Early onset or syndromic epilepsy

Gene: RPIA

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Red.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Red List (low evidence)

Limited evidence. Single case report where a patient had ribose-5-phosphate isomerase deficiency and developed epilepsy aged 4, who was compound heterozygous for a missense and a truncating variant, PMID 14988808.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Ribose 5-phosphate isomerase deficiency, 608611

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least five variants identified in three unrelated cases, with seizures as a phenotypic feature in two of these cases.

Created: 11 Dec 2018, 11:12 a.m.

Comment on list classification: Based on reviewers' comments and number of cases reported.

Created: 11 Dec 2018, 11:01 a.m.

I don't know

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: 9 Dec 2018, 1:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Ribose 5-phosphate isomerase deficiency, MIM 608611

Publications

• 14988808
• 20499043
• 28801340
• 30088433