ORPHA: 276435; DO: 0081356;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.23 | Spinal muscular atrophy, Jokela type | 615048 | Autosomal dominant | 3 | CHCHD10 | 615903 |
A number sign (#) is used with this entry because of evidence that the Jokela type of spinal muscular atrophy (SMAJ) is caused by heterozygous mutation in the CHCHD10 gene (615903) on chromosome 22q11.
The Jokela type of spinal muscular atrophy (SMAJ) is an autosomal dominant lower motor neuron disorder characterized by adult-onset of muscle cramps and fasciculations affecting the proximal and distal muscles of the upper and lower limbs. The disorder is slowly progressive, resulting in weakness and mild muscle atrophy later in life (summary by Jokela et al., 2011).
Jokela et al. (2011) reported 2 large unrelated Finnish families with late adult-onset spinal muscular atrophy. Twelve individuals were examined. Affected individuals developed painful muscle cramps associated with slowly progressive weakness and atrophy of the proximal and distal muscles of the upper and lower limbs. Fasciculations were almost always present, reflexes were absent, and EMG showed neurogenic changes. All retained the ability to walk independently, even after long disease duration. Five patients had pes cavus, 1 had pes planus, 3 had hammertoes, and 2 had calf hypertrophy. Five had reduced vibration sense in the distal part of the feet, and 5 had intention tremor. Serum creatine kinase was increased in most patients. Muscle imaging showed diffuse fatty degenerative changes in the posterior lower leg muscles. Muscle biopsy showed fiber-type grouping, consistent with denervation. Biopsy of 1 patient showed myopathic changes. None had bulbar signs, and extensor plantar responses were not present. The phenotype was consistent with a lower motor neuronopathy.
Penttila et al. (2015) reported 17 Finnish families with SMAJ, including follow-up of the 2 large multigenerational families originally reported by Jokela et al. (2011) and a patient reported by Muller et al. (2014) who was initially diagnosed with amyotrophic lateral sclerosis (ALS; 105400). The phenotype among all patients was relatively homogeneous, with onset at a mean age of 42 years (range 14 to 72) of slowly progressive muscle weakness predominantly affecting the proximal lower limbs and resulting in gait difficulties. There was more variable involvement of the distal muscles and upper limbs. Other features included fasciculations, tremor, and hypo- or areflexia. About half of patients developed mild distal sensory impairment later in the disease course. Upper motor neuron signs, such as extensor plantar responses, and respiratory symptoms were absent; bulbar symptoms were extremely rare and occurred only late in the disease course. EMG showed a neurogenic process, and serum creatine kinase was increased. Muscle imaging showed fatty degenerative changes of the gastrocnemius and soleus muscles in the lower leg. Muscle biopsies from 30 patients were similar to controls and inconsistent with a mitochondrial myopathy, although some patients had mildly increased COX-negative fibers and ragged-red fibers. None had frontotemporal dementia or ataxia.
The transmission pattern of adult-onset SMA in the families reported by Jokela et al. (2011) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis in the 2 families with SMA reported by Jokela et al. (2011) in which linkage to known SMA loci was excluded, Penttila et al. (2012) found linkage to an 18.9-Mb region on chromosome 22q11.2-q13.2 (maximum lod score of 3.43 at D22S315). The candidate region was flanked by markers D22S686 and D22S276. Haplotype analysis suggested a founder effect.
In 55 patients from 17 Finnish families with SMAJ, including the patients originally reported by Jokela et al. (2011), Penttila et al. (2012) identified a heterozygous missense mutation in the CHCHD10 gene (G66V; 615903.0003). The mutation, which was found by linkage analysis and whole-genome sequencing, segregated with the disorder in all families. Haplotype analysis indicated a founder effect. Functional studies of the variant were not performed.
Penttila et al. (2015) reported that the estimated prevalence of SMAJ exceeds the prevalence of ALS in eastern Finland, being as high as 12 in 100,000 in northern Karelia.
Jokela, M., Penttila, S., Huovinen, S., Hackman, P., Maija Saukkonen, A., Toivanen, J., Udd, B. Late-onset lower motor neuronopathy: a new autosomal dominant disorder. Neurology 77: 334-340, 2011. [PubMed: 21715705] [Full Text: https://doi.org/10.1212/WNL.0b013e3182267b71]
Muller, K., Andersen, P. M., Hubers, A., Marroquin, N., Volk, A. E., Danzer, K. M., Meitinger, T., Ludolph, A. C., Strom, T. M., Weishaupt, J. H. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter) Brain 137: e309, 2014. Note: Electronic Article. [PubMed: 25113787] [Full Text: https://doi.org/10.1093/brain/awu227]
Penttila, S., Jokela, M., Bouquin, H., Saukkonen, A. M., Toivanen, J., Udd, B. Late onset spinal motor neuronopathy is caused by mutation in CHCHD10. Ann. Neurol. 77: 163-172, 2015. [PubMed: 25428574] [Full Text: https://doi.org/10.1002/ana.24319]
Penttila, S., Jokela, M., Hackman, P., Saukkonen, A. M., Toivanen, J., Udd, B. Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2. Europ. J. Hum. Genet. 20: 1193-1196, 2012. [PubMed: 22535186] [Full Text: https://doi.org/10.1038/ejhg.2012.76]