RESUMEN
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.
Asunto(s)
Anoctaminas/genética , Creatina Quinasa/sangre , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/fisiopatología , Adulto , Estudios de Cohortes , Miopatías Distales/diagnóstico , Miopatías Distales/genética , Francia , Humanos , México , Debilidad Muscular/diagnóstico , Debilidad Muscular/fisiopatología , Atrofia Muscular/diagnóstico , Atrofia Muscular/genética , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , Mutación , Mialgia/diagnóstico , Mialgia/fisiopatología , LinajeAsunto(s)
Distrofia Muscular de Duchenne/epidemiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Comunicación Interdisciplinaria , Masculino , Martinica/epidemiología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Mutación , Estudios RetrospectivosRESUMEN
Primary dysferlinopathies are a group of recessive heterogeneous muscular dystrophies. The most common clinical presentations are Miyoshi myopathy and LGMD2B. Additional presentations range from isolated hyperCKemia to severe functional disability. Symptomatology begins in the posterior muscle compartment of the calf and its clinical course progresses slowly in Miyoshi myopathy whereas LGMD2B involves predominantly the proximal muscles of the lower limbs. The age of onset ranges from 13 to 60years in Caucasians. We present five patients that carry a novel mutation in the exon12/intron12 boundary: c.1180_1180+7delAGTGCGTG (r.1054_1284del). We provide evidence of a founder effect due to a common ancestral origin of this mutation, detected in heterozygosity in four patients and in homozygosity in one patient.