A clinical and genetic study of the skeletal muscle channelopathies

The skeletal muscle channelopathies are a group of inherited muscle diseases characterised by the abnormal functioning of voltage-gated ion channels expressed in skeletal muscle. They manifest as the non-dystrophic myotonias and the periodic paralyses. This thesis increases the current understanding of the clinical and genetic basis of this group of diseases. It identifies the overall prevalence in England as 1.12/100,000 and determines the individual minimum prevalence of each disease, which has not previously been documented. It presents a detailed phenotype study of periodic paralysis (PP), paramyotonia congenita (PMC) and sodium channel myotonia (SCM), which is the first comparative study of these diseases. In the process it uncovers the marked similarity between PMC and SCM and suggests that these may be a spectrum of one disease, rather than two distinct diseases as traditionally thought. It provides the first systematic study of pregnancy and anaesthetics in a large number of channelopathy patients, identifying a marked increase in severity of symptoms during pregnancy that has not previously been documented. To widen the spectrum of genetic diagnosis and techniques in this group of diseases, this thesis describes the first cases of large scale rearrangements in CLCN1 causing myotonia congenita. It demonstrates how, using whole exome sequencing, the genetic diagnosis rate can be improved and illustrates two cases that may be explained by variations in RYR1 and another case in which a genetic diagnosis of Liddle’s syndrome may underlie secondary PP. This suggests that RYR1 variations may account for some unconfirmed cases and others may be explained by genetic causes of secondary PP. Finally this thesis presents convincing evidence of the efficacy of mexiletine in non-dystrophic myotonia in a double-blind placebo-controlled trial. It demonstrates improvement of the primary outcome measure of patient-reported stiffness and the majority of secondary outcome measures assessed

Muscle MRI reveals distinct abnormalities in genetically proven non-dystrophic myotonias.

We assessed the presence, frequency and pattern of MRI abnormalities in non-dystrophic myotonia patients. We reviewed T1-weighted and STIR (short-tau-inversion-recovery) 3T MRI sequences of lower limb muscles at thigh and calf level in 21 patients with genetically confirmed non-dystrophic myotonia: 11 with CLCN1 mutations and 10 with SCN4A mutations, and 19 healthy volunteers. The MRI examinations of all patients showed hyperintensity within muscles on either T1-weighted or STIR images. Mild extensive or marked T1-weighted changes were noted in 10/21 patients and no volunteers. Muscles in the thigh were equally likely to be affected but in the calf there was sparing of tibialis posterior. Oedema was common in calf musculature especially in the medial gastrocnemius with STIR hyperintensity observed in 18/21 patients. In 10/11 CLCN1 patients this included a previously unreported "central stripe", also present in 3/10 SCN4A patients but no volunteers. Degree of fatty infiltration correlated with age (rho=0.46, p<0.05). Muscle MRI is frequently abnormal in non-dystrophic myotonia providing evidence of fatty infiltration and/or oedema. The pattern is distinct from other myotonic disorders; in particular the "central stripe" has not been reported in other conditions. Correlations with clinical parameters suggest a potential role for MRI as a biomarker

Prevalence study of genetically defined skeletal muscle channelopathies in England.

To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders

A new explanation for recessive myotonia congenita: exon deletions and duplications in CLCN1.

To assess whether exon deletions or duplications in CLCN1 are associated with recessive myotonia congenita (MC)