Clinical, biochemical and genetic characterization of an Egyptian patient with SRD5A3-congenital glycosylation disorder

Purpose To characterize an undiagnosed patient with retinal dystrophy, ataxia, and neurodevelopmental delay.Materials and Methods A 13-year-old female patient presenting with nystagmus and defective vision since infancy, underwent ophthalmological, neurological examination, ultra-wide field fundus photography, autofluorescence and electroretinogram. Exome sequencing (ES) was done followed by segregation analysis. Analysis of the glycosylation profiles of plasma glycoprotein markers was performed using immunoblotting.Results Visual acuity was counting fingers; her fundus examination and imaging revealed an Early Childhood Onset Retinal Dystrophy (ECORD) phenotype. Ichthyosiform skin lesions were noted, and neurological assessment revealed proximal limb-girdle pattern of weakness, hyperactive reflexes, extensor plantar responses with evidence of cerebellar dysfunction. ES uncovered a homozygous, likely pathogenic missense variant c.509A > G, p.(Tyr170Cys) in SRD5A3 gene. In silico functional analysis prediction tools supported the variant being deleterious. Segregation analysis confirmed carrier status of parents and the brother, while plasma glycoprotein markers for N- and O-glycosylation showed an aberrant glycosylation profile.Conclusion We report a variant in the SRD3A5 gene reported for the first time in a case of CDG. We are expanding the neurophenotypic spectrum by reporting proximal limb-girdle pattern of weakness combined with diffusely brisk reflexes and bilateral extensor plantar responses suggestive of corticospinal or neuromuscular axis involvement.