J. Toivanen

Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.

A study was undertaken to identify the responsible gene defect underlying late onset spinal motor neuronopathy (LOSMoN/SMAJ; Online Mendelian Inheritance in Man #615048), an autosomal dominant disease mapped to chromosome 22q11.2.

Late-onset lower motor neuronopathy: a new autosomal dominant disorder.

Objective: Characterization of a new type of late-onset autosomal dominant lower motor neuron disease. Methods: Patients from 2 families underwent detailed neurologic, electrophysiologic, muscle biopsy, and laboratory investigations. MRI of lower limbs was performed in selected patients. DNA samples from leukocytes were used for molecular genetic linkage studies. Results: First symptoms were muscle cramps and fasciculations after age 25–30, followed by a slowly progressive proximal and distal weakness without overt atrophy during the first decades of symptoms. Nerve conduction velocities were within normal range and EMG showed widespread neurogenic alterations. Muscle biopsy revealed characteristic neurogenic findings: fiber type grouping and group atrophy. MRI showed diffuse fatty-degenerative changes, marked in medial gastrocnemius. Conclusion: Exactly the same clinical phenotype has not previously been described, and linkage studies showed exclusion of known chromosomal loci for hereditary motor neuropathies, suggesting the disease we report may represent a new disorder.

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

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.

We previously described two Finnish families with a new autosomal dominant late-onset spinal motor neuronopathy that was mapped to chromosome 22q11.2-q13.2. In the current screening study of 43 lower motor neuron disease patients from Finland and Sweden, we identified 26 new late-onset spinal motor neuronopathy patients sharing the founder haplotype. In addition to the main symptoms and signs: painful cramps, fasciculations, areflexia and slowly evolving muscle weakness, new features such as mild bulbar findings, were identified. The disease is relatively benign in terms of life expectancy and rate of disability progression, and it is therefore noteworthy that three patients were initially misdiagnosed with ALS. Significant recombinants in this new patient cohort restricted the disease locus by 90% to 1.8Mb. Late-onset spinal motor neuronopathy seems not to be very rare, at least not in Finland, with 38 patients identified in a preliminary ascertainment.

CHCHD10 mutations and motor neuron disease: the distribution in Finnish patients

Motor neuron disorders (MNDs) are a heterogeneous group of diseases that result from degeneration of motor neurons. If both upper and lower motor neurons (UMNs and LMNs) are affected, the disease is classified as amyotrophic lateral sclerosis (ALS). Primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) selectively affect the UMNs or LMNs, respectively, but are sometimes considered to be incomplete ALS variants because their phenotype may evolve into typical ALS over time. Bulbar affection in a UMN disease would favour a diagnosis of PLS over hereditary spastic paraplegia (HSP), whereas rapid progression may separate PMA from adult-onset spinal muscular atrophy (SMA). Some SMA-like or even ALS-like phenotypes have been incorporated into the large category of sensorimotor axonal neuropathies (Charcot-Marie-Tooth disease type 2, CMT2),1 although sensory abnormalities may be subtle in some forms.2 On the other hand, spinal and bulbar muscular atrophy (Kennedy disease) is classified as a form of adult-onset SMA despite prominent sensory abnormalities. It has recently been argued that the current classification system of MNDs is unsatisfactory and should be revised to include genetically and prognostically important categories.3 We have recently identified a new form of motor neuron disease in 55 patients from 17 Finnish families, where distinctive phenotype did not match any pre-existing neuromuscular disease category.4–6 Spinal muscular atrophy Jokela type (SMAJ, OMIM #615048) is characterised by painful cramps, fasciculations, decreased or absent tendon reflexes, elevated creatine kinase and hand tremor. The first symptoms appear commonly after age 30–40. Electromyography (EMG) and muscle biopsy display widespread neurogenic findings and a proportion of patients show sensory abnormalities. Muscle weakness and atrophy appear much later in the disease course, and patients have remained ambulant for several decades and their life expectancy is within normal range.4 ,5 SMAJ is caused by a dominant …

G.P.97 Haplotype analyses reveal several new patients with late-onset spinal motor neuronopathy

Abstract Spinal muscular atrophies (SMA) 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 have previously described the clinical phenotype in two Finnish families with a unique autosomal dominant late-onset spinal motor neuronopathy (LOSMoN). As shown in the WMS 2011 poster these and two other families studied later showed significant linkage on chromosome 22q11.2. The disease-associated haplotype was identical in all four families suggesting a founder effect. Based on this we have screened more patients with an unknown late-onset SMA type of disease for the disease-associated haplotype. We screened 26 patients from 20 kindreds for 13 genetic markers that were shown to link to LOSMoN in the previously studied families. The unique disease-associated haplotype was found in 12 patients from six families. For most patients samples of the relatives were not available and thus small parts of the disease-associated haplotype could not be reliably recognized. Consequently we may have not detected all patients with LOSMoN in the cohort and furthermore, also informative recombinants may have remained unnoticed. By now we have identified altogether 33 patients from 10 families. The real prevalence of LOSMoN can be estimated when the disease causing gene has been determined. However, according to our data so far, LOSMoN seems to be fairly frequent in Finland. Whether and how frequently the disease occurs in other parts of the world remains to be clarified. Before the disease causing gene is known haplotype analysis seems to be an effective means for detecting new patients in restricted populations, at least when there are family members available for analysis.