July 2025!
Prenatal Triptan exposure outcomes, VARS2 and Valine, Urea cycle chaperones, IMDs in Older patients!
Association of Prenatal Exposure to Triptans, Alone or Combined With Other Migraine Medications, and Neurodevelopmental Outcomes in Offspring (Link)
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