Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ1-pyrroline-5-carboxylate synthase (P5CS)

• Published in: American journal of medical genetics. Part A 2011-08, Vol.155A (8), p.1848-1856
• Main Authors: Skidmore, David L., Chitayat, David, Morgan, Tim, Hinek, Alek, Fischer, Bjoern, Dimopoulou, Aikaterini, Somers, Gino, Halliday, William, Blaser, Susan, Diambomba, Yenge, Lemire, Edmond G., Kornak, Uwe, Robertson, Stephen P.
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; ALDH18A1; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Cell Proliferation; Cells, Cultured; Consanguinity; Contracture - genetics; Cornea - abnormalities; Cornea - surgery; corneal clouding; Corneal Transplantation; cutis laxa; Cutis Laxa - diagnosis; Cutis Laxa - genetics; Face - abnormalities; Fatal Outcome; Frameshift Mutation; Heart Septal Defects, Ventricular - genetics; Homozygote; Humans; Infant, Newborn; Medical genetics; Medical sciences; Molecular Sequence Data; neurocutaneous; Ornithine-Oxo-Acid Transaminase - genetics; P5CS; Phenotype; premature aging; proline; RNA Splice Sites - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.34057

We report on the third case of cutis laxa and progeroid features caused by a homozygous mutation in ALDH18A1 that encodes Δ1‐pyrroline‐5‐carboxylate‐synthase (P5CS). This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1, c.1923 + 1G > A which results in the production of two anomalous transcripts that are predicted to encode proteins lacking the catalytic site for the enzyme. The cellular phenotype is characterized by diminished production of collagen types I and III, altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts. This severe clinical and cellular phenotype overlaps with a broad group of neurocutaneous syndromes that include cutis laxa type II, wrinkly skin syndrome, de Barsy syndrome, and gerodermia osteodysplastica. The findings presented here emphasize the pleiotropic presentation of this group of conditions and suggest that multiple components of the extracellular matrix are perturbed in these disorders. © 2011 Wiley‐Liss, Inc.