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This summary describes the association between ALDH4A1 and hyperprolinemia type 2. The disorder is a rare autosomal recessive metabolic condition primarily affecting proline catabolism. In the reported case, a 64‑year‑old female presented with a long history of abdominal pain, vertical supranuclear gaze palsy, and episodes of generalized epileptic seizures accompanied by severe lactic acidosis (PMID:31884946). The clinical phenotype, although occurring in later life than typically expected, is consistent with impaired ALDH4A1 function.
The overall clinical validity is assessed as Strong. The evidence is based on a single well‐phenotyped proband showing compound heterozygous variants and a severe, life‐threatening clinical presentation (PMID:31884946). Despite the limited number of unrelated probands (1 proband), the detailed metabolic and neurological work‐up combined with molecular confirmation underscores the role of ALDH4A1 in hyperprolinemia type 2. Functional studies further support the pathogenicity of the reported variants (PMID:22516612).
Genetic evidence indicates an autosomal recessive inheritance pattern. In this case, the patient harbored compound heterozygous variants, with one allele carrying an intronic change and the other a missense change. Notably, the variant c.1055C>T (p.Ser352Leu) was identified among the reported alterations. Prior reports have described four distinct pathogenic mutations in ALDH4A1, reinforcing the gene’s role in disease pathogenesis (PMID:31884946). Family segregation data was not reported, and no additional affected relatives were documented.
Functional and experimental evidence strongly supports the association. Structural studies have demonstrated that the c.1055C>T (p.Ser352Leu) variant disrupts a critical hydrophilic pocket, abolishing NAD(+) binding and catalytic activity of the P5CDH enzyme (PMID:22516612). These findings align with the observed biochemical abnormalities in the patient, such as dramatically elevated proline levels in urine, CSF, and blood, and a consequent secondary pyridoxine deficiency. The consistency between the structural, biochemical, and clinical data further validates the loss‐of‑function mechanism as the pathogenic driver.
There is minimal conflicting evidence regarding this association. While the occurrence of a late‐onset phenotype may expand the known clinical spectrum of hyperprolinemia type 2, no studies have disputed the causal role of ALDH4A1 mutations. The convergence of genetic, biochemical, and functional data exceeds the maximum ClinGen scoring threshold, affirming its clinical utility for diagnostic decision‑making.
Key take‑home message: The integration of detailed genetic findings and robust functional data confirms that ALDH4A1 loss‐of‑function causing hyperprolinemia type 2 is a strong and actionable diagnosis, underscoring the importance of including gene analysis in patients with atypical metabolic presentations.
Gene–Disease AssociationStrong1 proband (PMID:31884946) with compound heterozygous variants and a severe clinical phenotype; supported by robust biochemical and functional data (PMID:22516612). Genetic EvidenceModerateThe case exhibits compound heterozygous variants including c.1055C>T (p.Ser352Leu) alongside previous reports of four pathogenic mutations, firmly establishing the gene’s involvement despite limited segregation data. Functional EvidenceStrongStructural analyses reveal that the c.1055C>T (p.Ser352Leu) variant leads to a loss of enzymatic activity through disruption of NAD(+) binding, perfectly mirroring the clinical phenotype. |