Leukodystrophies are a heterogeneous group of disorders affecting the white matter of the central nervous system, with or without affecting the peripheral nervous system. Biallelic variants in DEGS1, coding for desaturase 1 (Des1) protein, were recently reported to be associated with hypomyelinating leukodystrophy (HLD), a subclass of leukodystrophies where the formation of the myelin sheath is affected.
Genomic sequencing was performed on our index patient with severe developmental delay, severe failure to thrive, dystonia, seizures, and hypomyelination on brain imaging. Sphingolipid analysis was performed and dihydroceramide/ceramide (dhCer/Cer) ratios were obtained by the measurement of ceramide and dihydroceramide species.
A homozygous missense variant was identified in DEGS1 (c.565A > G:p Asn189Asp). The identified DEGS1 variant has been annotated as “conflicting reports of pathogenicity” on ClinVar. Follow-up sphingolipid analysis on our patient showed significantly raised dhCer/Cer and this was consistent with dysfunction of the Des1 protein, providing additional evidence to support the pathogenicity of this variant.
While rare, pathogenic variants in DEGS1 should be considered in patients with HLD phenotype. To date, 25 patients have been reported across four studies on DEGS1-related HLD, and, in this report, we summarize the literature. More such reports will enable deeper phenotypic characterization of this disorder.