Neuro-Ophthalmic Presentation of Steroid 5a-Reductase Type 3 Congenital Disorder of Glycosylation: A Case of Monozygotic Twins

We report a very rare autosomal recessive metabolic disorder in monozygotic twin sisters caused by the steroid 5a-reductase type 3 (SRD5A3) gene defect, a subtype of congenital disorder of glycosylation (CDG). SRD5A3 activity is required for N-glycosylation of proteins. This step is important for the protein to gain its function. The condition is characterized by severe neurodevelopmental delay, cerebellar atrophy or hypoplasia, ocular abnormalities, and ichthyotic skin changes. We describe 20-month-old female monozygotic twins born to non-consanguineous South Asian parents. Notably, both twins exhibited generalized tonic-clonic seizures starting in early infancy - a feature less commonly reported in SRD5A3-CDG. Physical examination of both children showed central hypotonia and bilateral horizontal nystagmus. Fundoscopy of the twins showed optic disc pallor suggestive of optic atrophy. Other features, such as ichthyosis and joint laxity, were absent. Crucially, despite prominent neurological symptoms, brain MRIs at 20 months were entirely normal, showing no evidence of cerebellar hypoplasia or atrophy typically associated with this condition. Whole-exome sequencing identified a homozygous nonsense mutation at exon 1 c.57G>A (p.Trp19Ter), in the SRD5A3 gene, classified as a pathogenic variant as per the American College of Medical Genetics and Genomics (ACMG), helping in establishing the diagnosis. SRD5A3-CDG should be one of the differentials in infants with unexplained seizures, hypotonia, and early ocular signs. This case highlights the phenotypic diversity of SRD5A3-CDG and demonstrates that structural brain anomalies may be absent in the early years of life. It underscores the importance of considering CDG as a differential in infants with unexplained hypotonia and ocular signs, even in the setting of normal neuroimaging.