A number sign (#) is used with this entry because of evidence that frontotemporal dementia and/or amyotrophic lateral sclerosis-2 (FTDALS2) is caused by heterozygous mutation in the CHCHD10 gene (615903) on chromosome 22q11.

For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).

Bannwarth et al. (2014) reported a large 5-generation French family in which multiple individuals had a late-onset neurodegenerative disorder comprising frontotemporal dementia, cerebellar ataxia, myopathy, and motor neuron disease consistent with amyotrophic lateral sclerosis. Clinical information, muscle biopsies, and DNA were available from 8 affected individuals, including 6 who were deceased. The proband presented at age 50 years with cerebellar ataxia associated with progressive bulbar dysfunction, dementia, and sensorineural deafness. She had extensor plantar responses, dysphagia, dysarthria, and a frontal lobe syndrome. She died at age 67. Seven other family members had variable manifestations of a similar disorder: some presented with ataxia, some with motor neuron disease, and some with both. All developed frontotemporal dementia, except 1 patient who died at age 51. Four patients had proximal muscle weakness, and electromyography (EMG) in 2 patients suggested a myopathic process. Muscle biopsies showed ragged-red fibers, cytochrome C oxidase (COX)-negative fibers, and mitochondrial DNA deletions; most patients also had combined mitochondrial respiratory chain deficiencies and fragmented mitochondrial networks in fibroblasts, all suggestive of mitochondrial dysfunction. An unrelated Spanish patient had a similar phenotype, with onset of walking difficulties at age 57 years. He then developed progressive pseudobulbar symptoms, with dysarthria and dysphagia, as well as frontotemporal dementia. EMG confirmed motor neuron disease. Other features included signs of parkinsonism, including akinesia and rigidity, sensorineural hypoacusis, and fatigue. Two sibs and a father reportedly had died of a similar neurodegenerative disorder.

The transmission pattern of FTDALS2 in the families reported by Bannwarth et al. (2014) was consistent with autosomal dominant inheritance.

In affected members of a family with FTDALS in whom mutations in C9ORF72 (614260) and other candidate genes were excluded, Bannwarth et al. (2014) identified a heterozygous missense mutation in the CHCHD10 gene (S59L; 615903.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Screening of the CHCHD10 gene in 21 additional families with a similar disorder identified the same heterozygous mutation in 1 proband. Overexpression of the mutant protein in HeLa cells led to fragmentation of the mitochondrial network as well as major ultrastructural abnormalities, similar to those observed in patient cells. The findings implicated a role for dysfunctional mitochondria in the pathogenesis of late-onset frontotemporal dementia with motor neuron disease.

Among 4,365 ALS patients and 1,832 controls from 7 different countries who underwent sequencing of the CHCHD10 gene, Project MinE ALS Sequencing Consortium (2018) found no significantly increased disease-associated mutation burden, suggesting that mutations in the CHCHD10 gene are rare in typical ALS. Three ALS-specific variants were identified in 5 unrelated patients. One woman with ALS without dementia and no family history of the disease carried a heterozygous R11G variant. Three additional unrelated patients, 1 Dutch and 2 American, carried a heterozygous R15L variant (615903.0002); 2 had a positive family history whereas the other did not. Finally, a Belgian patient carried a heterozygous P80L variant. The phenotype in some of these patients was atypical for ALS and included myopathic features and deafness. S59L was not found in either patients or controls. Functional studies of the variants and studies of patient cells were not performed.