OPLAH – 5-Oxoprolinase Deficiency

OPLAH encodes 5-oxoprolinase, the final enzyme in the gamma-glutamyl cycle. Autosomal recessive pathogenic variants have been identified in eight probands with persistent 5-oxoprolinuria and variable neurological involvement ([PMID:21651516]) and in five additional patients, including a sib-pair, harboring truncating and missense alleles ([PMID:25129617]). A truncating allele, c.3187C>T (p.Arg1063Ter), segregates with disease in molecularly characterized cases. Functional yeast assays demonstrate that missense variants p.Ser323Arg, p.Gly860Arg, and p.Asp1241Val abrogate enzymatic activity, supporting a loss-of-function mechanism ([PMID:25129617]). Phenotypic expressivity ranges from asymptomatic biochemical findings to mild-to-moderate neurological features, with limited segregation beyond sibships. While the biochemical defect appears benign in many individuals, molecular testing is essential to exclude overlapping metabolic disorders. Key Take-home: OPLAH variants cause autosomal recessive 5-oxoprolinase deficiency with variable clinical expressivity, warranting genetic testing for a definitive diagnosis.

References

• Clinical genetics • 2012 • 5-Oxoprolinase deficiency: report of the first human OPLAH mutation. PMID:21651516
• European journal of pediatrics • 2015 • New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition. PMID:25129617

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