Hyperprolinemia

Figure 30-11. Intermediates in i-hydroxyproline catabolism. (a-KA, a-keto acid a-AA, a-amino acid.) Numerals identify sites of metabolic defects in hyperhydroxyprolinemia and type II hyperprolinemia.

The corresponding open-chain aldehyde, formed by hydrolysis, can be oxidized back to glutamate by pyrroline 5-carboxylate dehydrogenase. 145a 147 Lack of this enzyme is associated with the human genetic deficiency causing hyperprolinemia.147-1483... 

Proline Hyperprolinemia, type 1 Probably not etiologically associated with any disease proline excreted Proline oxidase... 

Figure 20.19 Biosynthesis and degradation of proline, hydroxyproline and ornithine. Proline oxidase and S-pyrroIine-5-carboxylic acid dehydrogenase are both mitochondrial enzymes. A and B indicate defects in hyperprolinemia I and II, respectively.

Hyperprolinemia II Unclear Proline <5-Pyrroline-5-carboxylate dehydrogenase... 

Hyperprolinemia. typell 239510 Delta 1 Pyrroline-.. ... 5-carboxylate dehy-. drogenase <1 100,000) Mental retardation, seizures in early life. /... 

This disease has been described in two siblings with progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Besides hyperprolinemia, the metabolic phenotype consisted of hyperammonemia, hypoornithinemia, hypocitrullinemia, and hypoargininemia because proline as well as ornithine synthesis are impaired [15]. The disease is expected to be treatable with dietary proline and ornithine supplements. 

Py r roline - 5 - carb oxylate (P5CDH) dehydrogenase deficiency (Hyperprolinemia type 2) Liver, kidney, brain, leukocytes, fibroblasts 239510... 

Table 3.6, Proline oxidase deficiency (hyperprolinemia type 1) ...

Table 3 J A -Pyrrolme-5-carboxyUte dehydrogenase deficiency (P5CDH) (hyperprolinemia type 2)...

The deficiency of P5C dehydrogenase has been identified as the basis for the inborn error of metabolism, Type II hyperprolinemia (101). In these patients, plasma proline concentrations are elevated markedly and P5C is excreted in the urine. Due to the insensitivity of previously available assays for P5C, this molecule was not measurable in the plasma of these patients. But recent studies using a sensitive enzyme-coupled radioisotopic assay has quantitated P5C levels in the plasma of patients with HP II as well as in normal subjects. Plasma P5C in HP II is 15 to 20 times elevated over that of normals (30). 

The physiologic relevance of this parametabolic regulation requires the identification of P5C as an extracellular molecule. Heretofore, these studies have been difficult because of the insensitivity of existing assays for P5C (49). Even in patients with Type II hyperprolinemia, an inborn error of metabolism deficient in P5C dehydrogenase (101, 102), who excrete large amounts of P5C in the urine, P5C in plasma has been undetectible with previous assay methods (85). 

Finally, the deficiency of proline oxidase in Type I hyperprolinemia has not been associated with any clinical manifestations (85). Although the defect was established in one subject with postmortem enzyme measurements (25), the diagnosis in living subjects is made by exclusion. However, PRO/Re mice, an inbred strain with hyperprolinemia is clearly proline oxidase-deficient (9). The behavioral aberrations and infertility in these mice have yet to be related to the deficiency in proline oxidase. 

---