Hydroxyprolinemia

Description

Hydroxyproline is an imino acid normally present in human plasma. It is derived primarily from endogenous collagen turnover and the breakdown of dietary collagen. The finding of elevated (5- to 10-fold increase from the normal of less than 50 micromoles) serum hydroxyproline is thought to be an inherited defect in the catabolism of hydroxyproline.

Clinical Features

Elevated serum hydroxyproline appears not to cause any significant clinical symptoms. Pelkonen and Kivirikko (1970) described hydroxyprolinemia in a brother and sister. No clinical abnormality was present and the authors suggested that hydroxyprolinemia, like cystathioninuria, is a 'non-disease.'

Phang and Scriver (1989) stated that 'there is no evidence that the metabolic phenotype is a cause of clinical manifestation.' Bias of ascertainment is introduced by the fact that the hyperhydroxyprolinemia is found in patients investigated because of abnormality. They knew of reports of 6 probands.

Kim et al. (1997) prospectively studied a girl with untreated hydroxyprolinemia identified on neonatal screening and compared her with her unaffected dizygotic twin sister. In the affected twin, plasma and urine hydroxyproline were increased 10-fold and 100-fold, respectively. Both girls had normal growth. On neuropsychologic testing, the affected twin was within normal limits, performing slightly better than her sister on verbal achievement but less well on visual perceptual testing. Kim et al. (1997) concluded that hydroxyprolinemia caused no physical or cognitive deficits. They could not rule out a possible effect on visual perceptual functioning.

Inheritance

Even when only 1 case, in a female, was reported, this condition was thought to be an autosomal recessive because of its nature as an inborn error of metabolism and because the parents were thought to have been sibs (Scriver and Efron, 1972).

Pathogenesis

In vivo studies indicate a deficiency of hydroxy-L-proline oxidase, the enzyme that catalyzes the first step in the catabolic pathway, oxidizing hydroxyproline to delta(1)-pyrroline-3-hydroxy-5-carboxylic acid (Scriver and Efron, 1972; Phang et al., 2001).

History

Hydroxyprolinemia was originally thought to result in mental retardation. Efron et al. (1965) described a clinical syndrome in which mental retardation and microscopic hematuria were present. A defect in hydroxyproline oxidase was proposed (Efron et al., 1965). Scriver and Efron (1972) described another case with mental retardation observed by Noel Raine in Birmingham, England. However, the authors admitted that there may be no relation between the 2 findings, as the mother had mental retardation with normal hydroxyproline levels, and the child was believed to be born of related parents.

Roesel et al. (1979) reported affected sisters. The proband was a 51-year-old mentally retarded woman with episodic psychotic behavior. She had shown regression after meningitis at age 15 months and was institutionalized at age 30. One sister died in a psychiatric institution. The second sister with documented hydroxyprolinemia was seemingly not retarded. The sisters excreted 33 and 21% of an oral hydroxyproline load; their mother excreted 5.4%. Deficiency of hydroxyproline oxidase was indicated by the lack of delta-1-pyrroline-3-hydroxy-5-carboxylic acid excretion. Urinary glycolate and oxalate did not increase during the loading test.