Recessive PYROXD1 mutations cause adult-onset limb-girdle-type muscular dystrophy

Abstract

Objective To describe adult-onset limb-girdle-type muscular dystrophy caused by biallelic variants in the PYROXD1 gene, which has been recently linked to early-onset congenital myofibrillar myopathy. Methods Whole exome sequencing was performed for adult-onset neuromuscular disease patients with no molecular diagnosis. Patients with PYROXD1 variants underwent clinical characterization, lower limb muscle MRI, muscle biopsy and spirometry. A yeast complementation assay was used to determine the biochemical consequences of the genetic variants. Results We identified four patients with biallelic PYROXD1 variants. Three patients, who had symptom onset in their 20s or 30s, were homozygous for the previously described p.Asn155Ser. The fourth patient, with symptom onset at age 49, was compound heterozygous for p.Asn155Ser variant and previously unknown p.Tyr354Cys. All patients presented with a LGMD-type phenotype of symmetric muscle weakness and wasting. Symptoms started in proximal muscles of the lower limbs, and progressed slowly to involve also upper limbs in a proximal-predominant fashion. All patients remained ambulant past the age of 60. They had restrictive lung disease but no cardiac impairment. Muscle MRI showed strong involvement of anterolateral thigh muscles. Muscle biopsy displayed chronic myopathic changes. Yeast complementation assay demonstrated the p.Tyr354Cys mutation to impair PYROXD1 oxidoreductase ability. Conclusion PYROXD1 variants can cause an adult-onset slowly progressive LGMD-type phenotype. Electronic supplementary material The online version of this article (10.1007/s00415-018-9137-8) contains supplementary material, which is available to authorized users.

Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing

“…Imaging, echocardiography and pulmonary function testing of Patient II‐1 confirmed similarities between the 10 reported patients with PYROXD1 ‐related myopathy. Patient II‐1 had relative sparing of the rectus femoris and hip adductor group from atrophy on MRI consistent with MRI findings of other affected patients . Therefore, sparing of these muscle groups may be a common sign in PYROXD1 ‐associated myopathy.…”

“…described one patient with mild septal and anteroseptal dyskinesia . However, the majority of patients with PYROXD1 ‐associated myopathy (including the patients reported in this paper) did not show signs of cardiomyopathy even at advanced age . Thus, while future patients may benefit from periodic monitoring for cardiomyopathy, cardiomyopathy does not appear to be common in PYROXD1 ‐associated myopathy.…”

“…originally reported facial weakness, nasal speech and hyporeflexivity as universal features in the first nine patients with PYROXD1 ‐related autosomal recessive myopathy . However, these features have not been consistently reported in other patients with PYROXD1 ‐associated myopathy …”

“…Myopathy associated with PYROXD1 pathogenic variants was initially described with an onset in infancy or childhood, although adult‐onset myopathy has also been reported (Table S1). Cardiomyopathy and restrictive lung disease have also been reported in PYROXD1 ‐associated myopathy, although these phenotypes are variable …”

“…In the previously reported and unrelated families affected by myopathy, both compound heterozygous and homozygous variants in PYROXD1 including loss‐of‐function variants were reported. Causal variants identified to date include splice‐site mutations (c.285+1G>A and c.414+1G>A), missense variants (p.Asn155Ser, p.Tyr354 and p.Gly372His), frameshift variants (c.1159_1160insCAAA, p.Ala387fs*13) and a deep intronic variant (c.415‐976A>G) . The c.464A>G single nucleotide variant that is predicted to result in a nonsynonymous change p.Asn155Ser is observed in multiple independent families.…”