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

André M S Silva, Antônio R Coimbra-Neto, Paulo Victor S Souza, Pablo B Winckler, Marcus V M Gonçalves, Eduardo B U Cavalcanti, Alzira A D S Carvalho, Cláudia F D R Sobreira, Clara G Camelo, Rodrigo D H Mendonça, Eduardo D P Estephan, Umbertina C Reed, Marcela C Machado-Costa, Mario E T Dourado-Junior, Vanessa C Pereira, Marcelo M Cruzeiro, Paulo V P Helito, Laís U Aivazoglou, Leonardo V D Camargo, Hudson H Gomes, Amaro J S D Camargo, Wladimir B V D R Pinto, Bruno M L Badia, Luiz H Libardi, Mario T Yanagiura, Acary S B Oliveira, Anamarli Nucci, Jonas A M Saute, Marcondes C França-Junior, Edmar Zanoteli, André M S Silva, Antônio R Coimbra-Neto, Paulo Victor S Souza, Pablo B Winckler, Marcus V M Gonçalves, Eduardo B U Cavalcanti, Alzira A D S Carvalho, Cláudia F D R Sobreira, Clara G Camelo, Rodrigo D H Mendonça, Eduardo D P Estephan, Umbertina C Reed, Marcela C Machado-Costa, Mario E T Dourado-Junior, Vanessa C Pereira, Marcelo M Cruzeiro, Paulo V P Helito, Laís U Aivazoglou, Leonardo V D Camargo, Hudson H Gomes, Amaro J S D Camargo, Wladimir B V D R Pinto, Bruno M L Badia, Luiz H Libardi, Mario T Yanagiura, Acary S B Oliveira, Anamarli Nucci, Jonas A M Saute, Marcondes C França-Junior, Edmar Zanoteli

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.

Conflict of interest statement

Nothing to declare.

© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Muscle biopsy of patients with anoctaminopathy. Unspecific myopathic findings in patient #1.1 characterized by mild fiber size variability, increase in endomysial connective tissue, and increase in nuclei internalization (A) (H&E). More severe myopathic features (dystrophic aspect) in patient #2 (B) (H&E). Preserved muscle architecture with the presence of grouped necrotic fibers (C) (arrow heads) in patient #4; sparse necrotic fibers (D) in patient #26 (degeneration fiber with macrophagy indicated by the black arrowhead and without macrophagy indicated by the white arrowhead) (H&E). Bar = 50 µm (A, B and C); Bar = 20 µm (D).
Figure 2
Figure 2
The heatmap for muscle involvement in MRI, using the 5‐point scale for each muscle (right and left) of each patient. Muscles and patients were ordered in grade of severity based on the mean score of the muscle and patient. The score of a muscle in a patient is indicated by the color of the square. White squares mean that data are not available. R, right; L, left; LGMD, limb‐girdle muscular dystrophy; MMD3, Miyoshi‐like distal myopathy; NA, not available
Figure 3
Figure 3
Typical MRI findings of ANO5‐related myopathy. (A and B) Axial T1‐weighted images of the thighs reveal striking involvement of the posterior compartment (mainly the semimembranosus and the adductors) in patient #7; black asterisks in A show bilateral fatty degeneration of the adductors, and the white asterisk in A shows asymmetrical involvement of the semitendinosus. White asterisks in B show asymmetrical sparing of the short head of the left biceps femoris. (C and D) Axial T1‐weighted images of the legs show bilateral fatty infiltration of the medial head of the gastrocnemius (white arrows in C) and asymmetrical involvement of the soleus (black asterisk in D) in patient #7. (E) Axial T1‐weighted image of the lumbar spine of patient #9 reveals severe fatty degeneration of the posterior paravertebral muscles (white arrow). (F) Coronal T1‐weighted image of the thighs in patient #15 shows a craniocaudal gradient of involvement (the distal portion of the quadriceps muscles is more affected than the proximal portion). (G and H) Axial T1‐weighted image of the thighs of patient #29.1 shows severe fatty infiltration of the quadriceps and the “undulating fascia” sign (white arrowhead) in G, and areas of hyperintensity indicate muscle edema (white head) in H (axial STIR‐weighted image)

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