ALDH18A1 – Autosomal Dominant Cutis Laxa 3

Autosomal Dominant Cutis Laxa 3 (ADCL3) is caused by heterozygous de novo variants in ALDH18A1, encoding Δ¹-pyrroline-5-carboxylate synthetase (P5CS), a bifunctional enzyme critical for proline, ornithine and arginine biosynthesis. Clinical features include loose, inelastic skin (cutis laxa), variable short stature (HP:0004322), cataracts (HP:0000518) and joint hypermobility (HP:0001382).

Eleven unrelated sporadic probands have been reported with de novo heterozygous ALDH18A1 mutations presenting cutis laxa and connective tissue findings, without family history (PMID:32017139). The variant spectrum in ADCL3 comprises predominantly missense changes affecting functional domains of P5CS.

Inheritance is autosomal dominant; de novo occurrence precludes multi-generation segregation, and no additional affected relatives have been described. Variant c.1798C>G (p.Leu600Val) exemplifies a recurrent pathogenic missense allele reported in ADCL3.

Segregation and Segregating Relatives

No familial segregation beyond the proband generation has been documented due to de novo inheritance; affected_relatives = 0.

Functional Evidence

Biochemical assays of the R84Q variant demonstrate >90% reduction in P5CS activity and destabilization of the long isoform in vitro (PMID:11092761). Metabolomic and oligomerization studies of the p.Thr331Pro variant reveal impaired P5CS assembly, decreased proline and glutathione biosynthesis, and altered antioxidant pathways, supporting loss-of-function (PMID:36067040).

Mechanism and Pathogenesis

ADCL3 arises via dominant-negative loss-of-function of P5CS, leading to defective proline and ornithine synthesis, connective tissue fragility and metabolic derangements consistent with urea cycle-related dysfunction.

Conclusion and Clinical Utility

Collectively, 11 de novo probands, concordant functional assays and a clear dominant-negative mechanism support a Moderate ClinGen association between ALDH18A1 and ADCL3. ALDH18A1 sequencing should be considered in patients with unexplained cutis laxa and connective tissue abnormalities; metabolic supplementation trials may be explored.

References

• Journal of inherited metabolic disease • 2020 • Î1 -Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder. PMID:32017139
• 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
• Human molecular genetics • 2023 • Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. PMID:36067040

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