Citations

ABSTRACTThe limb‐girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous, autosomal inherited muscular dystrophies with a childhood to adult onset, manifesting with hip‐ and shoulder‐girdle muscle weakness. When the term LGMD was first conceptualized in 1954, it was thought to be a single entity. Currently, there are 8 autosomal dominant (LGMD1A–1H) and 26 autosomal recessive (LGMD2A–2Z) variants according to the Online Mendelian Inheritance in Man database. In addition, there are other genetically identified muscular dystrophies with an LGMD phenotype not yet classified as LGMD. This highlights the entanglement of LGMDs, which represents an area in continuous expansion. Herein we aim to simplify the complexity of LGMDs by subgrouping them on the basis of the underlying defective protein and impaired function. Muscle Nerve 58: 167–177, 2018

Background and purposeCACNA1S encodes Cav1.1, a voltage sensor for muscle excitation−contraction coupling, which activates the ryanodine receptor 1 (RYR1) leading to calcium release from the sarcoplasmic reticulum. CACNA1S mutations cause hypokalemic periodic paralysis, malignant hyperthermia and congenital myopathy. RYR1 mutations result in congenital myopathy, malignant hyperthermia and rhabdomyolysis.MethodsThe aim was to describe a novel phenotype associated with a CACNA1S variant at a site previously linked to hypokalemic periodic paralysis.ResultsThe patient presented with fluctuating asymptomatic creatine kinase elevation after an episode of rhabdomyolysis but has no history of periodic paralysis. His muscle biopsy showed core‐like structures occurring mainly in type 2 fibers. He carries a novel Cav1.1 variant (p.Arg528Leu) affecting a highly conserved amino acid. Different mutations at the same location cause hypokalemic periodic paralysis.ConclusionThis case underscores the similarity between the phenotypes caused by mutations in two functionally linked proteins, RYR1 and Cav1.1.

AbstractBackgroundCongenital myopathies due to ryanodine receptor (RYR1) mutations are increasingly identified and correlate with a wide range of phenotypes, most commonly that of malignant hyperthermia susceptibility and central cores on muscle biopsy with rare reports of distal muscle weakness, but in the setting of early onset global weakness.MethodsWe report a case of a patient presenting with childhood onset hand stiffness and adult onset progressive hand weakness and jaw contractures discovered to have two variants in the RYR1 gene.ResultsThe patient manifested with distal upper limb weakness which progressed to involve the distal lower limb, proximal upper limb, as well as the face in addition to limited jaw opening. Creatine kinase was mildly elevated with EMG findings supporting a myopathy. Muscle biopsy showed features consistent with centronuclear myopathy. Whole exome sequencing revealed a novel heterozygous pathogenic variant in RYR1 (c.12315_12328delAGAAATCCAGTTCC, p.Glu4106Alafs*8), and a heterozygous missense variant (c.10648C>T, p.Arg3550Trp) of unknown significance in compound heterozygous state.ConclusionWe expand the spectrum of RYR1‐related myopathy with the description of a novel phenotype in an adult patient presenting with hand weakness and suggest considering RYR1 analysis in the diagnosis of distal myopathies.

Background and purpose Amyloid myopathy frequently occurs in the setting of systemic amyloidosis and less commonly in isolation (isolated amyloid myopathy). Anoctaminopathy‐5 and dysferlinopathy were recently recognized as causes of isolated amyloid myopathy. The present study aimed to characterize the isolated amyloid myopathy and to compare it with amyloid myopathy associated with systemic amyloidosis. Methods We searched the Muscle Laboratory database to identify patients with pathologically confirmed amyloid myopathy seen in neurology clinics between January 1998 and September 2016. Patients with monoclonal gammopathy, peripheral neuropathy, organomegaly or symptoms or pathologic evidence of amyloid deposition outside skeletal muscle were classified as having systemic amyloidosis‐associated myopathy. Results Fifty‐two patients were identified, including 14 with isolated amyloid myopathy (eight anoctaminopathy‐5, two dysferlinopathy and four genetically unknown) and 38 with systemic amyloidosis (32 immunoglobulin light‐chain amyloidosis, four familial amyloid polyneuropathy and two senile systemic amyloidosis). Compared with patients with systemic amyloidosis, patients with isolated amyloid myopathy had a younger age of onset (median, 41.5 vs. 65 years), no dysphagia (0% vs. 26%) or weight loss (0% vs. 26%), but more frequent calf atrophy (57% vs. 0%), small collections of inflammatory cells on muscle biopsy (43% vs. 0%) and asymptomatic hyper CK emia at onset (21% vs. 0%). All patients with isolated amyloid myopathy had creatine kinase (CK) values >2.5 times the upper limit of normal. Conclusions Isolated amyloid myopathy accounts for 27% of patients with amyloid myopathy, mostly due to anoctaminopathy‐5. There are various clinical and laboratory parameters that can help to differentiate isolated amyloid myopathy from systemic amyloidosis.

ABSTRACTIntroduction: A calpain‐3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb‐girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation. Methods: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain‐3 muscle Western blots were performed in 3 unrelated individuals. Results: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain‐3 expression was reduced. Discussion: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679–683, 2018

ABSTRACTIntroduction: Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults. Methods: We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease‐causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded. Results: We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult‐onset Pompe disease, myofibrillar myopathy, multi‐minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified. Conclusion: We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881–886, 2017