Vol. 7, Issue 2, Part D (2025)

Ribose-5-phosphate isomerase deficiency represents one of the rarest inborn errors of metabolism, attributable to pathogenic mutations interrupting the function of the RPIA gene. The enzyme ribose-5-phosphate isomerase is an essential enzyme in the non-oxidative portion of the pentose phosphate pathway. It is responsible for the reversible reaction of ribulose-5-phosphate to ribose-5-phosphate, an important reaction for the synthesis of nucleotides and cellular redox balance. The inability to utilize RPI enzyme activity disrupts normal flux through the PPP leading to the accumulation of polyols, specifically ribitol and D-arabitol, which are biochemically elevated in the cerebrospinal fluid (CSF), plasma and urine of affected individuals. The clinical presentation of RPID is often severe neurological deficits which include developmental delay, progressive psychomotor regression, seizures, spasticity, optic atrophy and leukoencephalopathy on MRI. The pathophysiology of RPID is thought to include both reduced RNA synthesis and polyol-induced oxidative stress in order to preserve neuronal integrity. Since we first described the disorder in 1999, there have been only a handful of cases to date published worldwide, emphasizing the disorder's extreme rarity and underdiagnosis. Initial diagnostic evaluation for RPID includes chemical evaluations for polyols, neuroimaging, or genetic testing and sequencing for RPIA to confirm a diagnosis. Currently, there are no available therapies that directly target management of RPID; all treatment for those affected are considered supportive including anticonvulsants, physical rehabilitation, vision therapy, or individualized educational support.