ANO5Gene Analysis in a Large Cohort of Patients with Anoctaminopathy: Confirmation of Male Prevalence and High Occurrence of the Common Exon 5 Gene Mutation

Abstract

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases.

Early‐onset limb‐girdle muscular dystrophy‐2L in a female athlete

“…Muscle biopsy revealed central nuclei and increased fiber size variability . The c.989dupT (p.Leu330Phefs*6) variant in exon 10 of ANO5 was also previously reported by Sarkozy et al in a man with a missense variant in exon 18 (c.2018A>G) at an evolutionarily conserved amino acid residue (p.Tyr673Cys) in the DUF590 domain that falls within an extracellular loop . This patient also had a later onset of symptoms at ∼age 39 years and had CK values that ranged from 2,666 to 4,200 IU/L, distal weakness, difficulty walking on his toes, muscle atrophy distally in the upper limbs, thighs, and calf muscles, as well as hand weakness and back twitching …”

“…Testing of these 2 exons is sufficient for molecular diagnosis in a majority of cases, particularly in individuals of northern or central European descent. Approximately 80% of variants in ANO5 lead to loss of function (splice, stop, and frameshift variants), whereas, only ∼20% of the variants described so far result in pathogenic missense variants …”

Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic

“…This mutation was found heterozygously in 3 patients, and subsequent sequencing analysis of all exons and adjacent intron regions detected the mutation p.(Arg758Lys) in two of them (Table 2). This mutation was described in combination with c.191dupA in other studies [24], [31] and the associated phenotypes corresponded to distal non-dysferlin Miyoshi myopathy, unlike our patient 88 whose phenotype matches rather LGMD2L (a detailed description of the phenotype of patient 89 was not available). Analysis for this mutation was subsequently performed in all LGMD2 patients with unconfirmed diagnosis at the DNA level, but it was not detected.…”

First Japanese case of muscular dystrophy caused by a mutation in the anoctamin 5 gene

“…The clinical phenotype of anoctaminopathy is not uniform. Indeed, patients carrying the homozygous c.191dupA mutation, the most common mutation in ANO5 , have often been diagnosed with various phenotypes including MMD, LGMD or an overlap of disease, and there is no obvious correlation between genotype and phenotype . Thus, it could be considered that acquired factors lead to muscular differences.…”

“…Muscular dystrophy caused by ANO5 mutations, termed anoctaminopathy, presents characteristic findings, such as late onset, slow progression and asymmetric muscle involvement. Although some patients with anoctaminopathy show isolated hyper‐CK‐emia or pseudometabolic myopathy, the phenotype of anoctaminopaty is typically classified as limb girdle muscular dystrophy type 2L (LGMD2L) or Miyoshi muscular dystrophy 3 (MMD3) …”