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J Neurol. 2018 Dec 4. doi: 10.1007/s00415-018-9137-8. [Epub ahead of print]

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

Author information

1
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
2
Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Helsinki, Finland.
3
Department of Molecular and Cellular Genetics, CNRS, GMGM-UMR7156, Université de Strasbourg, Strasbourg, France.
4
Department of Pathology, HUSLAB and University of Helsinki, Helsinki, Finland.
5
Division of Clinical Neurosciences, Turku University Hospital, University of Turku, Turku, Finland.
6
Department of Neurology, Neuromuscular Research Center, University Hospital and University of Tampere, Tampere, Finland.
7
Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
8
Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
9
Neurology Department, Vasa Central Hospital, Vaasa, Finland.
10
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. henna.tyynismaa@helsinki.fi.
11
Department of Clinical and Medical Genetics, University of Helsinki, Helsinki, Finland. henna.tyynismaa@helsinki.fi.

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.

KEYWORDS:

Exome sequencing; Limb-girdle muscular dystrophy; Myopathy; PYROXD1

PMID:
30515627
DOI:
10.1007/s00415-018-9137-8

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