Ribose 5-Phosphate Isomerase Deficiency

A number sign (#) is used with this entry because of evidence that ribose 5-phosphate isomerase deficiency (RPIAD) is caused by compound heterozygous mutation in the RPIA gene (180430) on chromosome 2p11.

Clinical Features

Van der Knaap et al. (1999) reported a 14-year-old boy, born of unrelated parents, with leukoencephalopathy associated with a disturbance in the metabolism of polyols. The boy had psychomotor retardation from early in life and developed epilepsy at age 4 years. From age 7 years, a slow neurologic regression occurred with prominent cerebellar ataxia, some spasticity, optic atrophy, and a mild sensorimotor neuropathy. Neither organomegaly nor dysfunction of the internal organs was present. Motor and sensory nerve conduction velocities were mildly decreased in his arms and legs, confirming a polyneuropathy. Extensive abnormalities of the cerebral white matter were demonstrated by MRI of the brain at age 14 years. Proton magnetic resonance spectroscopy of the brain showed highly elevated abnormal peaks that were identified as representing pentitols ribitol and arabitol. Huck et al. (2004) demonstrated deficient activity of ribose 5-phosphate isomerase, one of the pentose phosphate pathway enzymes, in fibroblasts from the patient reported by van der Knaap et al. (1999). They noted that deficiency of transaldolase (602063), another enzyme in the pentose phosphate pathway, had previously been demonstrated in a patient with liver cirrhosis and abnormal polyol levels in body fluids. RPI deficiency represented the second instance of an inborn error in the reversible phase of the pentose phosphate pathway, confirming that defects in pentose and polyol metabolism constitute a group of inborn metabolic disorders.

Mahler et al. (2019) reported a child with severe global developmental delay, tapetoretinal degeneration, and coordination difficulties who was found to have a mutation in the RPIA gene.

Biochemical Features

Wamelink et al. (2010) studied 2 cell lines, fibroblast and lymphoblast, derived from the patient with RPIA deficiency reported by van der Knaap et al. (1999) and Huck et al. (2004). Western blot and mass spectrometry analysis confirmed reduced RPIA levels in both cell lines, with lymphoblasts retaining about 30% residual levels of the protein and fibroblast levels falling below the level of detection. Similarly, mRNA levels showed a greater decrease in fibroblasts than in lymphoblasts; enzyme activity was not detectable in fibroblasts but was reduced to 28% of controls in lymphoblasts. The truncated version of the protein was not detected, indicating that it either is not expressed or is rapidly degraded. Studies in yeast showed that the A61V missense mutation (180430.0002) had 30% residual activity when expressed at low levels, but that it could complement RPIA loss when expressed at high levels. Metabolic changes in yeast expressing the mutant allele were similar to those observed in the patient. The findings indicated that reduced RPIA activity and reduced expression of the mutant protein contributed to the phenotype.

Molecular Genetics

By sequence analysis of the RPI gene in a patient with deficiency of ribose 5-phosphate isomerase, Huck et al. (2004) demonstrated compound heterozygosity for a frameshift (180430.0001) and a missense (A61V; 180430.0002) mutation in the RPIA gene.

By whole-exome sequencing in a child with RPIA deficiency, Mahler et al. (2019) identified homozygosity for a missense mutation (W209C; 180430.0002) in the RPIA gene.