ALDH18A1 – ALDH18A1-related De Barsy Syndrome

Autosomal recessive cutis laxa type IIIA, also known as De Barsy syndrome, is caused by biallelic pathogenic variants in the ALDH18A1 gene encoding Δ1-pyrroline-5-carboxylate synthase (P5CS), a mitochondrial enzyme critical for proline, ornithine, and arginine biosynthesis. Patients present with wrinkled skin, skeletal anomalies, cataracts, and neurodevelopmental impairment, reflecting systemic connective tissue and metabolic dysfunction. Functional and genetic studies converge on a loss-of-function mechanism impeding P5CS activity and oligomerization.

The first reported family comprised two siblings homozygous for c.251G>A (p.Arg84Gln), demonstrating hyperammonemia, hypoornithinemia, and progressive neurodegeneration. Enzymatic assays of the R84Q variant in mammalian cells revealed dramatic reduction of both P5CS isoform activities and destabilization of the long isoform (PMID:11092761).

A multi-center study described 32 patients with P5CS deficiency, including 21 familial cases with homozygous or compound heterozygous ALDH18A1 variants in autosomal recessive cutis laxa type IIIA and 11 sporadic de novo heterozygous variants underlying an autosomal dominant cutis laxa. Twenty-one recessive probands were identified across multiple families, confirming autosomal recessive inheritance and variant segregation (PMID:32017139).

A recent case report detailed a patient with a homozygous missense c.1273C>T (p.Arg425Cys) variant presenting with severe urological and cerebrovascular involvement, further expanding the phenotypic spectrum of ALDH18A1-related De Barsy syndrome (PMID:35842092).

Functional metabolomic and transcriptomic profiling of a newly identified homozygous p.Thr331Pro variant in four probands from two unrelated families revealed impaired P5CS oligomerization, reduced glutamate-derived metabolite abundance, and altered extracellular matrix gene expression, underscoring disrupted amino acid and antioxidant pathways (PMID:36067040).

These genetic and experimental data support a loss-of-function mechanism of pathogenicity through haploinsufficiency of P5CS. No conflicting reports have been identified.

Key take-home: ALDH18A1 sequencing is warranted in patients with cutis laxa, skeletal anomalies, and neurodevelopmental deficits to guide diagnosis, management, and genetic counseling.

References

• Human molecular genetics • 2000 • Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. PMID:11092761
• Journal of inherited metabolic disease • 2020 • Δ1-Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder. PMID:32017139
• European journal of medical genetics • 2022 • Autosomal recessive cutis laxa type IIIA: Report of a patient with severe phenotype and review of the literature. PMID:35842092
• Human molecular genetics • 2023 • Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. PMID:36067040

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