Submission Details

The relationship between ALDH4A1 and hyperprolinemia type II, an autosomal recessive disorder of proline metabolism, was evaluated using the ClinGen Clinical Validity Framework as of October 21, 2020. ALDH4A1 encodes delta1-pyrroline-5-carboxylic acid dehydrogenase (P5CDh), a mitochondrial matrix protein that catalyzes the conversion of L-glutamate-γ-semialdehyde, the hydrolysis product of delta1-pyrroline-5-carboxylate (P5C), to L-glutamate. Individuals with hyperprolinemia type II have elevated P5C levels, about 10-20 times normal levels of plasma proline, and positive o-aminobenzaldehyde reaction in urine (due to presence of delta-pyrroline products). Some patients with hyperprolinemia have seizures and intellectual disability, and Vitamin B6 may be deficient. Biallelic variants in ALDH4A1 in individuals with hyperprolinemia type II were first reported in 1998 by Geraghty et al (PMID 9700195). One other paper has been published since then (Motte et al, 2019, PMID: 31884946). In total, data from 4 patients who are homozygous or compound heterozygous for ALDH4A1 variants were scored, including 5 unique variants (two missense, two frameshift, one splice variant). One of these variants, c.1560dup, was found to be homozygous in 7 individuals (a father and 6 affected children), and heterozygous in an unaffected sibling, in a branch of a large Irish traveler family (Flynn et al, 1989, PMID 2624476). Another individual with hyperprolinemia type II was reported to be homozygous for a missense variant, p.Pro16Leu, in ALDH4A1, but this variant may be benign based on the allele frequency and results of functional studies (PMID 9700195). This gene-disease relationship is supported by the biochemical function of P5CDh which is consistent with the biochemical differences observed in individuals with hyperprolinemia type II (Strecker, 1960, PMID 13835167; Valle et al, 1974, PMID 4369405; Hu et al, 1996, PMID: 8621661). P5C, which accumulates in individuals with hyperprolinemia type II, has been shown to react with pyridoxal phosphate, providing an explanation for low or low normal vitamin B6 levels in patients with hyperprolinemia II, a possible cause for seizures in affected individuals, and leading to the suggestion that individuals with hyperprolinemia type II may benefit from treatment with Vitamin B6 (Farrant et al, 2001, PMID 11134058; Hassel et al, 2019, PMID 30930802), although not all patients seem to show improvement (van den Ven et al, 2014, PMID 24173411). In addition to the biochemical function of P5CDh, the gene-disease relationship is also supported by the finding of elevated proline in a Drosophila model with a C-terminal deletion of a P5CDh orthologue (He and DiMario, 2011, PMID 21168532). In summary, there is definitive evidence to support this gene-disease relationship. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.