ALDH18A1 – Cutis Laxa

ALDH18A1 encodes Δ¹-pyrroline-5-carboxylate synthase (P5CS), a bifunctional mitochondrial enzyme catalyzing the first steps of proline, ornithine and arginine biosynthesis. Biallelic pathogenic variants in ALDH18A1 underlie autosomal recessive cutis laxa (MONDO:0016175), a multisystem connective tissue disorder marked by lax, wrinkled skin and systemic involvement.

In at least 4 unrelated probands, homozygous or compound heterozygous ALDH18A1 variants—including splice-site c.1923+1G>A (p.?)—have been identified in patients presenting with early-onset skin laxity, corneal clouding, hypotonia, feeding difficulties and severe global developmental delay (4 probands) (PMID:21739576; PMID:32143220; PMID:32859844; PMID:40018427). All variants disrupt P5CS function by loss-of-function mechanisms.

Inheritance is autosomal recessive, supported by homozygosity in a consanguineous pedigree and compound heterozygosity in non-consanguineous families, with co-segregation of biallelic variants in affected individuals and absence in unaffected relatives.

Functional studies of patient dermal fibroblasts demonstrated markedly reduced collagen I and III production, altered elastin ultrastructure, and diminished cellular proliferation, directly aligning with the cutaneous phenotype (PMID:21739576).

The clinical spectrum of ALDH18A1-related cutis laxa overlaps with progeroid and other neurocutaneous syndromes. Key findings include skin laxity, corneal clouding, hypotonia and neurodevelopmental delay; vascular tortuosity and skeletal anomalies may also be present.

Overall, the evidence supports a Moderate ClinGen clinical validity for the ALDH18A1–cutis laxa association, with multiple unrelated cases and concordant functional data. Genetic testing for ALDH18A1 variants and confirmation via fibroblast assays enable accurate diagnosis and guide management of skin fragility and systemic complications.

References

• American Journal of Medical Genetics. Part A • 2011 • Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ¹-pyrroline-5-carboxylate synthase (P5CS) PMID:21739576
• Neuropediatrics • 2020 • Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA. PMID:32143220
• Neurology India • 2020 • Predominant Motor Delay as a Major Presenting Clinical Sign in Cutis Laxa- Report of a Case with Review of Literature. PMID:32859844
• Clinical Case Reports • 2025 • De Novo Autosomal Dominant Cutis Laxa Type 3 With Global Developmental Delay and Musculoskeletal Features of Refractory Rickets. PMID:40018427

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