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At a glance

Inborn error of metabolism resulting from a defect in renal tubular amino acid transport leading to abnormal urinary excretion of glycine, proline, and hydroxyproline. The clinical features of this medical condition are seizures and variable intellectual disabilities. The presence of lactic academia, particularly in Type II Hyperprolinemia must be considered.


Prolinemia; Prolinuria.


There are two types that consist of:

  • Type I: Proline oxidase deficiency. It is difficult to determine the prevalence of hyperprolinemia type I, as many people with the condition are asymptomatic. Individuals with Hyperprolinemia Type I have proline blood levels between 3 and 10 times the normal level. Clinically, affected patients present seizures, intellectual disability, or other neurological problems.

  • Type II: Pyrroline carboxylate dehydrogenase deficiency. Hyperprolinemia Type II results in proline blood levels between 10 and 15 times higher than normal. This is related to the presence of byproducts called pyrroline-5-carboxylate. This disorder may appear benign. Clinically, it is associated with seizures and intellectual disability. It is reported that individuals with this condition may show lactic academia. Lactic acid is known to inhibit the breakdown of proline.


It is difficult to determine the prevalence of the disease in type I since most affected individuals are asymptomatic. In type II, it remains unknown but it is accepted to be very rare.

Genetic inheritance

Autosomal recessive; gene mapped on 22q11.2 for type I and 1p36 for type II.


Type I is a benign disorder resulting from deficiency of proline oxidase. Type II results from a deficiency of D-pyrroline-5-carboxylate (P-5-C) dehydrogenase and may be associated with neurologic manifestations. In both conditions, plasma proline levels are increased, and three amino acids (proline, hydroxyproline, glycine) are excreted in excess in urine.


Excess urinary proline, hydroxyproline, and glycine levels are a normal finding in the first 6 months of life. Type I is a diagnosis of exclusion: it includes all cases of hyperprolinemia not resulting from a P-5-C dehydrogenase deficiency (type II). Plasma proline level elevated but usually less than 2000 mM (normal: 100-450 mM). Urine proline also elevated. In Type II, plasma proline exceeds 2000 mM. The metabolic intermediate P-5-C is 10 to 40 times above normal in the plasma and urine.

Clinical aspects

Individuals with type I are asymptomatic. Seizures (grand mal, petit mal) and mental retardation have been associated with type II. Elevated cerebrospinal fluid (CSF) concentrations for gamma-aminobutyric acid (GABA), glutamate, and proline have been described in some patients, but their association with neurologic manifestations remains undetermined. Intestinal absorption of proline may be impaired. Heterozygotes have glycinuria only (plasma levels of amino acids are ...

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