ABSTRACT
BACKGROUND: Biallelic variants in Anoctamin 5 (ANO5) gene are causative of limb-girdle muscular dystrophy (LGMD) R12 anoctamin5-related, non-dysferlin Miyoshi-like distal myopathy (MMD3), and asymptomatic hyperCKemia. OBJECTIVE: To describe clinic, histologic, genetic and imaging features, of ANO5 mutated patients. METHODS: Five patients, four from France (P1, P2, P3 and P4) and one from Mexico (P5), from four families were included. P1 and P2, belonging to group 1, had normal muscle strength; Group 2, P3, P4 and P5, presented with muscular weakness. Muscle strength was measured by manual muscle testing, Medical Research Council (MRC) grades 1/5 to 5/5. Laboratory exams included serum CK levels, nerve conduction studies (NCS)/needle electromyography (EMG), pulmonary function tests, EKG and cardiac ultrasound. ANO5 molecular screening was performed with different approaches. RESULTS: Group 1 patients showed myalgias with hyperCKemia or isolated hyperCKemia. Group 2 patients presented with limb-girdle or proximo-distal muscular weakness. Serum CK levels ranged from 897 to 5000 UI/L. Muscle biopsy analysis in P4 and P5 showed subsarcolemmal mitochondrial aggregates. Electron microscopy confirmed mitochondrial proliferation and revealed discontinuity of the sarcolemmal membrane. Muscle MRI showed asymmetrical fibro-fatty substitution predominant in the lower limbs.P1 and P2 were compound heterozygous for c.191dupA (p.Asn64Lysfs*15) and c.1898â+âG>A; P3 was homozygous for the c.692G>T. (p.Gly231Val); P4 harbored a novel biallelic homozygous exons 1-7 ANO5 gene deletion, and P5 was homozygous for a c.172 Câ>âT (p.(Arg 58 Trp)) ANO5 pathogenic variant. CONCLUSIONS: Our cohort confirms the wide clinical variability and enlarge the genetic spectrum of ANO5-related myopathies.
Subject(s)
Anoctamins/genetics , Creatine Kinase/blood , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Muscular Diseases/physiopathology , Adult , Cohort Studies , Distal Myopathies/diagnosis , Distal Myopathies/genetics , France , Humans , Mexico , Muscle Weakness/diagnosis , Muscle Weakness/physiopathology , Muscular Atrophy/diagnosis , Muscular Atrophy/genetics , Muscular Dystrophies, Limb-Girdle/diagnosis , Muscular Dystrophies, Limb-Girdle/genetics , Mutation , Myalgia/diagnosis , Myalgia/physiopathology , PedigreeSubject(s)
Distal Myopathies/genetics , Rare Diseases/genetics , Biopsy , Brazil , Distal Myopathies/pathology , Female , Humans , Rare Diseases/pathology , Young AdultABSTRACT
We describe two Chilean patients with dysferlinopathy, a 32-year-old man with Miyoshi's distal myopathy and a 29-year-old woman with a proximodistal phenotype. Absence of dysferlin in frozen muscle biopsy allowed diagnostic confirmation. In these two patients, two mutations not previously identified in other populations were found: a homozygous c.1948delC (p.Leu650TyrfsX6) was found in the male patient; the heterozygous mutation c.1276G>A (p.Gly426Arg) was found in the female patient in association with the previously reported c.2858dupT (p.Phe954ValfsX2). To our knowledge, this is the first time that mutations in DYSF are identified in native Chileans. Our findings suggest the possibility that mutations in the DYSF gene were present in the Native American population before colonization.