DARS1 – Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a rare autosomal recessive leukodystrophy characterized by motor regression and spasticity. A single patient exhibited global developmental delay (HP:0001263) and developmental regression (HP:0002376) with progressive lower limb spasticity. Neuroimaging demonstrated diffuse hypomyelination of the cerebral white matter and spinal cord. Genetic testing revealed two compound heterozygous variants in DARS1: c.1363T>C and c.821C>G (PMID:35571067).

Based on ClinGen criteria, the gene–disease association is classified as Limited given one unrelated proband with biallelic DARS1 variants and no additional segregations (1 proband) (PMID:35571067). Genetic evidence is Limited (Tier 1) owing to a single case report without family segregation data. No functional studies specific to HBSL have been reported, yielding No reported functional evidence. Further familial and experimental validation is required to strengthen the clinical validity. Key take-home: Biallelic DARS1 variants cause HBSL, but evidence remains limited to a single case report.

References

• Frontiers in genetics • 2022 • Case Report: DARS Mutations Responsible for Hypomyelination With Brain Stem and Spinal Cord Involvement and Leg Spasticity PMID:35571067

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