ALDH4A1

ALDH4A1 is a human gene that encodes the enzyme delta-1-pyrroline-5-carboxylate dehydrogenase (P5CDH), a mitochondrial matrix enzyme in the aldehyde dehydrogenase family. The enzyme catalyzes the oxidation of pyrroline-5-carboxylate (P5C) to glutamate, representing the final step of proline catabolism and linking proline degradation to the glutamate pool and downstream metabolism.

Function and pathway: P5CDH operates within the mitochondrial proline catabolic pathway, converting P5C to glutamate. This reaction contributes to nitrogen and redox balance and feeds into the tricarboxylic acid cycle via glutamate and alpha-ketoglutarate. The enzyme's activity helps regulate levels of proline and related metabolites, and it participates in amino acid interconversion under normal physiological conditions.

Clinical significance: Pathogenic variants in ALDH4A1 cause hyperprolinemia type II, an autosomal recessive metabolic disorder. The condition is characterized by elevated plasma proline and, in some individuals, neurodevelopmental issues such as developmental delay, seizures, and cognitive impairment. The clinical presentation is variable, with some individuals remaining asymptomatic or exhibiting milder features. Diagnosis is typically based on biochemical testing showing elevated proline and confirmatory genetic testing identifying variants in ALDH4A1. Management is generally supportive, including monitoring and addressing metabolic or neurological symptoms; no universally established disease-specific therapy exists.

Genetics and expression: ALDH4A1 is a member of the aldehyde dehydrogenase family and is expressed in tissues involved in amino acid metabolism, with activity localized to mitochondria. Its study informs understanding of proline metabolism and related metabolic disorders.