RPIAdeficiency is caused by biallelic pathogenic variants in RPIA, encoding ribose-5-phosphate isomerase, a key enzyme of the non-oxidative pentose phosphate pathway.
Reported variant types include missense, frameshift, and compound heterozygous combinations, often involving one severe (loss-of-function) allele and one hypomorphic allele. Complete loss of function is presumed incompatible with life, consistent with the essential role of the pentose phosphate pathway.
Enzymatic function:
• Catalyzes the reversible interconversion of ribose-5-phosphate and ribulose-5-phosphate
• Supports nucleotide biosynthesis and metabolic flexibility within the PPP
The pentose phosphate pathway serves two critical functions: generation of NADPH (oxidative branch) and provision of ribose-5-phosphate for nucleotide synthesis (non-oxidative branch). Although RPIA acts within the non-oxidative arm, its deficiency likely has broader metabolic consequences:
• Ribose-5-phosphate deficiencymay impair DNA/RNA synthesis and cellular turnover, particularly in metabolically active cells
• Perturbation of PPP equilibrium may indirectly affect NADPH production, compromising antioxidant defenses
• Oligodendrocyte vulnerabilitymay reflect:
o High metabolic demand for myelin maintenance
o Dependence on nucleotide synthesis for membrane production
o Sensitivity to oxidative stress
Pathophysiology:
• Disruption of non-oxidative PPP flux
• Impaired availability of ribose-5-phosphate for nucleotide synthesis
• Secondary effects on cellular redox homeostasis via altered coupling with the oxidative PPP
• Accumulation of polyols (ribitol and D-arabitol), detectable in multiple body fluids and brain tissue
Insights from reported cases suggest a complex disease mechanism beyond simple metabolite accumulation. Residual enzyme activity appears to vary across tissues, and survival into childhood likely depends on partial function or compensatory metabolic pathways. The selective vulnerability of cerebral white matter indicates that oligodendrocytes and myelin maintenance are particularly sensitive to perturbations in pentose metabolism, potentially due to high demands for nucleotide synthesis and redox balance.
Neurochemical findings:
• Elevated ribitol and D-arabitol detectable in CSF and brain by proton MR spectroscopy
Diagnostic approach:
• Polyol analysis in urine, plasma, and CSF
• Brain MRI and MR spectroscopy
• Molecular confirmation via sequencing of RPIA
RPIA