Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37

• Published in: Brain (London, England : 1878) England : 1878), 2018-07, Vol.141 (7), p.1981-1997
• Main Authors: Corral-Juan, Marc, Serrano-Munuera, Carmen, Rábano, Alberto, Cota-González, Daniel, Segarra-Roca, Anna, Ispierto, Lourdes, Cano-Orgaz, Antonio Tomás, Adarmes, Astrid D, Méndez-del-Barrio, Carlota, Jesús, Silvia, Mir, Pablo, Volpini, Victor, Alvarez-Ramo, Ramiro, Sánchez, Ivelisse, Matilla-Dueñas, Antoni
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Ataxia; Cell Adhesion Molecules, Neuronal; Cerebellum - pathology; Extracellular Matrix Proteins; Female; Humans; Male; Microsatellite Repeats - genetics; Mutation; Nerve Tissue Proteins - genetics; Nervous System Diseases; Neuropathology; Pedigree; Purkinje Cells - pathology; Serine Endopeptidases; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - pathology; Spinocerebellar Degenerations - genetics
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awy137

Spinocerebellar ataxia type 37 is an adult-onset dominant ataxia characterised by altered vertical eye movements. Corral-Juan et al. demonstrate that an ATTTC expansion mutation within the DAB1 gene is the genetic cause of SCA37, present the first neuropathological findings, and provide evidence of cerebellar dysregulation of Reelin-DAB1 and PI3K/AKT signalling. Abstract The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5′ non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the S