PRODH – Type I Hyperprolinemia

Type I hyperprolinemia is an autosomal recessive disorder caused by deficiency of proline oxidase (POX), encoded by the PRODH gene. Affected individuals exhibit markedly elevated plasma and urine proline due to impaired proline catabolism, with clinical presentations ranging from asymptomatic hyperprolinemia to seizures, intellectual disability, and behavioral disturbances. Diagnosis relies on biochemical assays showing hyperprolinemia and genetic testing for biallelic PRODH variants.

Genetic evidence supports autosomal recessive inheritance of hyperprolinemia type I. Biallelic PRODH variants have been identified in ≥37 unrelated probands across multiple cohorts ([PMID:10957843], [PMID:20524212], [PMID:17412540]), with segregation in affected sibships (2 affected siblings) ([PMID:10957843]). The variant spectrum includes ≥16 missense alleles, frameshift, nonsense, splice-site changes, and whole-gene deletions. The recurrent missense variant c.1322T>C (p.Leu441Pro) has been reported in multiple families.

Functional assessments demonstrate that PRODH missense mutations severely impair POX activity. In vitro assays reveal that p.Leu441Pro and p.Arg453Cys confer >70% reduction in enzyme activity, while moderate (>30–70%) and mild (<30%) reductions occur with other alleles ([PMID:15662599]). The T466M allele shows FAD-responsive rescue in yeast models, indicating the potential for cofactor‐based modulation.

Residual POX activity correlates with biochemical phenotype: severe hyperprolinemia (>800 μM plasma proline) occurs with severe alleles, whereas moderate hyperprolinemia (300–500 μM) aligns with moderate-impact variants ([PMID:15662599]). Patients with severely impaired POX activity frequently present with early-onset seizures, cognitive delay, autistic features, and epilepsy ([PMID:17412540]).

Studies in 22q11 deletion (VCFS) cohorts indicate that PRODH-mediated hyperprolinemia modulates neuropsychiatric features, with plasma proline and COMT genotype independently influencing IQ and psychosis risk, but do not alter primary HPI diagnosis ([PMID:17135275]). These findings underscore PRODH’s role in neurodevelopment beyond metabolic dysfunction.

Overall, the cumulative genetic and functional data support a Strong clinical validity classification for PRODH and hyperprolinemia type I. Additional in vivo models could further elucidate pathomechanisms. Key take-home: Biallelic PRODH variants underlie Type I hyperprolinemia and provide a reliable target for metabolic and neurodevelopmental diagnostics and management.

References

• Indian journal of pediatrics • 2000 • Type I hyperprolinemia. PMID:10957843
• American journal of human genetics • 2005 • Functional consequences of PRODH missense mutations. PMID:15662599
• Human mutation • 2010 • Type I hyperprolinemia: genotype/phenotype correlations. PMID:20524212
• Brain & development • 2007 • Early neurological phenotype in 4 children with biallelic PRODH mutations. PMID:17412540
• Human molecular genetics • 2007 • Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. PMID:17135275

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