Genetic Cause
• Gene:PYCR1(Pyrroline-5-carboxylate reductase 1)
• Location:Chromosome 17q25.3
• Function:Catalyzes the final step in proline biosynthesis from pyrroline-5-carboxylate; critical for maintaining mitochondrial redox balance and connective-tissue integrity.
• Inheritance:Autosomal recessive — both alleles must be mutated.
Main Clinical Features
System Key Features
Skin & Connective Tissue Loose, redundant, inelastic skin (cutis laxa), wrinkled face, progeroid appearance, visible veins
Growth & Development Prenatal and postnatal growth retardation, failure to thrive
Neurologic Mild-to-moderate developmental delay, hypotonia, motor delay (often milder than ALDH18A1-related ARCL2A)
Musculoskeletal Joint hyperlaxity, scoliosis, pectus deformity
Craniofacial Prominent forehead, large ears, down-slanting palpebral fissures
Ocular Myopia, keratoconus, cataracts in some cases
Other Occasional cardiac or pulmonary involvement; mitochondrial dysfunction in fibroblasts
Prevalence
• Extremely rare, with <100 molecularly confirmed cases reported worldwide.
• Reported in diverse populations (Europe, Middle East, Asia).
• Likely underdiagnosed due to overlapping features with other ARCL types.
Pathophysiology
Loss of PYCR1 activity leads to:
• Reduced proline biosynthesis
• Impaired mitochondrial function and stress resistance
• Abnormal elastic-fiber formation in skin and connective tissue.
Differential Diagnosis
• ARCL2A (ATP6V0A2 mutations) – often with severe neurological impairment and abnormal glycosylation.
• ALDH18A1-related ARCL – more severe progeroid phenotype, often lethal early.
• EFEMP2, FBLN5, ELN mutations – other cutis laxa subtypes.
PYCR1