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Clinical and molecular findings in a cohort of ANO5-related myopathy.

ABSTRACT: OBJECTIVE:ANO5-related myopathy is an important cause of limb-girdle muscular dystrophy (LGMD) and hyperCKemia. The main descriptions have emerged from European cohorts, and the burden of the disease worldwide is unclear. We provide a detailed characterization of a large Brazilian cohort of ANO5 patients. METHODS:A national cross-sectional study was conducted to describe clinical, histopathological, radiological, and molecular features of patients carrying recessive variants in ANO5. Correlation of clinical and genetic characteristics with different phenotypes was studied. RESULTS:Thirty-seven patients from 34 nonrelated families with recessive mutations of ANO5 were identified. The most common phenotype was LGMD, observed in 25 (67.5%) patients, followed by pseudometabolic presentation in 7 (18.9%) patients, isolated asymptomatic hyperCKemia in 4 (10.8%) patients, and distal myopathy in a single patient. Nine patients presented axial involvement, including one patient with isolated axial weakness. The most affected muscles according to MRI were the semimembranosus and gastrocnemius, but paraspinal and abdominal muscles, when studied, were involved in most patients. Fourteen variants in ANO5 were identified, and the c.191dupA was present in 19 (56%) families. Sex, years of disease, and the presence of loss-of-function variants were not associated with specific phenotypes. INTERPRETATION:We present the largest series of anoctaminopathy outside Europe. The most common European founder mutation c.191dupA was very frequent in our population. Gender, disease duration, and genotype did not determine the phenotype.

SUBMITTER: Silva AMS

PROVIDER: S-EPMC6649425 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Clinical and molecular findings in a cohort of ANO5-related myopathy.

Silva André M S AMS Coimbra-Neto Antônio R AR Souza Paulo Victor S PVS Winckler Pablo B PB Gonçalves Marcus V M MVM Cavalcanti Eduardo B U EBU Carvalho Alzira A D S AADS Sobreira Cláudia F D R CFDR Camelo Clara G CG Mendonça Rodrigo D H RDH Estephan Eduardo D P EDP Reed Umbertina C UC Machado-Costa Marcela C MC Dourado-Junior Mario E T MET Pereira Vanessa C VC Cruzeiro Marcelo M MM Helito Paulo V P PVP Aivazoglou Laís U LU Camargo Leonardo V D LVD Gomes Hudson H HH Camargo Amaro J S D AJSD Pinto Wladimir B V D R WBVDR Badia Bruno M L BML Libardi Luiz H LH Yanagiura Mario T MT Oliveira Acary S B ASB Nucci Anamarli A Saute Jonas A M JAM França-Junior Marcondes C MC Zanoteli Edmar E

Annals of clinical and translational neurology 20190611 7

<h4>Objective</h4>ANO5-related myopathy is an important cause of limb-girdle muscular dystrophy (LGMD) and hyperCKemia. The main descriptions have emerged from European cohorts, and the burden of the disease worldwide is unclear. We provide a detailed characterization of a large Brazilian cohort of ANO5 patients.<h4>Methods</h4>A national cross-sectional study was conducted to describe clinical, histopathological, radiological, and molecular features of patients carrying recessive variants in AN ...[more]

PMID: 31353849

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Project description:Importance:YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives:To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants:An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. Main Outcome and Measures:The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Results:Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes. Conclusions and Relevance:The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.

Project description:Oculopharyngodistal myopathy (OPDM) is an extremely rare, adult-onset hereditary muscular disease characterized by progressive external ocular, pharyngeal, and distal muscle weakness and myopathological rimmed vacuole changes. The causative gene is currently unknown; therefore, diagnosis of OPDM is based on clinical and histopathological features and genetic exclusion of similar conditions. Moreover, variable manifestations of this disorder are reported in terms of muscle involvement and severity. We present the clinical profile and magnetic resonance imaging (MRI) changes of lower limb muscles in 14 mainland Chinese patients with OPDM, emphasizing the role of muscle MRI in disease identification and differential diagnosis. The patients came from 10 unrelated families and presented with progressive external ocular, laryngopharyngeal, facial, distal limb muscle weakness that had been present since early adulthood. Serum creatine kinase was mildly to moderately elevated. Electromyography revealed myogenic changes with inconsistent myotonic discharge. The respiratory function test revealed subclinical respiratory muscle involvement. Myopathological findings showed rimmed vacuoles with varying degrees of muscular dystrophic changes. All known genes responsible for distal and myofibrillar myopathies, vacuolar myopathies, and muscular dystrophies were excluded by PCR or targeted next-generation sequencing. Muscle MRI revealed that the distal lower legs had more severe fatty replacement than the thigh muscles. Serious involvement of the soleus and long head of the biceps femoris was observed in all patients, whereas the popliteus, gracilis and short head of biceps femoris were almost completely spared, even in advanced stages. Not only does our study widen the spectrum of OPDM in China, but it also demonstrates that OPDM has a specific pattern of muscle involvement that may provide valuable information for its differential diagnosis and show further evidence supporting the conclusion that OPDM is a unique disease phenotype.

Dataset Information

Clinical and molecular findings in a cohort of ANO5-related myopathy.

Publications

Clinical and molecular findings in a cohort of ANO5-related myopathy.

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