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Sir,

In a relatively short period of time, an increasing body of evidence has accumulated confirming the primary role of mitochondrial dysfunction in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) clinical spectrum through the involvement of CHCHD10 both in familial and sporadic cases (Bannwarth et al., 2014; Chaussenot et al., 2014; Johnson et al., 2014; Müller et al., 2014; Ronchi et al., 2015). In a new Letter to the Editor submitted to Brain, Kurzwelly et al. (2015) report another large German family with a history of autosomal dominant pure ALS. Affected individuals harboured the c.44G > T (p.Arg15Leu) heterozygous mutation in CHCHD10, which has been previously identified in five of six families with pure ALS associated with mutations in this gene (two from Germany and three from the USA) (Johnson et al., 2014; Müller et al., 2014). The main characteristics of patients reported with CHCHD10 mutations and FTD-ALS clinical spectrum have been summarized in Table 1. The additional German family reported by Kurzwelly et al. highlights several important clinical points that are of diagnostic significance. First, all patients exhibited upper limb onset, spasticity and bulbar signs rather late in the disease course, similar to the affected patients from the two other reported German families carrying the p.Arg15Leu mutation (Müller et al., 2014). In our original paper in Brain, which first established a pathological link between CHCHD10 mutations and FTD-ALS, we performed in-depth phenotyping of an extensive French family that was found to carry the p.Ser59Leu mutation (Bannwarth et al., 2014). We subsequently identified CHCHD10 mutations in three other unrelated probands presenting with FTD and ALS phenotypes (Chaussenot et al., 2014). Interestingly, in all four of these independent families, the clinical presentation was characterized by early and predominant bulbar symptoms, in marked contrast to the German family reported by Kurzwelly et al. (2015) in their letter. Despite a lack of detailed clinical information on the three families reported by Johnson et al. (2014), Kurzwelly et al. (2015) suggested that the three German families share a common disease phenotype with predominant upper limb manifestations. However, this clinical presentation is not specific to the p.Arg15Leu mutation because Ronchi et al. (2015) described an Italian patient, carrying the p.Pro80Leu mutation, who developed a flail-arm syndrome with sparing of both the bulbar and lower limb muscles.

Issue Section:
Letters to the Editor
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