Submission Details

ALDH18A1 was first reported in relation to semidominant P5CS deficiency in 2000. This gene, which encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), was first characterized in a family with autosomal recessive cutis laxa (Baumgartner et al., PMID: 11092761). However, more recently it has been implicated in both autosomal dominant and resessive forms of cutis laxa and spastic paraplegia (PMIDs: 26026163, 26320891). At least fifteen unique variants (e.g. missense, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, significant segregation data, and experimental data. Variants in this gene have been reported in at least seventeen probands in seven publications (PMIDs: 11092761, 21739576, 24913064, 26026163, 26297558, 26320891, 28228640). Variants in this gene also segregated with the disorder in over twenty-five additional family members, the majority of which were confirmed via whole exome sequencing. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is a variable loss-of-function, depending on the specific mutation(s) present. ALDH18A1 variants fall on a spectrum of severity based on the amount of P5CS residual activity, ranging from the less severe dominant negative missense variants (AD cutis laxa/AD spastic paraplegia) to the highly severe null or grossly misfolded variants that show little to no activity (AR cutis laxa/AR spastic paraplegia) (Marco-Marin et al., 2020; PMID: 32017139). This gene-disease association is additionally supported by a limited amount of experimental evidence. P5CS is a crucial enzyme in several amino acid pathways, catalyzing the de novo biosynthesis of proline, ornithine, and arginine by converting glutamate into P5C. This function additionally matches the probands' metabolic phenotype, commonly consisting of hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and/or hypoprolinemia. A similar function is shared by PYRC1, an enzyme that catalyzes the last step in proline synthesis and is established as a causative agent in de Barsy syndrome (AKA AR Cutis Laxa Type III). Immunoflorescent analysis of skin fibroblast mitochondria additionally demonstrates colocalization of PYCR1 and P5CS (PMID: 19648921). In summary, ALDH18A1 is definitively associated with semidominant P5CS deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.