Adult-Onset Limb-Girdle Phenotype Associated With a Homozygous PYROXD1 Variant: The Case of a North African Family
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 nonirritable 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.