P.6.8 Late-onset spinal motor neuronopathy (LOSMoN) – Increasing number of patients, decreasing number of candidate genes

Abstract

Spinal muscular atrophies (SMA) form a category of inherited motor neuron disorders that predominantly affect lower motor neurons. Different SMA types are clinically and genetically heterogeneous and many of them show significant phenotypic overlap. Nine different genes have been reported to underlie autosomal dominant distal forms of SMA and five genes are known to cause dominant proximal SMA. We have previously described the clinical phenotype of autosomal dominant late-onset spinal motor neuronopathy (LOSMoN). The main symptoms and signs are painful cramps, fasciculations, areflexia and slowly evolving muscle weakness. The disorder is linked to a new neuromuscular locus on chromosome 22q11.2. All characterized patients in the initially studied families have shared an identical disease-associated haplotype suggesting a founder effect in the Finnish population. In order to find the disease causing gene by restricting the linked locus we have screened a number of potential LOSMoN patients and their family members for the disease associated haplotype. By now we have identified 51 patients from 19 families. In three families there were significant recombinants that restricted the disease locus to the region of 1.1 Mb, as small as the microsatellite markers allow. The area contains 17 genes and sequencing of them is ongoing. This is so far the largest cohort of late-onset autosomal dominant SMA reported. The large number of patients has enabled us to expand the phenotype and diversify the characteristics of LOSMoN, including mild bulbar findings in a minority and rimmed vacuoles in muscle biopsies of some patients. Although life expectancy in LOSMoN patients appears to be normal, it is noteworthy that weakness and neurogenic changes in electromyography can occur in all spinal segments (cervical, thoracal, lumbosacral) and also the bulbar region similarly to amyotrophic lateral sclerosis. Because age of onset also overlaps with ALS, misdiagnosis sometimes occurs.