Adult-Onset Limb-Girdle Phenotype Associated With a Homozygous PYROXD1 Variant: The Case of a North African Family
- 1DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, USA
- 2Medicine, Royal College of Surgeons in Ireland - Bahrain, Busaiteen, BHR
- 3Neurosciences, Hamad Medical Corporation, Doha, QAT
Abstract
Mutations in the pyridine nucleotide-disulfide oxide reductase domain-containing protein 1 (PYROXD1) gene are characteristically linked to early-onset congenital myofibrillar myopathy, typically presenting with generalized weakness, hypotonia, and respiratory insufficiency in infancy or early childhood. However, emerging evidence suggests phenotypic heterogeneity.
We report the case of a 45-year-old Tunisian woman, born to non-consanguineous parents, who presented with a slowly progressive limb-girdle muscular dystrophy (LGMD) phenotype; her older brother, subsequently confirmed to carry the same homozygous variant, had a similar but more severe clinical history of proximal weakness. The patient’s symptoms began at age 17 with running difficulties, progressing by age 35 to difficulty rising from a seated position and climbing stairs, and by age 45 to exertional dyspnea, dysphagia, and sleep-disordered breathing. Physical examination revealed a high-arched palate, scoliosis, joint hypermobility, limited ankle dorsiflexion, palatal weakness, and mild neck flexion weakness alongside a proximal-dominant limb-girdle pattern of weakness. Her brother showed a matching but more severe phenotype starting at age 12. Electrodiagnostic studies demonstrated normal nerve conduction and a non-irritable myopathy; serum creatine kinase was entirely normal, and pulmonary function testing revealed a restrictive ventilatory defect with mild obstructive sleep apnea on polysomnography. Clinical exome sequencing confirmed a pathogenic homozygous c.464A>G (p.Asn155Ser) mutation in the PYROXD1 gene in both affected siblings, with both parents confirmed as unaffected heterozygous carriers. This represents the first molecularly confirmed family with PYROXD1-related myopathy in Tunisia and North Africa, and only the second family identified across the African continent; a single unrelated Tunisian case harboring the same variant has also recently been reported.
This case expands the known clinical spectrum of PYROXD1 variants to include adult-onset LGMD-like presentations with respiratory and bulbar involvement, emphasizes the diagnostic utility of recognizing associated dysmorphic features (scoliosis, high-arched palate, nasal speech, and joint hypermobility), and highlights the pivotal role of comprehensive genomic testing in atypical adult myopathies.
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BibTeX
@article{alhatou2026adultonset,
title = {{Adult-Onset Limb-Girdle Phenotype Associated With a Homozygous PYROXD1 Variant: The Case of a North African Family}},
author = {Abraham Alhatou and Omar M Alhatou and Mohammed Alhatou},
journal = {Cureus},
year = {2026},
month = oct,
doi = {10.7759/cureus.117414},
url = {https://europepmc.org/article/PMC/PMC13728484},
note = {CC BY},
}
RIS
TY - JOUR
TI - Adult-Onset Limb-Girdle Phenotype Associated With a Homozygous PYROXD1 Variant: The Case of a North African Family
AU - Abraham Alhatou
AU - Omar M Alhatou
AU - Mohammed Alhatou
PY - 2026
DA - 2026/10/04
JO - Cureus
DO - 10.7759/cureus.117414
UR - https://europepmc.org/article/PMC/PMC13728484
AB - Mutations in the pyridine nucleotide-disulfide oxide reductase domain-containing protein 1 (PYROXD1) gene are characteristically linked to early-onset congenital myofibrillar myopathy, typically presenting with generalized weakness, hypotonia, and respiratory insufficiency in infancy or early childhood. However, emerging evidence suggests phenotypic heterogeneity. We report the case of a 45-year-old Tunisian woman, born to non-consanguineous parents, who presented with a slowly progressive limb-girdle muscular dystrophy (LGMD) phenotype; her older brother, subsequently confirmed to carry the same homozygous variant, had a similar but more severe clinical history of proximal weakness. The patient’s symptoms began at age 17 with running difficulties, progressing by age 35 to difficulty rising from a seated position and climbing stairs, and by age 45 to exertional dyspnea, dysphagia, and sleep-disordered breathing. Physical examination revealed a high-arched palate, scoliosis, joint hypermobility, limited ankle dorsiflexion, palatal weakness, and mild neck flexion weakness alongside a proximal-dominant limb-girdle pattern of weakness. Her brother showed a matching but more severe phenotype starting at age 12. Electrodiagnostic studies demonstrated normal nerve conduction and a non-irritable myopathy; serum creatine kinase was entirely normal, and pulmonary function testing revealed a restrictive ventilatory defect with mild obstructive sleep apnea on polysomnography. Clinical exome sequencing confirmed a pathogenic homozygous c.464A>G (p.Asn155Ser) mutation in the PYROXD1 gene in both affected siblings, with both parents confirmed as unaffected heterozygous carriers. This represents the first molecularly confirmed family with PYROXD1-related myopathy in Tunisia and North Africa, and only the second family identified across the African continent; a single unrelated Tunisian case harboring the same variant has also recently been reported. This case expands the known clinical spectrum of PYROXD1 variants to include adult-onset LGMD-like presentations with respiratory and bulbar involvement, emphasizes the diagnostic utility of recognizing associated dysmorphic features (scoliosis, high-arched palate, nasal speech, and joint hypermobility), and highlights the pivotal role of comprehensive genomic testing in atypical adult myopathies.
SN - 2168-8184
ER -