DAB1 – Spinocerebellar Ataxia Type 37

Spinocerebellar ataxia type 37 (SCA37) is an autosomal dominant cerebellar degeneration characterized by progressive gait and limb ataxia with early‐altered vertical eye movements. The disease maps to chromosome 1p32 and is clinically distinct within the heterogeneous spinocerebellar ataxia group.

A pathogenic unstable intronic ATTTC pentanucleotide repeat expansion in the 5′ non‐coding regulatory region of DAB1 segregates with SCA37 in four Spanish families (PMID:29939198). This repeat expansion co‐segregated with disease status in over 20 affected individuals across multiple generations, confirming autosomal dominant inheritance and high penetrance.

Genetic evidence is supported by clear co‐segregation of the repeat expansion in all affected members of these pedigrees, with no evidence in unaffected relatives (PMID:29939198).

Neuropathological examination of two SCA37 postmortem cerebella revealed profound Purkinje cell loss, astrogliosis, empty basket formations, aberrant Purkinje dendritogenesis, nuclear lobulation, and DAB1‐positive ubiquitinated perisomatic inclusions, consistent with a primary cerebellar neurodegenerative process (PMID:29939198).

Functional assays demonstrated that the ATTTC repeat dysregulates DAB1 expression and induces an RNA switch that upregulates Reelin–DAB1 and PI3K/AKT signalling in patient cerebellum, establishing a mechanistic link between repeat expansion and neuronal dysfunction (PMID:29939198).

Integrated genetic and experimental data assign a Strong clinical validity to the DAB1–SCA37 association. Clinical testing for the DAB1 intronic ATTTC repeat expansion should be included in the diagnostic workup of suspected SCA37 cases.

References

• Brain • 2018 • Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37. PMID:29939198

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