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We describe three patients with asymmetric congenital myopathy without definite nemaline bodies and one patient with severe nemaline myopathy. In all four patients, the phenotype had been caused by pathogenic missense variants in ACTA1 leading to the same amino acid change, p.(Gly247Arg). The three patients with milder myopathy were mosaic for their variants. In contrast, in the severely affected patient, the missense variant was present in a de novo, constitutional form. The grade of mosaicism in the three mosaic patients ranged between 20 % and 40 %. We speculate that the milder clinical and histological manifestations of the same ACTA1 variant in the patients with mosaicism reflect the lower abundance of mutant actin in their muscle tissue. Similarly, the asymmetry of body growth and muscle weakness may be a consequence of the affected cells being unevenly distributed. The partial improvement in muscle strength with age in patients with mosaicism might be due to an increased proportion over time of nuclei carrying and expressing two normal alleles., Competing Interests: Declaration of Competing Interest The authors declare no competing interests. Author MV is and stockholder of Invitae, and TLW is a former employee of Invitae., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Primary acetylcholine receptor deficiency is the most common subtype of congenital myasthenic syndrome, resulting in reduced amount of acetylcholine receptors expressed at the muscle endplate and impaired neuromuscular transmission. AChR deficiency is caused mainly by pathogenic variants in the ε-subunit of the acetylcholine receptor encoded by CHRNE, although pathogenic variants in other subunits are also seen. We report the clinical and molecular features of 13 patients from nine unrelated kinships with acetylcholine receptor deficiency harbouring the CHRNA1 variant NM_001039523.3:c.257G>A (p.Arg86His) in homozygosity or compound heterozygosity. This variant results in the inclusion of an alternatively-spliced evolutionary exon (P3A) that causes expression of a non-functional acetylcholine receptor α-subunit. We compare the clinical findings of this group to the other cases of acetylcholine receptor deficiency within our cohort. We report differences in phenotype, highlighting a predominant pattern of facial and distal weakness in adulthood, predominantly in the upper limbs, which is unusual for acetylcholine receptor deficiency syndromes, and more in keeping with slow-channel syndrome or distal myopathy. Finally, we stress the importance of including alternative exons in variant analysis to increase the probability of achieving a molecular diagnosis., Competing Interests: Declaration of interest We gratefully acknowledge the UK NHS National Highly Specialised Service for funding to the Diagnostic and Advisory service for CMS in Oxford. PMRC receives the support of a Junior Leader fellowship from “la Caixa” Foundation (ID 100010434) and from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648. The fellowship code is LCF/BQ/PI21/11830012. GR is supported by an NHMRC EL2 Fellowship (APP2007769). ASC receives BRC funding for clinical research activity and has received support for advisory work from Argenx. LGQ acknowledges a grant from FIS PI15/01898, funded by ISCIII and FEDER, ‘Una manera de hacer Europa’ and an ACCI grant from CIBERER. NGL was supported by Australian National Health and Medical Research Council Fellowship APP1117510 and Targeted Call for Research Grant APP1113531. HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). DB held MRC Programme Grant MR/M006824/1. JP has received support for advisory work from Argenx and Amplo Biotechnology. All other authors have no conflict of interest to declare that are relevant to the content of this article., (Copyright © 2022. Published by Elsevier B.V.)

The major advances in genetic neuromuscular disorders in the last 30 years have been: (a) identification of the genetic basis for hundreds of these disorders, (b) through knowing the genes, understanding their pathobiology and (c) subsequent implementation of evidence-based treatments for some of the disorders. New genomic technologies are providing precision diagnosis, mode of inheritance and likely prognosis for more patients than ever before. Parents of children with a genetic diagnosis can then use preimplantation or prenatal diagnosis to avoid having further affected children if they wish. But is this the best we can do for genetic neuromuscular disorders? Since the 1980s, it has been argued it would be better to identify Duchenne muscular dystrophy carrier mothers, rather than diagnose their affected sons. Carrier screening for recessive disorders can identify couples with a high chance of having affected children. It allows couples reproductive choice and can prevent infant morbidity and mortality and significant distress for families. Professional bodies in many countries now recommend prospective parents should be informed about carrier screening. Implementing and funding expensive therapies increases the cost-effectiveness of carrier screening, increasing its attractiveness to governments. Best practice for genetic neuromuscular disorders should include equitable access to carrier screening., Competing Interests: Declaration of Competing Interest None of the authors have any declarations of interest, (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cylindrical spirals are a rare ultrastructural finding on muscle biopsy, with fewer than 20 reported cases since its first description in 1979. These structures are sometimes observed with tubular aggregates and are thought to comprise longitudinal sarcoplasmic reticulum. While mutations in genes encoding key components of Ca 2+ handling (ORAI1 and STIM1) underlie tubular aggregate myopathy, no causative genes have been associated with cylindrical spirals. Here we describe two families with cylindrical spirals on muscle biopsy with a suspected genetic cause. In one family we identified a known truncating variant in EBF3, previously associated with a neurodevelopmental disorder. The affected individuals in this family present with clinical features overlapping with those described for EBF3 disease. An isolated proband in the second family harbours bi-allelic truncating variants in TTN and her clinical course and other features on biopsy are highly concordant for titinopathy. From experimental studies, EBF3 is known to be involved in Ca 2+ regulation in muscle, thus EBF3 dysregulation may represent a novel mechanism of impaired Ca 2+ handling leading to cylindrical spirals. Additional cases of EBF3 disease or titinopathy with cylindrical spirals need to be identified to support the involvement of these genes in the pathogenesis of cylindrical spirals., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Myopathies due to recessive MYH7 mutations are exceedingly rare, reported in only two families to date. We describe three patients from two families (from Australia and the UK) with a myopathy caused by recessive mutations in MYH7. The Australian family was homozygous for a c.5134C > T, p.Arg1712Trp mutation, whilst the UK patient was compound heterozygous for a truncating (c.4699C > T; p.Gln1567*) and a missense variant (c.4664A > G; p.Glu1555Gly). All three patients shared key clinical features, including infancy/childhood onset, pronounced axial/proximal weakness, spinal rigidity, severe scoliosis, and normal cardiac function. There was progressive respiratory impairment necessitating non-invasive ventilation despite preserved ambulation, a combination of features often seen in SEPN1- or NEB-related myopathies. On biopsy, the Australian proband showed classical myosin storage myopathy features, while the UK patient showed multi-minicore like areas. To establish pathogenicity of the Arg1712Trp mutation, we expressed mutant MYH7 protein in COS-7 cells, observing abnormal mutant myosin aggregation compared to wild-type. We describe skinned myofiber studies of patient muscle and hypertrophy of type II myofibers, which may be a compensatory mechanism. In summary, we have expanded the phenotype of ultra-rare recessive MYH7 disease, and provide novel insights into associated changes in muscle physiology., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nephropathic cystinosis is an autosomal recessive lysosomal disease in which cystine cannot exit the lysosome to complete its degradation in the cytoplasm, thus accumulating in tissues. Some patients develop a distal myopathy involving mainly hand muscles. Myopathology descriptions from only 5 patients are available in the literature. We present a comprehensive clinical, pathological and genetic description of 3 patients from 2 families with nephropathic cystinosis. Intrafamiliar variability was detected in one family in which one sibling developed a severe distal myopathy while the other sibling did not show any signs of skeletal muscle involvement. One of the patients was on treatment with Cysteamine for over 12 years but still developed the usual complications of nephropathic cystinosis in his twenties. Novel pathological findings consisting in sarcoplasmic deposits reactive for slow myosin were identified. Three previously known and one novel mutation are reported. Nephropathic cystinosis should be included in the differential diagnosis of distal myopathies in those with early renal failure. Novel clinical and pathological features are reported here contributing to the characterization of the muscle involvement in nephropathic cystinosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Autosomal dominant mutations of DYNC1H1 cause a range of neurogenetic diseases, including mental retardation with cortical malformations, hereditary spastic paraplegia and spinal muscular atrophy. Using SNP array, linkage analysis and next generation sequencing, we identified two families and one isolated proband sharing a known spinal muscular atrophy, lower extremity predominant (SMALED) causing mutation DYNC1H1 c.1792C>T, p.Arg598Cys, and another family harbouring a c.2327C>T, p.Pro776Leu mutation. Here, we present a detailed clinical and pathological examination of these patients, and show that patients with DYNC1H1 mutations may present with a phenotype mimicking a congenital myopathy. We also highlight features that increase the phenotypic overlap with BICD2, which causes SMALED2. Serial muscle biopsies were available for several patients, spanning from infancy and early childhood to middle age. These provide a unique insight into the developmental and pathological origins of SMALED, suggesting in utero denervation with reinnervation by surrounding intact motor neurons and segmental anterior horn cell deficits. We characterise biopsy features that may make diagnosis of this condition easier in the future., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Fetal akinesia deformation sequence is a clinically and genetically heterogeneous disorder characterized by a variable combination of fetal akinesia, intrauterine growth restriction, developmental abnormalities such as cystic hygroma, hydrops fetalis, pulmonary hypoplasia, occasional arthrogryposis, and pterygia. The pathogenetic mechanisms of fetal akinesia deformation sequence include neuropathy, muscular disorders, neuromuscular junction disorders, maternal myasthenia gravis, restrictive dermopathy and others. We here report an Egyptian family presenting with recurrent lethal multiple pterygium syndrome. The diagnosis was based on antenatal sonographic demonstration of complete fetal akinesia and a large cystic hygroma with severe limb contractures evident on postmortem examination. Next generation sequencing performed on the second affected fetus identified a novel homozygous essential splice-site variant in the nebulin gene. In conclusion, our report adds further evidence for the involvement of the nebulin gene in the etiology of fetal akinesia deformation sequence/lethal multiple pterygium syndrome., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1., (Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.)

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Myosin-heavy-chain 7 (MYH7)-myopathy manifests clinically with a distal, scapuloperoneal, limb-girdle (proximal), or axial distribution and may involve the respiratory muscles. Cardiac involvement is frequent, ranging from relaxation impairment to severe dilative cardiomyopathy. Progression and earlier onset of cardiac disease in successive generations with MYH7-myopathy is unreported. In a five-generation family MYH7-myopathy due to the novel c.5566G > A (p.E1856K) mutation manifested with late-onset, distal > proximal myopathy and variable degree of cardiac involvement. The index patient developed distal myopathy since age 49 y and anginal chest pain. Her mother had distal myopathy and impaired myocardial relaxation. The daughter of the index patient had discrete myopathy but left ventricular hypertrabeculation/noncompaction and ventricular arrhythmias requiring an implantable cardioverter defibrillator. The granddaughter of the index patient had infantile dilated cardiomyopathy without overt myopathy. Cardiac involvement may be present in MYH7-myopathy and may be progressive between the generations, ranging from relaxation abnormality to noncompaction, ventricular arrhythmias, and dilated cardiomyopathy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Over the past decade there have been major advances in defining the genetic basis of the majority of congenital myopathy subtypes. However the relationship between each congenital myopathy, defined on histological grounds, and the genetic cause is complex. Many of the congenital myopathies are due to mutations in more than one gene, and mutations in the same gene can cause different muscle pathologies. The International Standard of Care Committee for Congenital Myopathies performed a literature review and consulted a group of experts in the field to develop a summary of (1) the key features common to all forms of congenital myopathy and (2) the specific features that help to discriminate between the different genetic subtypes. The consensus statement was refined by two rounds of on-line survey, and a three-day workshop. This consensus statement provides guidelines to the physician assessing the infant or child with hypotonia and weakness. We summarise the clinical features that are most suggestive of a congenital myopathy, the major differential diagnoses and the features on clinical examination, investigations, muscle pathology and muscle imaging that are suggestive of a specific genetic diagnosis to assist in prioritisation of genetic testing of known genes. As next generation sequencing becomes increasingly used as a diagnostic tool in clinical practise, these guidelines will assist in determining which sequence variations are likely to be pathogenic., Competing Interests: We declare that the authors have no conflict of interest or financial relationship with this work., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

MYH7 mutations are an established cause of Laing distal myopathy, myosin storage myopathy, and cardiomyopathy, as well as additional myopathy subtypes. We report a novel MYH7 mutation (p.Leu1597Arg) that arose de novo in two unrelated probands. Proband 1 has a myopathy characterized by distal weakness and prominent contractures and histopathology typical of multi-minicore disease. Proband 2 has an axial myopathy and histopathology consistent with congenital fiber type disproportion. These cases highlight the broad spectrum of clinical and histological patterns associated with MYH7 mutations, and provide further evidence that MYH7 is likely responsible for a greater proportion of congenital myopathies than currently appreciated., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The clinically and genetically heterogenous foetal akinesias have low rates of genetic diagnosis. Exome sequencing of two siblings with phenotypic lethal multiple pterygium syndrome identified compound heterozygozity for a known splice site mutation (c.691+2T>C) and a novel missense mutation (c.956A>G; p.His319Arg) in glycogen branching enzyme 1 (GBE1). GBE1 mutations cause glycogen storage disease IV (GSD IV), including a severe foetal akinesia sub-phenotype. Re-investigating the muscle pathology identified storage material, consistent with GSD IV, which was confirmed biochemically. This study highlights the power of exome sequencing in genetically heterogeneous diseases and adds multiple pterygium syndrome to the phenotypic spectrum of GBE1 mutation., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We examined three patients with a severe infantile type of congenital myopathy due to dominant, missense ACTA1 mutations. In addition to muscle weakness, all three patients showed developmental delay in word comprehension during early childhood. All also showed frontal lobe hypoplasia and lateral ventricular dilatation. One patient in addition exhibited features of multiple congenital malformations including skeletal dysplasia, hepatomegaly and urinary tract stenosis. These findings may suggest a link between extramuscular expression of α-skeletal muscle actin and clinical symptoms in non-skeletal muscle tissues of patients with ACTA1 mutations, and probably a functional role of α-skeletal muscle actin during fetal development., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We describe a severe congenital myopathy patient of Xhosa native African origin with a novel de novo p.Gly152Ala skeletal muscle α-actin gene (ACTA1) mutation, who died at 6 months of age. The muscle pathology demonstrated abundant cytoplasmic and intranuclear rods, core-like areas and the unusual feature of larger type I than type II fibres. Our results further expand the phenotypes associated with ACTA1 mutations and provide support for the hypothesis that the structural abnormalities seen are a pathological continuum dependent on the precise mutation and biopsy location. Our results also demonstrate the likely world-wide distribution of de novo mutations in this gene., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)

We report a female newborn, diagnosed with fetal akinesia in utero, who died one hour after birth. Post-mortem muscle biopsy demonstrated actin-filament myopathy based on immunolabelling for sarcomeric actin, and large areas of filaments, without rod formation, ultrastructurally. Analysis of DNA extracted from the muscle disclosed a novel de novo heterozygous c.44G>A, GGC>GAC, 'p.Gly15Asp' mutation in the ACTA1 gene. Analysis of the location of the mutated amino-acid in the actin molecule suggests the mutation most likely causes abnormal nucleotide binding, and consequent pathological actin polymerization. This case emphasizes the association of fetal akinesia with actin-filament myopathy., (2010 Elsevier B.V. All rights reserved.)

In 2004, Anderson et al. reported a homozygous 2502 bp deletion including exon 55 of the nebulin gene in five Ashkenazi Jewish probands with nemaline myopathy. We determined the occurrence of this deletion in a world-wide series of 355 nemaline myopathy probands with no previously known mutation in other genes and found the mutation in 14 probands, two of whom represented families previously ascertained by Anderson et al. Two of the families were not of known Ashkenazi Jewish descent but they had the haplotype known to segregate with this mutation. In all but two of eight homozygous patients, the clinical picture was more severe than in typical nemaline myopathy.

As with many skeletal muscle diseases, the extraocular muscles (EOMs) are spared in skeletal muscle alpha-actin diseases, with no ophthalmoplegia even in severely affected patients. We hypothesised that the extraocular muscles sparing in these patients was due to significant expression of cardiac alpha-actin, the alpha-actin isoform expressed in heart and foetal skeletal muscle. We have shown by immunochemistry, Western blotting and a novel MRM-mass spectrometry technique, comparable levels of cardiac alpha-actin in the extraocular muscles of human, pig and sheep to those in the heart. The sparing of extraocular muscles in skeletal muscle alpha-actin disease is thus probably due to greater levels of cardiac alpha-actin, than the negligible amounts in skeletal muscles, diluting out the effects of the mutant skeletal muscle alpha-actin.

"Cap myopathy" or "cap disease" is a congenital myopathy characterised by cap-like structures at the periphery of muscle fibres, consisting of disarranged thin filaments with enlarged Z discs. Here we report a deletion in the beta-tropomyosin (TPM2) gene causing cap disease in a 36-year-old male patient with congenital muscle weakness, myopathic facies and respiratory insufficiency. The mutation identified in this patient is an in-frame deletion (c.415_417delGAG) of one codon in exon 4 of TPM2 removing a single glutamate residue (p.Glu139del) from the beta-tropomyosin protein. This is expected to disrupt the seven-amino acid repeat essential for making a coiled coil, and thus to impair tropomyosin-actin interaction. Missense mutations in TPM2 have previously been found to cause rare cases of nemaline myopathy and distal arthrogryposis. This mutation is one not previously described and the first genetic cause identified for cap disease.

Myosin storage myopathy/hyaline body myopathy is a rare congenital myopathy, with less than 30 cases reported in the literature. It is characterised by the presence of subsarcolemmal hyaline bodies in type 1 muscle fibres and predominantly proximal muscle weakness. Recently, a single mutation (Arg1845Trp) in the slow/beta-cardiac myosin heavy chain gene (MYH7) was identified in four unrelated probands from Sweden and Belgium. The clinical severity and age of onset was variable, despite the same disease-causing mutation and similar histological findings. Here, we report the clinical and morphological findings of two brothers of English/Scottish background with the Arg1845Trp mutation in MYH7. This case report adds to the clinical description of this rare disorder and confirms that Arg1845Trp is a common mutation associated with this phenotype, at least in the White European population.

Most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal muscle alpha-actin (ACTA1) genes. Here we report for the first time three patients with severe nemaline myopathy and mutations of the ACTA1 stop codon: TAG>TAT (tyrosine), TAG>CAG (glutamine) and TAG>TGG (tryptophan). All three mutations will cause inclusion of an additional 47 amino acids, translated from the 3' UTR of the gene, into the mature actin protein. Western blotting of one patient's muscle demonstrated the presence of the larger protein, while expression of one of the other mutant proteins fused to EGFP in C2C12 cells demonstrated the formation of rod bodies.

Myosin storage myopathy (OMIM 608358), a congenital myopathy characterised by subsarcolemmal, hyaline-like accumulations of myosin in Type I muscle fibres, was first described by Cancilla and Colleagues in 1971 [Neurology 1971;21:579-585] in two siblings as 'familial myopathy with probable lysis of myofibrils in type I muscle fibres'. Two mutations in the slow skeletal myosin heavy chain gene (MYH7) have recently been associated with the disease in other families. We have identified a novel heterozygous Leu1793Pro mutation in MYH7 in DNA from paraffin sections of one of the original siblings. This historical molecular analysis confirms the original cases had myosin storage myopathy.

Nemaline Myopathy with Intranuclear Rods is a rare variant of nemaline myopathy, due in almost all instances to mutation of ACTA1, the gene encoding skeletal muscle alpha-actin. We describe the novel autosomal dominant occurrence in a three-generation kindred, and review previously reported cases. Onset of myopathic symptoms in our kindred was in infancy or early childhood. Beyond infancy, limb muscle weakness was non-disabling and minimally progressive. A tall thin face and facial myopathy were prominent features in the affected adults. By light microscopy, muscle biopsies ranged from almost normal, to chronic myopathy with sarcoplasmic and intranuclear rods. A heterozygous GTG-ATG mutation (Val163Met) was found in exon 4 of ACTA1 in affected individuals. Actin is normally present within the nucleus in only trace amounts. Mutation at postion 163 may result in intranuclear rods by virtue of its close proximity to a nuclear export signal within the actin molecule.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide range of phenotypes, comprising central core disease and distinct subgroups of multi-minicore disease. We report muscle MRI findings of 11 patients from eight families with RYR1 mutations (n=9) or confirmed linkage to the RYR1 locus (n=2). Patients had clinical features of a congenital myopathy with a wide variety of associated histopathological changes. Muscle MR images showed a consistent pattern characterized by (a) within the thigh: selective involvement of vasti, sartorius, adductor magnus and relative sparing of rectus, gracilis and adductor longus; (b) within the lower leg: selective involvement of soleus, gastrocnemii and peroneal group and relative sparing of the tibialis anterior. Our findings indicate that patients with RYR1-related congenital myopathies have a recognizable pattern of muscle involvement irrespective of the variability of associated histopathological findings. Muscle MRI may supplement clinical assessment and aid selection of genetic tests particularly in patients with non-diagnostic or equivocal histopathological features.

We present comparisons of the clinical pictures in a series of 60 patients with nemaline myopathy in whom mutations had been identified in the genes for nebulin or skeletal muscle alpha-actin. In the patients with nebulin mutations, the typical form of nemaline myopathy predominated, while severe, mild or intermediate forms were less frequent. Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases. In the patients with actin mutations, the severe form of nemaline myopathy was the most common, but some had the mild or typical form, and a few showed other associated features such as intranuclear rods or actin accumulation. Most cases were sporadic, but in addition there were instances of both autosomal dominant and autosomal recessive inheritance, while two families showed mosaicism for dominant mutations. Although no specific phenotype was found to be associated with mutations in either gene, clinical and histological features together with pedigree data may be used in guiding mutation detection. Finding the causative mutation(s) determines the mode of inheritance and permits prenatal diagnosis if requested, but will not as such permit prognostication.

Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype-phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown.