Peer-reviewed article
Adult-Onset Limb-Girdle Phenotype Associated With a Homozygous PYROXD1 Variant: The Case of a North African Family
Abraham Alhatou, Omar Mohammed Alhatou, Mohammed Alhatou ·
Summary
Written by AI, not yet AICS's view · claude-sonnet-5-5This is a clinical case report of a Tunisian family with a rare genetic muscle disease linked to the PYROXD1 gene. A 45-year-old woman and her older brother both carry the same variant and have slowly worsening muscle weakness. Their symptoms started in adolescence or early adulthood, not in infancy as is usual for this gene. The report argues that genetic testing is useful for unusual adult muscle disease. It is not about children's well-being or an intervention for children.
Key points
- PYROXD1 variants are usually linked to early-onset congenital myofibrillar myopathy.
- The woman's symptoms began at age 17 and her brother's at age 12, with a limb-girdle pattern of weakness.
- Both siblings carry a homozygous c.464A>G (p.Asn155Ser) variant, and both parents are unaffected carriers.
- This is the first molecularly confirmed PYROXD1 family in Tunisia and North Africa, and the second in Africa.
- Scoliosis, high-arched palate, nasal speech and joint hypermobility may help clinicians recognise the condition.
Limitations
It describes a single family, so it cannot show how common this presentation is or what treatments work. It focuses on adult clinical features and says nothing about child well-being, services or interventions.
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 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.