Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation

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.

Table 1.

Review of studies reporting CHCHD10 mutations

	Bannwarth et al., 2014	Chaussenot et al., 2014	Müller et al., 2014	Johnson et al., 2014	Ajroud-Driss et al., 2015	Ronchi et al., 2015	Kurzwelly et al., 2015
Patients with CHCHD10 mutations (n)	8	3	5	6	10	3	4
Families (n)	1	3	3	3	1	3	1
FTD	7/8 (87.5%)	3/3 (100%)	–	–	–	–	–
MND onset/predominance	6/8 (75%)	3/3 (100%)	5/5 (100%)	6/6 (100%)	–	3/3 (100%)	4/4 (100%)
	Pseudobulbar	Pseudobulbar	Upper limbs (4/5)	?		Upper limbs (1/3)	Upper limbs
Cerebellar signs	Ataxia 5/8 (62.5%)	–	–	–	–	–	Oculomotor signs 1/4 (25%)
Parkinsonism	–	1/3 (33.3%)	–	–	–	–	–
Other symptoms	Ptosis, myopathy, deafness	Deafness	–	–	Myopathy, short stature	–	–
Age at onset (average)	49-65y	59-67 y	35-73 y	?	First decade	25-75 y	41-73 y
	(55.5)	(61.6)	(46.7)	(?)	(?)	(53)	(59.5)
Mean disease duration (min-max)	>10 y	?	10.7 y	?	>30 y	?	6.3 y
	(1-27 y)	(4-8 y)	(6-17 y)	(?)	(?)	(2-8 y)	(2-15 y)
Muscle biopsy (patients, n)	RRF, COX-(8/8)	ND	ND	ND	RRF, lipid accumulation	RRF, COX-(1/3)	ND
Penetrance	Complete	Insufficient information	Incomplete	?	Complete	NA	Complete
Mutations (families, n)	p.Ser59Leu (1/1)	p.Ser59Leu (1/3)	p.Arg15Leu (2/3)	p.Arg15Leu (3/3)	p.Arg15Ser / p.Gly58Arg in cis (1/1)	p.Pro80Leu (2/3)	p.Arg15Leu (1/1)
		p.Pro34Ser (2/3)	p.Gly66Val (1/3)			p.Pro34Ser (1/3)
Frequency of patients with CHCHD10 mutations in the studied disease cohorts	NA	3/115 FTD-ALS patients (2.6%)	3/128 patients with familial ALS (2.3%)	3/85 patients with familial ALS (3,5%)	NA	3/224 patients with sporadic ALS (1.3%)	NA

MND = motor neuron disease; ? = unknown; ND = not done; NA = not applicable; RRF = ragged-red fibres.

Second, patients from the French family that we described initially presented with a complex phenotype including motor neuron disease and cognitive decline but eventually, five of eight patients (nearly two-thirds) also developed cerebellar ataxia. This observation suggested that it might be useful to screen for CHCHD10 mutations in cases with familial ataxia. However, ataxia has not been reported in all the five series of non-French patients carrying CHCHD10 mutations that have been published subsequently. In the family described by Kurzwelly et al. (2015), one patient out of four exhibited cerebellar oculomoteur dysfunction but no other clinical signs of ataxia. With the caveat that large ataxia cohorts will need to be screened, the currently available data suggest that cerebellar ataxia is probably infrequent in disorders associated with CHCHD10 mutations.

The last point that we would like to make relates to the issue of incomplete penetrance raised by Müller et al. (2014) in their two German ALS families carrying the p.Arg15Leu mutation. In contrast, the family reported by Kurzwelly et al. was consistent with complete phenotypic penetrance given the absence of unaffected individuals transmitting the disease. In our French family carrying the Ser59Leu mutation, Individual II.3 was labelled as being asymptomatic due to the lack of detailed information at the time (Bannwarth et al., 2014). We have since obtained additional information regarding this CHCHD10 mutational female carrier who died after having developed a neurological illness, therefore suggesting complete penetrance in this French family as well. It can be difficult to ascertain true disease status in late-onset neurodegenerative disorders and it should, therefore, be noted that the age of unaffected individuals, who are still alive or who have died, were not specifically mentioned by Müller et al. (2014) in their two German ALS families.

In conclusion, it is becoming increasingly apparent that CHCHD10 mutations can present with a spectrum of clinical manifestations that can also vary in their chronological development. It shows that it is difficult for the time being to identify clinical criteria that can direct research towards CHCHD10 rather than to other genes associated with FTD and ALS clinical presentations. The p.Arg15Leu mutation seems to predominate in familial pure ALS and further studies will be necessary to clarify the intriguing hypothesis that this could be due to a mutational founder effect. Although functional analyses are still lacking that explain how CHCHD10 mutations eventually promote the emergence of motor neuron disorder, this new case report by Kurzwelly et al. (2015) further strenghtens the mechanistic link between primary mitochondrial dysfunction and ALS.

Funding

This work was made possible by grants to V.P-F. from the Association Française contre les Myopathies (AFM) and the Fondation pour la Recherche Médicale (FRM), to H.S. from National Institutes of Health (GM089853) and to A.B by the program “Investissements d’avenir” ANR-10-IAIHU-06, ‘The Programme Hospitalier de Recherche Clinique’ (to I.L.B.) and the 7th framework program of the European Union (FP7, E12009DD, Neuromics). P.Y.W.M. is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK). P.YWM also receives funding from Fight for Sight (UK) and the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration.