Phenotypic Spectrum of Myopathies with Recessive Anoctamin-5 Mutations

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.1898 + G>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 C > T (p.(Arg 58 Trp)) ANO5 pathogenic variant. Conclusions: Our cohort confirms the wide clinical variability and enlarge the genetic spectrum of ANO5-related myopathies.

An integrated approach to the evaluation of patients with asymptomatic or minimally symptomatic hyperCKemia

“…39 In our analysis, the most frequent pathogenic variants were in the ANO5 gene, which were identified in eight patients. This finding is in line with those in previous reports, according to which ANO5-related muscle diseases frequently manifest in patients with a long-standing history of hyperCKemia without muscle weakness and commonly present in association with exercise intolerance, myalgia, and, more rarely, episodes of rhabdomyolysis, 40,41 in addition to the muscle biopsy not showing specific pathological signs. 42 Three patients presented with a pathogenic RYR1 variant, further confirming the frequency of this disorder in hyperCKemia patients.…”

ANO5-related muscle diseases: From clinics and genetics to pathology and research strategies

“…These clinical findings suggest that ANO5 should be considered as a candidate gene even if “only” one of the above-mentioned symptoms is present without further overt muscle symptoms such as manifest muscle weakness or -pain. 11 , 14 , 15 , 16 , 21 …”

“…So far, no pulmonary peculiarities including ventilatory failure or nocturnal hypoventilation have been identified in ANO5 -patients. 7 , 9 , 11 , 21 , 25 , 26 …”

“…Subsarcolemmal mitochondrial proliferation was also confirmed by electron microscopy. 21 However, it remains to be elucidated whether mitochondrial abnormalities are a common feature associated with recessive ANO5 -mutations.…”

Update Distale Myopathien

“…Darüber hinaus sind Patientinnen mit Mutationen im ANO5-Gen beschrieben, die mit einer HyperCKämie, Myalgien oder einer Hypertrophie der Wade ohne relevante weitere klinische Symptomatik einhergehen. In der Diagnostik zeigt sich eine deutlich erhöhte CK (10-fach erhöht), ein myopathisches Muster im EMG sowie in der Histologie ein myopathisches Gewebssyndrom mit nekrotischen Fasern 23 24 25 . Das MRT zeigt eine Beteiligung beider M. gastrocnemius (lateralis und medialis), des M. soleus, der Hüftadduktoren sowie der Quadrizepsgruppe 26 .…”