Annie Verschueren

A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.

Mutations of the FHL1 Gene Cause Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias. So far, only 35% of EDMD cases are genetically elucidated and associated with EMD or LMNA gene mutations, suggesting the existence of additional major genes. By whole-genome scan, we identified linkage to the Xq26.3 locus containing the FHL1 gene in three informative families belonging to our EMD- and LMNA-negative cohort. Analysis of the FHL1 gene identified seven mutations, in the distal exons of FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families. Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy. Interestingly, four of the FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two. Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available. In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy.

Multifocal motor neuropathy with and without conduction block A single entity

Objective: To assess if multifocal motor neuropathy (MMN) with and MMN without conduction block (CB) are similar or distinct diseases. Methods: The authors reviewed the clinical features and responses to IV immunoglobulin (IVIg) treatment of patients with MMN with and without CB at diagnosis, after 4 years of follow-up and at the last examination. They included all patients showing clinical features of MMN who had been followed for at least 4 years: All had asymmetric purely motor weakness with a peripheral nerve distribution, without any sensory, bulbar, or respiratory signs and without any upper motor neuron involvement. Results: Twenty patients had CB and 13 had no CB. Median follow-up time was 7 years. There were no differences between the two groups in term of age, sex, time from onset to diagnosis, anti-GM1 antibody titers, or CSF data. Nerve distribution, number of affected limb regions, predominant weakness in distal upper extremities, asymmetric weakness, cramps, fasciculations, and Medical Research Council sum-scores in upper and lower limbs were comparable at diagnosis, 4 years of follow-up, and last examination. Few significant differences were observed. Involvement of median nerve was less frequent at 4 years of follow-up (14/20 vs 4/13; p = 0.027) and at the last examination (17/20 vs 5/13; p = 0.009) in patients without CB. Proximal weakness was less frequent in patients with MMN without CB at the last examination (7/20 vs 0/13; p = 0.027). Fewer nerves were involved in patients without CB at the last examination (4.5 vs 2; p = 0.04). Efficacy of IVIg was similar in MNN patients without CB (8/13) and with CB (14/20; p > 0.05). Conclusion: After a median follow-up time of 7 years, patients with and without conduction block showed similar clinical features and a similar response to IV immunoglobulin treatment.

Lewis-Sumner syndrome and multifocal motor neuropathy.

We compared the clinical, electrophysiological, laboratory, and pathological features of 13 patients with Lewis–Sumner syndrome (LSS) with those of 20 patients with multifocal motor neuropathy (MMN). LSS and MMN patients have several common clinical features: age at onset, weakness in the distribution of individual peripheral nerves, mild wasting, cramps and fasciculations, partial areflexia, and frequent stepwise disease course. Cerebrospinal fluid protein level was normal or slightly elevated, but always less than 100 mg/dl. Conduction blocks are the electrophysiological hallmarks of these two neuropathies, and no differences in distribution and number of blocks were found. Contrary to MMN, lower‐limb involvement at onset was frequent in LSS but extension to the upper limbs was a frequent later feature of the disease. Cranial nerve involvement was noted in 4 LSS patients during relapses and absent in all MMN patients. The major distinguishing features were the clinical and electrophysiological sensory involvement in LSS, and the lack of anti‐GM1 antibodies in LSS, whereas IgM anti‐GM1 were found in 40% of MMN patients. Some LSS patients responded to steroid therapy, whereas this was ineffective in MMN. From these features, LSS can be considered an entity distinct from MMN, with its own clinical, laboratory, and electrophysiological characteristics, and as an intermediate link between chronic inflammatory demyelinating polyneuropathy and MMN. Muscle Nerve, 2005

Reply: CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis

Sir, We read with interest the paper recently published in Brain (Bannwarth et al. , 2014) reporting a mutation in CHCHD10 (c.176C > T, p.Ser59Leu) in familial amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Interestingly, the mutated patients also showed signs of muscle mitochondrial pathology consisting of cytochrome c oxidase (COX)-negative fibres, ultrastructural mitochondrial abnormalities, impaired respiratory chain activity, and altered mitochondrial DNA (mtDNA) maintenance (multiple deletions). Additional CHCHD10 mutations were reported by Muller et al. (2014) who identified the c.44C > A variant (p.Arg15Leu) in two German familial ALS cases and the variant c.197C > A (p.Gly66Val) in a Finnish patient with familial motor neuron disease with predominant lower motor neuron involvement. Chaussenot et al. (2014) screened CHCHD10 in a cohort of 80 French patients with sporadic FTD-ALS, disclosing the p.Pro34Ser mutation in two independent subjects. Mutated patients also featured sensorineural hypoacusia typically associated with mitochondrial disease, but mitochondrial dysfunction was not formally documented. Finally Johnson et al. (2014) investigated 85 independent North American cases with familial ALS, reporting the p.Arg15Leu mutation in three of them. Here we report clinical, biochemical, and molecular findings of an Italian patient affected by sporadic early-onset ALS and muscle mitochondrial pathology associated with a novel CHCHD10 mutation. Moreover we investigated a cohort of Italian sporadic ALS patients, supporting the modest, but not negligible causative role of CHCHD10 variations. We previously found severe histochemical COX deficiency in 7 of 50 muscle biopsies from patients with sporadic ALS (Crugnola et al. , 2010). Sequence analysis of ALS-related genes was negative in all patients but two (SOD1: p.Gln22Arg and TDP43: p.Ala382Thr). We sequenced CHCHD10 coding regions in the remaining five patients, disclosing the novel heterozygous transition c.239C > T in exon 2, resulting in the amino acid change p.Pro80Leu, in one of them (Fig. 1 …

Magnetic stimulation using a triple-stimulation technique in patients with multifocal neuropathy without conduction block

It has been suggested previously that multifocal motor neuropathy (MMN) without conduction block (CB) or other features of demyelination is axonal in nature. Conventional transcranial magnetic stimulation (TMS) and the triple‐stimulation technique (TST) performed on 10 MMN patients without CB revealed a proximal focal CB in 4 patients. In 3 other patients, the amplitude ratio obtained in response to conventional TMS was abnormally low, but the area ratio was normal. The TST amplitude ratio and area ratio were normal in these 3 patients. This pattern suggested the occurrence of temporal dispersion without CB. The occurrence of temporal dispersion or CB was associated with a relatively satisfactory response to intravenous immunoglobulins. These findings suggest that some forms of MMN previously thought to be axonal are in fact proximal variants of MMN with CB. Muscle Nerve, 2005

Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy

Objective: To determine the responses to treatment of patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies. Methods: Patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies followed in our department for at least 12 months between 2001 and 2008 were identified and studied retrospectively. Patients were tested at regular intervals using the INCAT disability score. Patients whose disability scores improved by at least one point were taken to have responded to the treatment. Intravenous immunoglobulin (IVIg; 2 g/kg) was administered for 3 to 5 days once every 6 weeks or corticosteroids at an initial daily dose of 1 mg/kg. Results: 13 patients treated during the 8-year period of interest were included in this study. Seven of 13 patients displayed IgM anti-GQ1b, GT1b and GD3 antibodies suggesting reactivity against disialosyl epitope. IgM gammopathy was detected in four of six of serum with anti-disialosyl antibodies and two of the seven other sera. Nine of the 13 patients improved in response to IVIg. Oral corticosteroid treatment was attempted on four patients prior to IVIg treatment, and partial recovery occurred in one, who became steroid-dependent and showed little benefit in the long term. Conclusions: Screening for anti-GD1b IgM antibodies should be carried out on all patients with chronic ataxic sensory neuropathies. In 69% of the cases studied, the patients’ condition improved in response to IVIg. This study shows the short-term efficiency of this treatment. Sustained responses were obtained in the long term by continuing the infusions.

Modafinil for the Treatment of Hypersomnia Associated With Myotonic Muscular Dystrophy in Adults: A Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled, 4-Week Trial

BACKGROUND Myotonic muscular dystrophy type 1 (MMD1) is the most common form of adult MD, with a mean prevalence of 1 in 8000. Excessive daytime sleepiness (ie, hypersomnia) is a common complication of MMD1. OBJECTIVE The aim of this study was to evaluate the efficacy and tolerability of modafinil for the treatment of hypersomnia in adults with MMD1. METHODS This multicenter, prospective, randomized, double-blind, placebo-controlled study consisted of a prerandomization period (90 to 2 days before randomization) and a 4-week randomization period in which patients were assigned to receive either active treatment (modafinil 300 mg/d) or placebo. The study was conducted at 3 clinics in France between February 2000 and June 2002. Adult patients aged > or =18 years, with genetically proven MMD1, an Epworth Sleepiness Scale (ESS) score >10, and a mean latency to sleep onset < or =8 minutes measured by the Multiple Sleep Latency Test (MSLT) were eligible. The primary efficacy end point was the Maintenance of Wakefulness Test (MWT) score at 4 weeks. Secondary end points included the mean MSLT score and scores from the ESS, physicians assessment of the therapeutic effect and the patients global self-assessment via visual analog scale, the 17-item Hamilton Depression Rating Scale, and the Short Form Health Survey (SF-36) quality-of-life assessment. RESULTS A total of 28 patients (15 men, 13 women; mean [SD] age, 40 [12.7] years [range, 18-69 years]; 100% white; modafinil group, 13; placebo group, 15) completed the study without protocol violations. Of the 28 patients with MMD1 included in the analysis, 21 had adult-onset MMD1. At 4 weeks, the mean MWT score was 16.4 (3.3) minutes in the modafinil group and 15.8 (3.8) minutes in the placebo group (P = NS). At the end of the randomization period, there were no significant between-group differences in any secondary outcome. A total of 8 patients (4 in each group) reported > or =1 adverse event, including digestive, neurologic, and skin symptoms. Weight loss was reported in 1 patient (2 kg). CONCLUSION In this small study conducted in an adult population with MMD1 and a high prevalence of hyper-somnia, modafinil had no significant effects on daytime somnolence measured using objective MWTs.

ALS with respiratory onset: Clinical features and effects of non-invasive ventilation on the prognosis

Abstract Respiratory muscle involvement is one of the main prognostic factors in amyotrophic lateral sclerosis (ALS). Acute respiratory failure is sometimes the first manifestation of the disease, although onset can be more insidious. In the present retrospective study, it was proposed to review the clinical features and to assess the effects of non-invasive ventilation (NIV) on the prognosis of patients with respiratory onset, which was taken to be present when the first symptoms of muscular weakness were dyspnoea at exertion, dyspnoea at rest, or orthopnoea. Respiratory onset ALS is uncommon, since it accounts for less than 3% of ALS cases. ALS with respiratory onset has some common clinical features: male predominance, frequent camptocormia or dropped head, frequent widespread fasciculations, limb mobility fairly well preserved and significant weight loss in the early stages. ALS patients with respiratory onset still have a poor prognosis compared with those with bulbar or spinal forms. NIV should be proposed promptly because it improves the symptoms, general state of health and survival time. Efforts should be made to inform general practitioners and chest physicians and remind them that neuromuscular respiratory insufficiency may be attributable to this particular form of ALS.

Magnetic stimulation including the triple-stimulation technique in amyotrophic lateral sclerosis.

To study the relative importance of upper motor neuron (UMN) dysfunction in the weakness of amyotrophic lateral sclerosis (ALS) and to compare the sensitivity of several transcranial magnetic stimulation (TMS) parameters as means of assessing UMN impairment in ALS, we used TMS to evaluate one upper limb of 63 patients. The triple‐stimulation technique (TST) and silent period (SP) were found to be the most frequently abnormal parameters (55.6% and 47.6%, respectively), without significant difference in their diagnostic sensitivity. The SP was found to be a useful parameter in patients with suspected or possible ALS. A positive correlation was found between weakness and the TST amplitude ratio, indicating that weakness may partly be caused by UMN dysfunction. Thus, the TST provides a quantitative tool for assessing UMN conduction failure. When used in association with the SP, the TST provides a sensitive diagnostic tool for use on ALS patients. Muscle Nerve, 2007