Phenotypical variability and atypical presentations in a French cohort of Andersen-Tawil syndrome.

BACKGROUND AND PURPOSE: Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized. METHODS: A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted. RESULTS: Thirty-five patients from 27 unrelated families carrying 17 different missense KCNJ2 mutations (four novel mutations) and a heterozygous KCNJ2 duplication are reported. The typical triad was observed in 42.9% of patients. Cardiac abnormalities were observed in 65.7%: 56.5% asymptomatic and 39.1% requiring antiarrhythmic drugs. 71.4% of patients exhibited dysmorphic features. Muscle symptoms were reported in 85.7%, amongst whom 13.3% had no cardiopathy and 33.3% no dysmorphic features. Periodic paralysis was present in 80% and was significantly more frequent in men. Common triggers were exercise, immobility and carbohydrate-rich diet. Ictal serum potassium concentrations were low in 53.6%. Of the 35 patients, 45.7% had permanent weakness affecting proximal muscles, which was mild and stable or slowly progressive over several decades. Four patients presented with exercise-induced pain and myalgia attacks. Diagnostic delay was 14.4 ± 9.5 years. ENMG long-exercise test performed in 25 patients (71.4%) showed in all a decremental response up to 40%. Muscle biopsy performed in 12 patients revealed tubular aggregates in six patients (associated in two of them with vacuolar lesions), dystrophic features in one patient and non-specific myopathic features in one patient; it was normal in four patients. DISCUSSION: Recognition of atypical features (exercise-induced pain or myalgia and permanent weakness) along with any of the elements of the triad should arouse suspicion. The ENMG long-exercise test has a high diagnostic yield and should be performed. Early diagnosis is of utmost importance to improve disease prognosis.

Case Report: A Novel AChR Epsilon Variant Causing a Clinically Discordant Salbutamol Responsive Congenital Myasthenic Syndrome in Two Egyptian Siblings.

Congenital myasthenic syndromes (CMS) are inherited disorders that lead to abnormal neuromuscular transmission. Post-synaptic mutations are the main cause of CMS, particularly mutations in CHRNE. We report a novel homozygous CHRNE pathogenic variant in two Egyptian siblings showing a CMS. Interestingly, they showed different degrees of extraocular and skeletal muscle involvement; both presented only a partial response to cholinesterase inhibitors, and rapidly and substantially ameliorated after the addition of oral ß2 adrenergic agonists. Here, we enlarge the genetic spectrum of CHRNE-related congenital myasthenic syndromes and highlight the importance of a ß2 adrenergic agonists treatment.

Diagnostic yield of a practical electrodiagnostic protocol discriminating between different congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) are a group of heterogeneous diseases of the neuromuscular junction. We report electrodiagnostic testing (EDX) and genetic findings in a series of 120 CMS patients tested with a simple non-invasive EDX workup with surface recording of CMAPs and 3Hz repetitive nerve stimulation of accessory, radial and deep fibular nerves. Five ENMG phenotypes were retrieved based on the presence or not of R-CMAPs and the distribution pattern of decremental CMAP responses which significantly correlated with genetic findings (p <0.00001). R-CMAPs were found in all COLQ-mutated patients (CMS1A) and Slow Channel CMS (SCCMS) (CMS1B). CMS1A exhibited greater decrements in accessory nerve RNS than CMS1B. Patients without R-CMAPs were classified into CMS2A (DOK7-, MUSK-, GFPT1-, GMPPB-, TOR1AIP-mutated) when exhibiting predominant accessory nerve RNS decrements, CMS2B (CHRNE, CHRND, RAPSN) with predominant radial nerve RNS decrements, or CMS2C (AGRN) if there were predominant fibular decrements. Our algorithm may have a major impact on diagnostic and therapeutic monitoring in CMS patients, as well as for validation of the pathogenicity of genetic variants. It should also be part of the evaluation of unexplained muscle weakness or complex neuromuscular phenotypes.

Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function.

Although mitochondrial DNA deletions have been shown to accumulate in cytochrome c oxidase deficient muscle fibres of ageing muscle, this has not been demonstrated for point mutations. In this study, we investigated the occurrence of mitochondrial DNA alterations (point mutations and deletions) in cytochrome c oxidase deficient muscle fibres from 14 individuals, without muscle disease, aged 69-82 years. Immunohistochemical investigation showed that the majority of the cytochrome c oxidase deficient muscle fibres expressed reduced levels of subunit II of cytochrome c oxidase, which is encoded by mitochondrial DNA, whereas there was normal or increased expression of subunit IV of cytochrome c oxidase, which is encoded by nuclear DNA. This pattern is typical for mitochondrial DNA mutations causing impaired mitochondrial translation. Single muscle fibres (109 cytochrome c oxidase deficient and 109 normal fibres) were dissected and their DNA extracted. Mitochondrial DNA point mutations were searched for in five tRNA genes by denaturing gradient gel electrophoresis while deletions were looked for by polymerase chain reaction amplification. High levels of clonally expanded point mutations were identified in eight cytochrome c oxidase deficient fibres but in none of the normal ones. They included the previously described pathogenic tRNALeu(UUR)A3243G and tRNALysA8344G mutations and three original mutations: tRNAMetT4460C, tRNAMetG4421A, and a 3-bp deletion in the tRNALeu(UUR) gene. Four different large-scale mitochondrial DNA deletions were identified in seven cytochrome c oxidase deficient fibres and in one of the normal ones. There was no evidence of depletion of mitochondrial DNA by in situ hybridisation experiments. Our data show that mitochondrial DNA point mutations, as well as large-scale deletions, are associated with cytochrome c oxidase deficient muscle fibre segments in ageing. Their focal accumulation causes significant impairment of mitochondrial function in individual cells in spite of low overall levels of mitochondrial DNA mutations in muscle.