Hyperprolinemia type 1

Hyperprolinemia type 1 (HP1), also known as proline oxidase deficiency or proline dehydrogenase deficiency, is a rare autosomal recessive inborn error of amino acid metabolism caused by deficiency of the enzyme proline dehydrogenase (proline oxidase), encoded by the PRODH gene located on chromosome 22q11.21. This enzyme catalyzes the first step in the degradation of proline to glutamate. Deficiency leads to elevated levels of proline in the blood (hyperprolinemia) and increased urinary excretion of proline, hydroxyproline, and glycine due to shared renal tubular transport mechanisms. Hyperprolinemia type 1 is generally considered a benign biochemical condition, and many affected individuals are asymptomatic and identified incidentally through newborn screening or family studies. However, some individuals have been reported with seizures, intellectual disability, and other neurological features, though it remains debated whether these associations are causative or coincidental, as ascertainment bias may play a role. Plasma proline levels in HP1 are typically elevated to 3–10 times normal but are generally lower than those seen in hyperprolinemia type 2 (caused by P5C dehydrogenase deficiency), which tends to be more clinically significant. There is no specific treatment for hyperprolinemia type 1. Dietary restriction of proline has been attempted but is generally not recommended, as it has not been shown to be effective and proline is a non-essential amino acid synthesized endogenously. Management is primarily supportive and focused on addressing any associated clinical features, such as seizure control with standard antiepileptic medications if needed. Genetic counseling is recommended for affected families. The clinical significance of this condition remains a subject of ongoing research, particularly regarding its potential association with neuropsychiatric phenotypes.

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