argument for a molecular (genetic testing) based newborn screen. In just focusing on this paper, earlier diagnosis and detection does lead to faster implementation of therapeutic interventions which likely does improve developmental outcomes. It will be interesting to see if this gets adopted in other provinces or countries.

Feasibility of newborn screening of triple H syndrome using dried urine spots analyzed by flow-injection mass spectrometry (Link)

Triple H syndrome (Hyperornithinemia–Hyperammonemia– Homocitrullinuria, HHH) is an autosomal recessive that affects the ornithine transporter in the inner mitochondrial membrane is compromised leading to the dysfunction of the urea cycle, and hyperammonemia. Early diagnosis is crucial to provide timely treatment and avoid irreversible damages.

Researchers in Quebec, where HHH is highly prevalent, discuss how they have diagnosed two cases of HHH syndrome in the newborn period thanks to the Quebec Neonatal Urine Screening Program (QNUSP). This program aims to detect IEM using dried urine spots (DUS) collected from 21-day-old babies at home by parents. Using a previously devised flow-injection mass spectrometry assay, they evaluated orotic acid and uracil levels as biomarkers of the disease and have shown that HHH syndrome screening might be feasible in DUS.

My thoughts: As a US based fellow, I had no clue Quebec had a dried urine spot screening program! This seems like it would be beneficial in catching some conditions which are not readily diagnosed on dried blood spot tests, such as HHH syndrome.

Bonus Fun Read:

Biochemical testing for congenital disorders of glycosylation: A technical standard of the American College of Medical Genetics and Genomics (ACMG) (Link)

For those of you interested in some basic information on congenital disorders of glycosylation (CDGs), this technical standard set forth by ACMG is a great starting point. Not only does it break down what a CDG is, but it also talks about the various categories of CDGs in simple language. Most importantly to me, this standard discusses the various tests available to diagnose CDGs and reasons for false positives for each test.

Sincerely,

Max

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Breath biopsy in inborn errors of metabolism: A proof-of-principle study in propionic acidemia (Link)

Big Picture: Our generations world experts in organic acidemias have just published a paper essentially stating they have developed a breathalyzer that can potentially diagnose propionic acidemia (PA).

A Deeper Dive:

These authors hypothesized that impaired oxidation of branched chain amino acids may give rise to volatile organic compounds (VOCs) and that these VOCs would be present in the exhaled breath of patients with organic acidemias. Using five patients and five matched controls, as well as a non-invasive breath sampling platform paired with thermal desorption-gas chromatography–mass spectrometry, they identified 3-pentanone as a possible marker for propionic acidemia. 3-Pentanone abundance positively correlated with plasma propionylcarnitine (p = 0.01), plasma 2-methylcitrate (p < 0.05), and 3-OH-propionate (p < 0.01). It also inversely correlated with the whole-body in vivo oxidation of 1-¹³C-propionate (p < 0.05).

Interestingly, in a study participant who received a liver transplant, 3-pentanone levels were lower and segregated with “mild” PA.

Takeaway: Non-invasive breath sampling could emerge as a non-invasive way to diagnose and monitor propionic acidemia, other organic acidemias, and may even help us stratify disease severity in those with organic acidemias.

Feasibility of newborn screening for pyridoxine-dependent epilepsy (Link)

There’s always talk about what conditions should be included on the Recommended Uniform Screening Panel (RUSP) and ultimately on every states newborn screen. This paper looks to make an argument as to why pyridoxine-dependent epilepsy (PDE-ALDH7A1) should be considered on every newborn screen.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizures that are resistant to antiseizure medications. PDE-ALDH7A1 is caused by the deficiency of α-aminoadipic semialdehyde (α-AASA) dehydrogenase, an enzyme involved in the conversion of α-AASA to α-aminoadipic acid within the lysine metabolism pathway. Early treatment with pyridoxine and lysine reduction therapies are associated with seizure control and improved developmental outcomes.

Unfortunately, many patients with PDE-ALDH7A1 experience a significant delay between the onset of seizures, diagnosis of PDE-ALDH7A1, and treatment with pyridoxine. This delay can result in multiple hospitalizations due to poorly controlled seizures, worsened developmental outcomes, significant psychosocial impact on parents and caregivers, and rarely, death. For all these cases, newborn screening may be life (or quality of life) saving.

Recently, two new metabolites were identified (2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid, 2-OPP and 6-oxo-pipecolate, 6-oxo-pip) and were evaluated to see if they could be used as biomarkers for newborn screening. Using 2-OPP as the initial marker, they were able to identify 7 of 8 affected participants using commercially available newborn screening equipment. The addition of 6-oxo-pip as a second tier testing demonstrated significantly elevated 6-oxo-pip in all affected participants.

Big Takeaway: Although the study was limited by the limited number of patients, it does provide a proof of concept that PDE-ALDH7A1 may be a good candidate for the RUSP. Future studies, including prospective population-based screening, will be needed to evaluate the sensitivity and specificity of newborn screening for PDE-ALDHA7A1.

Community-Sourced Reporting of Mortalities in Angelman Syndrome (1979–2022) (Link)

Trigger warning: this article discusses death

The causes of death in Angelman Syndrome (AS) have not been previously researched, making it difficult for families to pay closer attention to possible mortality risks for their loved ones with this condition.

The research reported here compiled, for the first time, a list of deceased individuals with AS in order to identify the leading causes of death in those with AS. It also breaks it down by age group.

As a refresher before we talk numbers: Angelman syndrome (AS) is a neurodevelopmental disorder caused by lack of functional UBE3A protein in neurons. The four molecular etiologies for AS: Deletion of the AS critical region on the maternal chromosome 15q11q13, paternal uniparental disomy (UPD) for chromosome 15, pathogenic variants in maternally inherited UBE3A, and imprinting defect (ID) of the maternal copy of UBE3A.

Lets dive into the data (n=150):

1. The age of death ranged from 1 to 78 years old, with a median age of 18 years.

2. The leading cause of death overall was pneumonia/respiratory illness (n=32), followed by accidents (n=28), seizures (n=23), sudden unexpected death in sleep (SUDS) (n=17) and cancer (n=17).

3. Among people under 18 years of age, seizures and accidents were the leading cause of death.

4. In young adults, aged 19–29 years, respiratory illnesses was the leading cause.

5. In those >30 years old, cancer was the leading cause of death.

My personal additional take home point: Accidents were the leading cause of death in school-aged children (6–12 years old), specifically drownings. Because of the behavioral profile that includes fascination with water, and the ability of most school-aged children with AS to ambulate, pediatric providers need to be intentional in counseling families about the real concern of being unattended near standing bodies of water.

Overall, the standard of care for AS should include attention to prevention of these mortality risks.

Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders (Link)

In this proof of concept study, researchers utilized long-read whole genome sequencing for episignature detection.

Episignatures are genome-wide methylation patterns linked to specific disorders— and have emerged as vital diagnostic tool when determining the pathogenicity of some variants of unknown significance (VUS). Over 60 disorders now feature identifiable episignatures, and recent methylome studies in patients with unexplained developmental delay revealed rare epigenetic changes in 23% of patients (Barbosa et al., 2018 - Link).

By pairing these two testing modalities, this now means this technology can detect: methylation changes, single nucleotide variants (SNVs), structural variants (SVs), X-chromosome inactivation (XCI), phasing of variants, and imprinting disturbances. This is HUGE. Its essentially like an iPhone of genetic testing, with all your apps (or tests) in one machine.

The study:

They performed long-read whole genome nanopore sequencing (lrWGS) of 20 patients representing 13 different rare developmental disorders (DD) with known episignatures, as well as 40 controls. In 17/20 patients with a DD, the classifiers recognized an episignature and assigned the sample to the right disease. All healthy individuals were classified as controls. In three samples, the classifier did not recognize any of the reference episignatures. For those cases, clinical testing using EpiSign also returned negative (proving non-inferiority). The study also confirmed the detection of imprinting as well as haplotype-aware skewed XCI in an untargeted setting.

My Takeaway: By simultaneously applying long-read whole genome sequencing and episignature detection testing, I believe we can end diagnostic odysseys much sooner in the future.

Sincerely,

Max and Paige

The Discount Code for the EveryGene Flashcards is GENE2025

Phenylalanine hydroxylase deficiency diagnosis and management: A 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG) (Link)

Out with the old, in with the new!

New 2023 guidelines for PKU have been published, and without getting into the nitty gritty of things (I’ll let you read the article and do that), there are some notable updates.

Key recommendations from the 2014 guideline that were not supported by strong evidence that are now strongly supported include:

1. Treatment for PAH deficiency should be lifelong for individuals with untreated phenylalanine (Phe) levels >360 μmol/L. *Paging all insurance companies!*

2. Individuals with lifelong Phe levels ≤360 μmol/L have better intellectual outcomes than those who have higher levels.

3. Achieving Phe levels ≤360 μmol/L before conception prevents pregnancy complications and negative outcomes for the offspring.

4. Genetic testing for PAH variants is recommended at birth

Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer (Link)

Imagine this: you are pregnant and opt in to the recommended cell-free DNA (cfDNA) sequence analysis to screen for fetal aneuploidy. After some days, your test results return and say “unusual clinical cfDNA-sequencing results” or “results are nonreportable” (i.e., the fetal aneuploidy status could not be assessed). What does this mean?

Well, in 48.6% of women, it meant they had cancer. Yes, cancer. I think what’s most surprising is that many of these women had no symptoms (55.8%), or if they did have symptoms they were written off as symptoms related to pregnancy or other causes.

Among the 52 participants with cancer, lymphoma was the most common diagnosis (31 participants; 59.6%), followed by colorectal cancer (9 participants; 17.3%) and breast cancer (4 participants; 7.7%).

Should you or a patient you care for end up in this scenario, the sensitivity and specificity of whole-body MRI in detecting occult cancer were 98.0% and 88.5%, respectively (which is pretty good).

The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders (Link)

In mitochondrial disease, sensitive and specific biomarkers are limited. At my institution in particular, GDF-15 is often obtained when mito disease is on the differential. Even so, we don’t necessarily have a great way of interpreting the results other than “this is normal” or “this is high”. What complicates this even further is that GDF-15 seems to be affected by multiple factors including liver disease, nutritional status, and critical illness.

Thankfully, researchers in Colorado have done some deep dives into GDF-15 which have allowed us to better understand this biomarker.

Biggest takeaways:

1. GDF-15 is most useful at predicting mtDNA-related primary mitochondrial disorders, so long as abnormal liver function and critical illness are excluded.

   1. The optimal cut-off value to identify these target mtDNA-related disorders was 815 pg/mL, with sensitivity 76%, specificity 88%, positive predictive value of 41% and negative predictive value of 97%.

2. They found that GDF-15 was NOT great for predicting structural or other nuclear-encoded primary mitochondrial disorders.

Cardiomyopathies in 100,000 genomes project: interval evaluation improves diagnostic yield and informs strategies for ongoing gene discovery (Link)

The 100,000 Genomes Project (100KGP), run by Genomics England (GEL), is a UK government funded research project which sequenced thousands of genetically undiagnosed rare disease patients.

In the current study, researchers queried 90,190 individuals (affected individuals and unaffected relatives) to determine the yield of molecular testing for cardiomyopathy, the yield of adult vs pediatric cardiomyopathy cases, and then also compared panel based testing vs whole genome testing in pediatric patients.

Big Takeaways:

1. The diagnostic yield of cardiomyopathy was higher for children (19%) than for adults (11%).

2. Intronic or splice region variants predicted to impact splicing, or structural variants were identified in 12/111 (11%); these would possibly be missed by panel or exome testing.

3. Family history was reported in 45% (22/49) of diagnoses.

4. 11% of overall diagnoses were made in genes not on the existing UK pediatric or syndromic Cardiomyopathy panel.

My thoughts:

1. Currently, practices in the US vary as to what testing is performed in cases of cardiomyopathy. In the National Health Service (UK), “genome sequencing is already standard practice for pediatric and syndromic CM.” By ordering panel testing in regions where genome sequencing is available, not only are we limiting ourself to the genes present on the panel, but we also lack the ability to expand the panel if/when new genes are discovered or implicated in cardiomyopathy.

2. The landscape of cardiomyopathy and the interplay with genetics is rapidly expanding. New treatments are arising frequently. By potentially being in that 11% of missed diagnosis due to narrow panel testing, you may be missing the chance to provide therapy for a newly treatable disease.

Phase 1 Study of AAV9.LAMP2B Gene Therapy in Danon Disease (Link)

Phase 1 gene therapy trial results for Danon Disease have been published in the New England Journal of Medicine. As background, Danon disease is a rare, X-linked, monogenic cardiomyopathy caused by mutations in the lysosomal-associated membrane 2 gene (LAMP2). In males, the predominant phenotype is progressive cardiac hypertrophy, cardiac dysfunction, and early death.

The study: They evaluated the safety and efficacy of a single infusion of RP-A501 (n=7), a recombinant adeno-associated virus serotype 9 containing the transgene LAMP2B, which encodes an isoform of LAMP2.

Side effects: Complement-mediated thrombotic microangiopathy (grade 4) with thrombocytopenia and acute kidney injury (n=1), Glucocorticoid-related exacerbation (grade 3) of Danon disease–related skeletal myopathy (n=3), and progressive heart failure requiring transplantation 5 months after infusion (n=1)

Results: In the six patients with normal left ventricular ejection fraction at baseline, there was observed cardiac LAMP2 protein expression and a reduction from baseline in or stabilization of the left ventricular mass index, preservation of left ventricular ejection fraction, and reduction in or stabilization of the levels of cardiac troponin I and N-terminal pro–B-type natriuretic peptide. At 24 to 54 months, all the patients were alive, with complete resolution of side effects.

Sincerely,

Max and Paige