Late infantile and adult‐onset metachromatic leukodystrophy due to novel missense variants in the PSAP gene: Case report from India

Abstract Metachromatic leukodystrophy (MLD) due to Sap‐B deficiency is a rare autosomal recessive disorder caused due to biallelic variants in the PSAP gene. The PSAP gene encodes a precursor protein prosaposin, which is subsequently cleaved to form four active glycoproteins: Sap‐A, Sap‐B, Sap‐C, and Sap‐D. In case of deficiency of the sphingolipid activator protein Sap‐B, there is a gradual accumulation of cerebroside‐3‐sulfate in the myelin of the nervous system resulting in progressive demyelination. Only 12 variants have been reported in the PSAP gene causing Sap‐B deficiency to date. Here, we report two cases of MLD due to Sap‐B deficiency (late‐infantile and adult‐onset form) harboring two novel missense variants c.688T > G and c.593G > A in the PSAP gene respectively. This study reports the third case of adult‐onset MLD due to Sap‐B deficiency in the world. The proband, a 3‐year‐old male child presented with complaints of hypotonia, lower limb tremors and global developmental delay. His MRI showed hyperintense signals in the bilateral cerebellar white matter. Overall, the findings were suggestive of metachromatic leukodystrophy. The second case was a 19‐year‐old male child with clinical features of regression of speech, gait ataxia and bilateral tremors referred to our clinic. MRI data suggested metachromatic leukodystrophy. Normal enzyme activity of arylsulfatase‐A led to a suspicion of saposin B deficiency. For both cases, targeted sequencing was performed. This identified homozygous variant c.688T > G (p.Cys230Gly) and c.593G > A (p.Cys198Tyr) in exon 6 of the PSAP gene, respectively.