A distinct clinical phenotype in a German kindred with motor neuron disease carrying aCHCHD10mutation

Sir, Emerging data provide evidence for CHCHD10 as a new candidate gene in familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (Bannwarth et al., 2014; Johnson et al., 2014; Müller et al., 2014). This gene encodes a mitochondrial protein located in the intermembrane space (Bannwarth et al., 2014). Mutant CHCHD10 may lead to altered mitochondrial genome stability and maintenance of cristae junctions (Bannwarth et al., 2014; Chaussenot et al., 2014). So far, three different mutations located either in the non-structured N-terminal region or in the -helix of the CHCHD10 gene have been attributed to cause both ALS and ALS-FTD phenotypes. Here we report another large German family with a history suggestive of autosomal-dominant motor neuron disorder (Fig. 1). After excluding a repeat expansion in C9orf72 and mutations in 25 other known ALS genes in parallel by next-generation sequencing we performed whole-exome sequencing of three affected individuals (Patients III.1, III.2 and III.9). This identified a heterozygous c.44G4T variant (p.Arg15Leu) in exon 2 of the CHCHD10 gene which has recently been reported by Müller et al. (2014) as the likely cause of pure ALS in two German families and was also identified in three families with familial motor neuron disease in the USA (Johnson et al., 2014). The mutation segregated with disease in another cousin (Patient III.5) of our index patient (Patient III.1) and could not be identified in his 41-year-old son (Patient IV.1) and an 85-year-old aunt (Patient II.7), who are both unaffected. No DNA samples were available from the deceased Patients I.1, II.3, II.6 and II.9, as well as from further to-date unaffected family members. However, because of the variable age of onset ranging from 41 to 73 years (59.5 11.2 years; mean SD) only such individuals without clinical signs of a motor neuron disorder clearly after the latest disease onset within the family may really be regarded healthy. In our case, only individuals from the second generation (Fig. 1) would now have fulfilled this criterion with all other unaffected family members still being at risk. Of note, seven of eight affected patients were males. All of them were diagnosed with motor neuron disease/ALS. Similar to the German families carrying the p.Arg15Leu mutation described by Müller et al. (2014), all of our patients exhibited upper limb onset exclusively, presenting with progressive, mostly atonic paresis, muscle wasting and fasciculations in either proximal (Patients II.6 and III.1 with symmetrical onset) or distal muscles (Patients III.2, III.5 and III.9 with a more asymmetrical distribution at onset), spreading out slowly and leading to severe disability of the upper extremities as disease progressed. At least three patients developed bulbar symptoms, however, not requiring supplemental tube feeding. None showed emotional instability. Patients III.1, III.2, III.5 and III.9 doi:10.1093/brain/awv014 BRAIN 2015: 138; 1–3 | e376