P.215 Non 5Q SMA: a Brazilian cohort study

Abstract

Spinal muscular atrophy (SMA) describes a group of hereditary motor neuron disorders, characterized by progressive muscle weakness due to the degeneration of the anterior horn cells. This process is a consequence of structural alterations of the lower motor neurons, 95% of the time caused by loss-of-function <i>SMN1</i> mutations on chromosome 5. Recently, with the advance of next generation sequencing, several potentially causative genes outside the chromosome 5 have been recognized. This subgroup of wide phenotypic variability and inheritance pattern, in which proximal muscle weakness predominates, is known as non-5q spinal muscular atrophy. We sought to describe the clinical and neurogenetic spectrum of non 5q proximal SMA patients enrolled in the ICGNMD (International Centre for Genomic Medicine in Neuromuscular Diseases) study. Cases from a neuromuscular clinic were reviewed. Patients with proximal neurogenic weakness (<i>SMN1</i> testing negative) or those with clinical evaluation suggestive of motor neuronopathy were included. So far 95 patients from 48 families were identified, 45 (48%) of them, male. Eleven of the patients (12%) started symptoms at birth, 50 patients (53%) had from 1 to 30 years and 30 (32%) had more than 30 years when symptoms started. The inheritance pattern was autosomal dominant in 51 (53%), recessive in 9 (10%), X-linked in one (1%), mitochondrial in 2 (2%) and sporadic in 32 (33%). Molecular analysis is ongoing and, so far, 52 (55%) have a definitive diagnosis. The phenotype is complex in 71 patients (75%) and many associated features have been described: dysautonomia, pyramidal signs, ophthalmoplegia, scoliosis, arthrogryposis, cognitive impairment, sensory neuropathy, ataxia, among others. Non-5q SMA is genetically diverse, and many genes will be novel. Our cohort will be fully genetically investigated using next-generation sequencing techniques with targeted panels and/or whole exome sequencing. So far, the results highlight this heterogeneity of genes and associated features.