Ribose-5-phosphate isomerase deficiency

Mechanism

In the search for an explanation for this rarity, it has been found that the patient has a seldom-seen allelic combination. One allele is a nonfunctional null allele, while the other encodes for a partially active enzyme. Furthermore, the partially functional allele has expression deficits that depend on the cell type in which it is expressed. Therefore, some of the patient's cells have a considerable amount of RPI activity, whereas others do not.

The molecular cause of the pathology is not fully understood. One hypothesis is that ribose-5-phosphate may be insufficient for RNA synthesis. Another possibility is that the accumulation of D-ribitol and D-arabitol may be toxic. However, Klussman et al. evaluated the toxicity of polyols on a rat neurochip model and concluded that the accumulation of polyols has likely only a secondary effect on brain dysfunction, if any at all.

In rat prefrontal cortex, mitochondrial superoxide production was elevated with the addition of ribitol, but not with arabitol. Furthermore, the activity of three antioxidant enzymes was increased under the influence of ribitol, while arabitol showed no such effect. Neither polyol had any impact on the glutathione content in the rat prefrontal cortex. Additionally, neither polyol influenced the oxidation levels of proteins or lipids.

Paradoxically, downregulation of ribose-5-phosphate isomerase in Drosophila melanogaster leads to a fitter phenotype: enhanced tolerance to oxidative stress and extended lifespan. Artificial downregulation of RPI has been therefore suggested as a treatment against disease caused by polyglutamine neutroxicity (such as Huntington's disease) but also to counteract normal ageing.

Diagnosis

Symptoms include optic atrophy, nystagmus, cerebellar ataxia, seizures, spasticity, psychomotor retardation, leukoencephalopathy and global developmental delay.

RPI can be diagnosed by gene sequencing or increased polyol levels in blood or urine. Patients also present highly elevated polyols in the brain, which can be revealed by proton magnetic resonance spectroscopy.

Treatment

There is no current treatment or prognosis for ribose-5-phosphate isomerase deficiency.

History

The first known patient with ribose-5-phosphate isomerase deficiency was a male born in 1984 to healthy, unrelated parents. Early in life, the patient exhibited psychomotor retardation and developed epilepsy at age four. From age seven, a gradual neurological regression occurred, characterized by prominent cerebellar ataxia, mild spasticity, optic atrophy, and a sensorimotor neuropathy, without organomegaly or dysfunction of internal organs. MRI scans performed at ages eleven and fourteen revealed extensive abnormalities of the cerebral white matter and elevated concentrations of D-ribitol and D-arabitol.

In 1999, van der Knaap and colleagues reviewed this case, then a 14-year-old boy, and characterized the clinical presentation of ribose-5-phosphate isomerase deficiency as including developmental delay, progressive psychomotor regression, epilepsy, leukoencephalopathy, and abnormalities in polyol metabolism.

Subsequent cases have been reported. In 2017, Naik and colleagues described an 18-year-old man presenting with seizures, psychomotor regression, and diffuse white matter abnormalities. A third case, reported in 2018 by Sklower Brooks and colleagues, involved a child with neonatal-onset leukoencephalopathy and psychomotor delay. A fourth case was published in 2019 by Kaur and colleagues, describing a patient with progressive leukoencephalopathy and elevated urinary concentrations of the polyols arabitol and ribitol.

References

References

1. "OMIM Entry - # 608611 - Ribose 5-Phosphate Isomerase Deficiency".
2. (2010). "The difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency". [[Journal of Molecular Medicine.
3. Dalling, Robert. (2017-02-10). "These twins are 'trapped' in their living room as work plans stall".
4. (April 2004). "Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy". American Journal of Human Genetics.
5. (December 2005). "Influence of D -arabitol and ribitol on neuronal network activity". Journal of Inherited Metabolic Disease.
6. (October 2014). "Polyols accumulated in ribose-5-phosphate isomerase deficiency increase mitochondrial superoxide production and improve antioxidant defenses in rats' prefrontal cortex". International Journal of Developmental Neuroscience.
7. (February 2012). "Reduced neuronal expression of ribose-5-phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila". Aging Cell.
8. (2011). "Reduced neuronal expression of ribose-5-phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila". Aging Cell.
9. "Ribose 5-Phosphate Isomerase Deficiency disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials".
10. (2004). "Ribose-5-phosphate isomerase deficiency: New inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy". American Journal of Human Genetics.
11. (April 2004). "Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy". American Journal of Human Genetics.
12. (December 1999). "Leukoencephalopathy associated with a disturbance in the metabolism of polyols". Annals of Neurology.
13. (September 2017). "Rare case of ribose 5 phosphate isomerase deficiency with slowly progressive leukoencephalopathy". Neurology.
14. (October 2018). "Further Delineation of Ribose-5-phosphate Isomerase Deficiency: Report of a Third Case". Journal of Child Neurology.
15. (August 2019). "Confirmation of a Rare Genetic Leukoencephalopathy due to a Novel Bi-allelic Variant in RPIA". European Journal of Medical Genetics.