Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3

Abstract

The spinal muscular atrophies (SMA) or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, 'hereditary motor and autonomic neuronopathy', and attribute the term, 'survival of motor and autonomic neurons 1' (SMAN1) to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

A clinical phenotype of distal hereditary motor neuronopathy type II with a novel HSPB1 mutation

“…Hereditary motor and autonomic neuronopathy, reported in a Brazilian family, was quite different in its general severity [19]. Patient 1 had uncontrolled DM.…”

The history behind ALS type 8: from the first phenotype description to the discovery of VAPB mutation

“…In 2004, Marques Jr. et al described a large Brazilian family with late-onset, autosomal dominant, proximal and progressive SMA associated with dysautonomic symptoms and severe weakness of the abdominal muscles that resulted in a prominent abdomen 12 . The authors identified the localization of this disorder with chromosome 20q13.2-13.3 and called it hereditary motor and autonomic neuropathy 1 12 . In the same year, Nishimura et al defined that a mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.…”

Expanding the phenotypes of the Pro56SerVAPBmutation: Proximal SMA with dysautonomia

“…We recently studied new cases in a five‐generation family with adult‐onset, autosomal‐dominant disease exhibiting a progressive, proximal muscle weakness and atrophy previously described by others 10. We mapped the disease gene segregating in this kindred to chromosome 20q13.2‐13.3,18 a region containing at least 33 known genes. While we were investigating several candidate genes in this region, Nishimura et al22 found a point mutation in the synaptobrevin‐associated membrane protein ( VAPB) gene in several Brazilian families with different phenotypes of motor neuron disorders, including families with amyotrophic lateral sclerosis (ALS) type 8, families with atypical ALS, and three families identified as having late‐onset spinal muscular atrophy of the type described by Finkel,10 although no detailed phenotypic description of these families was presented.…”