Hyperprolinemia, Type I

A number sign (#) is used with this entry because hyperprolinemia type I (HYRPRO1) is caused by homozygous or compound heterozygous mutation in the proline dehydrogenase gene (PRODH; 606810) on chromosome 22q11.

The PRODH gene falls within the region deleted in the 22q11 deletion syndrome, including DiGeorge syndrome (188400) and velocardiofacial syndrome (192430).

Description

Phang et al. (2001) noted that prospective studies of HPI probands identified through newborn screening as well as reports of several families have suggested that it is a metabolic disorder not clearly associated with clinical manifestations. Phang et al. (2001) concluded that HPI is a relatively benign condition in most individuals under most circumstances. However, other reports have suggested that some patients have a severe phenotype with neurologic manifestations, including epilepsy and mental retardation (Jacquet et al., 2003).

Genetic Heterogeneity of Hyperprolinemia

See also hyperprolinemia type II (HYRPRO2; 239510), which is caused by mutation in the gene encoding pyrroline-5-carboxylate dehydrogenase (P5CDH, ALDH4A1; 606811) on chromosome 1p36.

Clinical Features

Scriver et al. (1961) and Schafer et al. (1962) described a Scottish-Irish family in which the male proband and 3 sibs had elevated plasma and urinary proline. There was also increased urinary hydroxyproline and glycine, presumably because these 3 amino acids share a renal tubular active transport mechanism that may be overloaded by the high level of proline in the glomerular filtrate (see iminoglycinuria, 242600). Other genetic disorders in this family included hereditary nephropathy, deafness, and photogenic epilepsy, which segregated in a different pattern and were presumably unrelated to the hyperprolinemia.

Efron (1965) reported an Italian family with hyperprolinemia; the enzyme defect was found to be in proline oxidase.

Perry et al. (1968) reported type I hyperprolinemia in 2 generations of a consanguineous American Indian family. Hereditary renal abnormalities occurred in members of 3 generations. The proband later developed Wilms tumor. Perry et al. (1968) observed that marked elevations of plasma proline occur in homozygotes and normal or moderately elevated levels in heterozygotes. Goyer et al. (1968) observed hereditary nephritis, neurosensory hearing loss, prolinuria, and ichthyosis in various combinations in 23 members of a kindred.

Ishikawa et al. (1991) reported a 9-year-old Japanese girl with type I hyperprolinemia who also had photogenic epilepsy. EEG showed epileptic discharges and she demonstrated regression in speech and motor activities from 7 years of age. Her plasma proline levels were 3 to 4 times higher than control levels. Proline oxidase activity of the liver biopsy tissues was about 23.5% of normal controls. She showed progressive speech and motor deterioration in spite of the restriction of proline and protein intake.

Humbertclaude et al. (2001) reported a patient with hyperprolinemia type I who had a severe neurologic disorder including psychomotor delay, right hemiparesis, and epilepsy. There were increased levels of proline in the serum, urine, and cerebrospinal fluid. Fluorescence in situ hybridization excluded a chromosome 22q11 deletion. Treatment with vigabatrin for the seizures appeared to aggravate the condition and was discontinued. In the following months, the patient had marked psychomotor improvement, without modification of the epilepsy.

Jacquet et al. (2003) reported a 4-year-old boy, born of consanguineous parents of Egyptian origin, who was referred for severe psychomotor delay, hyperactivity, sleep disturbance with bruxism, and status epilepticus. Metabolic screening showed a very high level of proline in plasma, urine, and CSF. Genetic analysis identified a homozygous 350-kb deletion on chromosome 22q11, including the entire PRODH gene as well as some neighboring loci. The findings clearly indicated that a severe form of type I hyperprolinemia with neurologic deficits can be caused by inactivation of the PRODH gene.

Afenjar et al. (2007) reported 4 unrelated patients with HPI and a severe neurologic phenotype. Common features included psychomotor delay from birth, often associated with hypotonia, severe language delay, autistic features, behavioral problems, and seizures. One patient who was heterozygous for a 22q11 microdeletion also had dysmorphic features. Four previously reported patients with HPI and neurologic involvement had a similar phenotype. Afenjar et al. (2007) concluded that HPI may not always be a benign condition, and that the severity of the clinical phenotype appears to correlate with the serum proline level.

Di Rosa et al. (2008) reported 4 unrelated Italian children with HPI and neurologic manifestations, including epilepsy and mental retardation. Clinical features included early motor and cognitive developmental delay, speech delay, autistic features, hyperactivity, stereotypic behaviors, and seizures. All patients had increased plasma and urine proline levels. All patients had biallelic mutations in the PRODH gene, often with several variants on the same allele. Residual enzyme activity ranged from null in the most severely affected patient to 25 to 30% in those with a relatively milder phenotype. Di Rosa et al. (2008) postulated that hyperprolinemia type I may be associated with neuropsychiatric disorders, which may ultimately correlate with PRODH genotype.

Inheritance

Most familial cases of hyperprolinemia type I, particularly those with neurologic manifestations, show autosomal recessive inheritance (Afenjar et al., 2007). The patient reported by Rokkones and Loken (1968) had uncle-niece parents.

Perry et al. (1968) reported type I hyperprolinemia in 2 generations of a consanguineous American Indian family, observing marked elevations of plasma proline in homozygotes and normal or moderately elevated levels in heterozygotes.

Jacquet et al. (2002) suggested that the mode of inheritance of type I hyperprolinemia may be more complex than simple autosomal recessive inheritance. Some patients with heterozygous PRODH mutations can show increased proline levels. Jacquet et al. (2002) also found that some individuals with increased serum proline carry clusters of several DNA variants in the PRODH gene, each with mild functional consequences on enzyme activity. It is the combination of these variants that determines residual enzyme activity and thus phenotypic expression.

Cytogenetics

Jaeken et al. (1996) described a patient with type I hyperprolinemia in whom a submicroscopic 22q11 deletion was demonstrated by FISH analysis. The patient exhibited symptoms of DiGeorge syndrome, a contiguous gene deletion syndrome involving 22q11, and also appeared to be heterozygous for deletion of the heparin cofactor II gene (HCF2; 142360), which maps to 22q11. The parents and sister of the patient had normal levels of proline and heparin cofactor II, and did not have the deletion at 22q11. The results of Campbell et al. (1997), taken together with the patient reported by Jaeken et al. (1996), suggested that the gene mutant in type I hyperprolinemia, proline oxidase, is located on 22q11.2.

Goodman et al. (2000) reported that 8 of 15 patients with deletions in the velocardiofacial syndrome critical region 22q11.2 had elevated proline levels ranging from 278 to 849 micromol/l while 7 were in the normal range of 51 to 271 micromol/l. Goodman et al. (2000) suggested that the hyperprolinemia is caused by the hemizygous deletion of the proline oxidase gene, which maps to this region. Goodman et al. (2000) concluded that elevations in plasma proline levels should be considered a biochemical feature of the chromosome 22q11.2 deletion syndromes and suggested that patients with isolated hyperprolinemia should be studied for the microdeletion at 22q11.2.

Molecular Genetics

In a patient with hyperprolinemia type I and neurologic manifestations reported by Humbertclaude et al. (2001), Jacquet et al. (2002) identified a homozygous mutation in the PRODH gene (L441P; 606810.0004). He was also heterozygous for another PRODH mutation (R453C; 606810.0002). Another unrelated patient with hyperprolinemia type I and neurologic manifestations and severe seizures was also found to be homozygous for the L441P mutation.

In 2 sibs with type I hyperprolinemia and schizophrenia-4 (600850), Jacquet et al. (2002) identified a heterozygous deletion of the entire PRODH gene (606810.0001). Their unaffected mother was also heterozygous for the deletion. Two heterozygous mutations in the PRODH gene, leu441 to pro (L441P; 606810.0004) and leu289 to met (L289M; 606810.0003), were identified in 3 of 63 patients with schizophrenia, but not in 68 controls, and were associated with increased plasma proline levels. In the families harboring either the PRODH deletion or the L441P mutation, a second PRODH nucleotide variation cosegregated with higher plasma levels of proline. The authors concluded that type I hyperprolinemia is present in a subset of patients with schizophrenia.

In 4 unrelated children with HPI and a homogeneous severe neurologic phenotype, Afenjar et al. (2007) identified biallelic mutations or small deletions in the PRODH gene (see, e.g., 606810.0002; 606810.0004; 606810.0009) that led to severe reduction of PRODH activity. One of the patients was compound heterozygous for a 22q11 microdeletion and a point mutation.

History

Oyanagi et al. (1987) described a severely retarded infant with type I hyperprolinemia and partial duplication of the short arm of chromosome 10. Whether the findings in this patient indicate that a gene for proline oxidase is located on 10p could not be determined; it is possible that the extra genetic material on 10p was derived from somewhere else. The karyotype in both parents was normal. In the affected infant reported by Oyanagi et al. (1987), proline oxidase activity of liver tissue obtained by biopsy was about 9% of that of controls. Restriction of dietary proline resulted in a prompt fall of plasma proline levels with satisfactory growth, but no improvement in mental development. The patient had the facial appearance characteristic of hyperprolinemia and suffered from convulsions beginning at age 10 months. By mixing experiments, it was possible to exclude the deficiency of an activator of proline oxidase.