Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2

Abstract

Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of lower motor neurons. Different SMA types are clinically and genetically heterogeneous and many of them show significant phenotypic overlap. We recently described the clinical phenotype of a new disease in two Finnish families with a unique autosomal dominant late-onset lower motor neuronopathy. The studied families did not show linkage to any known locus of hereditary motor neuron disease and thus seemed to represent a new disease entity. For this study, we recruited two more family members and performed a more thorough genome-wide scan. We obtained significant linkage on chromosome 22q, maximum LOD score being 3.43 at marker D22S315. The linked area is defined by flanking markers D22S686 and D22S276, comprising 18.9 Mb. The region harbours 402 genes, none of which is previously known to be associated with SMAs. This study confirms that the disease in these two families is a genetically distinct entity and also provides evidence for a founder mutation segregating in both pedigrees.

Late-onset spinal motor neuronopathy – A common form of dominant SMA

“…Patients and family members indicated in the pedigrees (Fig. 1) were genotyped for microsatellite markers D22S264, D22S446, D22S306, D22S686, D22S926, D22S419 and D22S421 that were previously shown to be part of the founder haplotype [6]. To confirm and refine the haplotypes six additional markers, D22S303, SHGC-106816, D22S301, D22S345, D22S343 and D22S925, were analyzed.…”

“…In genome-wide screening the disease showed significant linkage to chromosome 22q11.2-q13.2 [6]. Based on a founder effect hypothesis we screened a cohort of patients with late-onset SMA or undetermined lower motor neuron disease (LMND) for the disease-associated haplotype, and identified several new LOSMoN families comprising 26 affected members.…”

Late onset spinal motor neuronopathy is caused by mutation in CHCHD10

“…[1][2][3] The numbering of the previously described patients has not changed, apart from Family F3, where inclusion of 1 older generation adds to the generation numbering in all family members (eg, previous F3:II-4 is now F3:III-4). Clinical details of 37 patients have already been reported.…”

“…2,3 Fluorescently labeled polymerase chain reaction (PCR) products were analyzed using an ABI3130xl automatic DNA Genetic Analyzer (Applied Biosystems, Foster City, CA) and Peak Scanner Software v1.0 (Applied Biosystems). Finnish patients and unaffected family members were genotyped for microsatellite markers D22S264, D22S446, D22S306, D22S686, D22S303, SHGC-106816, D22S301, D22S345, D22S343, D22S925, D22S926, D22S419, and D22S421, which were previously shown to be part of the founder haplotype.…”

“…The main early symptoms and signs commonly appear after age 30 to 40 years: cramps, fasciculations, decreased or absent tendon reflexes, elevated creatine kinase (CK), and hand tremor. 2,3 Until very recently, none of the genes in locus 22q11.2 was known to be associated with motor neuron diseases. The patients have remained ambulant for several decades after onset of the disease and the life expectancy of the patients is within normal range.…”