Milone, Margherita

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

ABSTRACTIntroduction: Fluoxetine is a selective serotonin reuptake inhibitor and long‐lived open channel blocker of the acetylcholine receptor, often used in the treatment of slow‐channel congenital myasthenic syndromes (CMS). Methods: We report a 42‐year‐old woman who had a history of episodic limb weakness that worsened after initiation of fluoxetine for treatment of depression. Genetic testing for CMS revealed a homozygous pathogenic mutation in the rapsyn (RAPSN) gene (p.Asn88Lys). Electrodiagnostic testing was performed before and 1 month after discontinuation of fluoxetine. Results: The 2 Hz repetitive nerve stimulation of the fibular and spinal accessory nerves showed a baseline decrement of 36% and 14%, respectively. One month after discontinuing fluoxetine, the spinal accessory nerve decrement was no longer present, and the decrement in the fibular nerve was improved at 17%. Conclusions: This case demonstrates worsening of both clinical and electrophysiologic findings in a patient with CMS secondary to a RAPSN mutation treated with fluoxetine. Muscle Nerve 55: 131–135, 2017