Undiagnosed metabolic disorders

Gene: RPIA

Review by Konstantinos Varvagiannis for the Genetic Epilepsy syndromes panel. 9 Dec 2018, 1:44 a.m.
Panel version: 0.1488
Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611. PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T or p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG or p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548]. PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis. PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis. 2 of the 3 patients described in the literature presented seizures. As a result this gene can be considered for inclusion in this panel as amber. [This gene is also present in the Undiagnosed metabolic disorders gene panel as red. Please consider upgrade based on these further publications.]. Sources: Literature

Created: 11 Dec 2018, 11:31 a.m.

Comment on list classification: Based on additional variants reported in PMIDs 28801340; 30088433.

Created: 11 Dec 2018, 11:21 a.m.

Red List (low evidence)

Associated with phenotype in OMIM, not in G2P. At least 2 variants reported in one case, supporting in vitro data in yeast model presented in PMID 20499043. Over expression of RPIA can induce oncogenes in human hepatocellular carcinoma (PMID 25429733)

Created: 23 Feb 2017, 5:15 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Ribose 5-phosphate isomerase deficiency 608611

Publications

• 14988808
• 20499043