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ARSA encodes the lysosomal enzyme arylsulfatase A, whose deficiency causes metachromatic leukodystrophy (MLD). The juvenile form of MLD presents between 4 and 16 years of age with cognitive decline, gait disturbance, and leukodystrophy on neuroimaging. Biallelic ARSA mutations lead to impaired sulfatide catabolism, resulting in progressive demyelination and neurologic regression. This summary reviews the genetic and functional data supporting ARSA’s role in juvenile MLD.
Autosomal recessive inheritance is established for juvenile MLD. Compound heterozygous or homozygous ARSA variants have been identified in at least 4 unrelated juvenile‐onset MLD probands ([PMID:9600244]) with segregation in multiple families. Enzyme assays and familial studies confirm that these variants co-segregate with low arylsulfatase A activity and clinical disease.
The variant spectrum includes missense substitutions, splice-site mutations, and frameshift null alleles. For example, c.410T>C (p.Leu137Pro) abolishes enzyme activity in transient expression studies ([PMID:9600244]). Splice-site mutation c.465+1G>A and frameshift alleles further truncate the protein, consistent with loss-of-function.
Functional assays demonstrate that ARSA missense and null mutations yield negligible residual activity. Transient transfection of p.Asp335Val and p.Thr276Met constructs failed to restore activity in vitro ([PMID:8723680]). In mouse ASA–/– models, retroviral delivery of wild-type ARSA corrects visceral storage but only modestly ameliorates neurologic symptoms ([PMID:11399225]), underscoring the challenge of CNS delivery.
Confounding pseudodeficiency alleles exist, notably c.376T>C (p.Leu76Pro), found homozygous in 6/20 controls and heterozygous in 12/20 without clinical MLD ([PMID:8707308]). These polymorphisms reduce ASA activity in vitro but do not cause pathology, necessitating combined enzymatic and molecular diagnostics.
Collectively, over 20 ARSA variants in juvenile MLD probands, consistent autosomal recessive segregation, and concordant functional data support a Strong gene–disease validity. Integrative diagnostic protocols—combining leukocyte enzyme assays, molecular testing for ARSA mutations and pseudodeficiency alleles—enable accurate carrier detection, prognosis, and family planning.
Key Take-home: Comprehensive ARSA genotyping and enzyme analysis provide definitive diagnosis for juvenile MLD and guide genetic counseling and therapeutic strategies.
Gene–Disease AssociationStrongCompound heterozygous ARSA mutations in ≥4 unrelated juvenile MLD probands, multi-family segregation, concordant functional loss-of-function data Genetic EvidenceStrongBiallelic missense, splice-site, and null ARSA variants identified in multiple unrelated juvenile-onset cases with segregation and enzyme deficiency Functional EvidenceModerateIn vitro assays show abolished enzyme activity for key ARSA variants; ASA–/– mouse model exhibits CNS pathology with partial correction upon gene therapy |