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This retrospective study evaluated the phenotypic and genotypic features of 14 patients with McArdle disease attending the West of Scotland adult muscle clinic. Although all patients experienced exercise-induced cramps, exercise intolerance and hyperCKaemia, only 71% (n = 10) experienced the second wind phenomenon, rhabdomyolysis and/or myoglobinuria. We observed a high rate of fixed muscle weakness (50%; n = 7), coronary artery disease (36%; n = 5), and psychological comorbidity (50%; n = 7). Although 79% had symptom onset in the first decade of life, the mean age at presentation and at genetic diagnosis was 43.8 years and 47.7 years, respectively. 93% had at least one copy of the common PYGM pathogenic variant, c.148C > T, p.(Arg50*), with 50% (n = 7) of the cohort being homozygous. Our cohort highlights the phenotypic variability seen in McArdle disease and underscores the potential for late-onset presentations. It emphasises the need for improved awareness and recognition of this condition amongst neurologists, rheumatologists and general physicians. A history of exercise intolerance and second wind phenomenon may not always be volunteered by the patient, underscoring the need to ask specific questions in clinic to extrapolate the relevant symptoms in this patient cohort., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Myotonic dystrophy type 1 (DM1) is a multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3'-untranslated region of the DMPK gene. The repeat expansion is somatically unstable and tends to increase in length with time, contributing to disease progression. In some individuals, the repeat array is interrupted by variant repeats such as CCG and CGG, stabilising the expansion and often leading to milder symptoms. We have characterised three families, each including one person with variant repeats that had arisen de novo on paternal transmission of the repeat expansion. Two individuals were identified for screening due to an unusual result in the laboratory diagnostic test, and the third due to exceptionally mild symptoms. The presence of variant repeats in all three expanded alleles was confirmed by restriction digestion of small pool PCR products, and allele structures were determined by PacBio sequencing. Each was different, but all contained CCG repeats close to the 3'-end of the repeat expansion. All other family members had inherited pure CTG repeats. The variant repeat-containing alleles were more stable in the blood than pure alleles of similar length, which may in part account for the mild symptoms observed in all three individuals. This emphasises the importance of somatic instability as a disease mechanism in DM1. Further, since patients with variant repeats may have unusually mild symptoms, identification of these individuals has important implications for genetic counselling and for patient stratification in DM1 clinical trials.

Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed., (2008 Wiley-Liss, Inc.)