RPIA – Ribose-5-phosphate Isomerase Deficiency

Ribose-5-phosphate isomerase deficiency is a rare autosomal recessive leukoencephalopathy characterized by progressive white matter degeneration and peripheral neuropathy. The disorder reflects loss of function in the pentose phosphate pathway enzyme RPI, encoded by RPIA (PMID:14988808). The first patient presented in childhood with motor and cognitive decline, MRI demonstrating confluent cerebral white matter hyperintensities, and peripheral neuropathic signs. Proton magnetic resonance spectroscopy revealed markedly elevated ribitol and D-arabitol levels in brain and body fluids. Fibroblast cultures confirmed deficient RPI enzymatic activity, establishing biochemical diagnosis. This foundational report defined the core clinical and metabolic phenotype of RPI deficiency.

A subsequent report described a novel patient and reviewed three previously published cases, bringing the total number of documented individuals to four (PMID:14988808; PMID:31247379). All subjects exhibited progressive gait disturbance, spasticity, and leukoencephalopathy on neuroimaging, with consistently elevated urine arabitol and ribitol. Clinical onset ranged from infancy to adolescence, indicating variable age at presentation. No additional systemic manifestations beyond hepatic or ocular involvement were observed. Molecular analysis in the new patient identified a homozygous missense variant c.770T>C (p.Ile257Thr), absent from population databases. Comparative phenotype analysis across the four individuals demonstrated uniform white matter involvement. These findings reinforce a consistent clinical spectrum for RPI deficiency.

Genetic studies have revealed biallelic RPIA variants underlying this disorder. To date, four unrelated probands harbor two missense (c.404C>T (p.Ala135Val); c.770T>C (p.Ile257Thr)) and one frameshift (c.762del (p.Asn255fs)) allele, with one additional hypomorphic missense (p.Ala61Val) reported in functional assessments (PMID:14988808; PMID:31247379; PMID:20499043). All cases exhibit autosomal recessive inheritance, with compound heterozygosity or homozygosity. There is no evidence of recurrent or founder variants in specific populations. Segregation analysis is limited to index cases, with no reports of multi-generational variant transmission. Overall, the variant spectrum supports a loss-of-function mechanism.

Functional characterization of RPIA alleles corroborates pathogenicity. In patient-derived fibroblasts, RPI enzyme activity and protein levels are markedly reduced, while mRNA expression varies among cell types (PMID:20499043). A transgenic yeast model expressing human RPIA variants displays metabolic perturbations and enzymatic deficits mirroring the human phenotype. Rescue experiments demonstrate that the frameshift allele is null, while missense alleles retain partial activity, consistent with a hypomorphic mechanism. Collectively, cellular and yeast models confirm that disease results from compound null and hypomorphic alleles leading to diminished flux through the pentose phosphate pathway. These data establish a concordant functional narrative supporting variant pathogenicity.

There are no published reports disputing the association between RPIA variants and ribose-5-phosphate isomerase deficiency. No alternative phenotypes or benign variant annotations have been identified in these cases. Furthermore, no large-scale population studies have detected biallelic RPIA variants in healthy individuals. Database searches (e.g., gnomAD) reveal complete depletion of homozygous loss-of-function alleles. The absence of segregation beyond index cases remains a minor limitation. However, the rarity of the condition and uniform clinical presentation mitigate concerns regarding misclassification.

Integrating genetic, clinical, and experimental evidence supports a moderate level of clinical validity for the RPIA–ribose-5-phosphate isomerase deficiency association. Four probands with consistent phenotypes and biallelic variants, along with robust functional data, fulfill criteria for a moderate classification. Additional segregation data or larger cohort studies could upgrade this to a strong association. Clinically, measurement of polyol levels and targeted sequencing of RPIA enable definitive diagnosis. Early recognition supports genetic counseling and potential metabolic interventions. Key Take-home: Biallelic RPIA variants cause an autosomal recessive leukoencephalopathy with peripheral neuropathy, diagnosable by biochemical profiling and RPIA genetic testing.

References

• American journal of human genetics • 2004 • Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. PMID:14988808
• European journal of medical genetics • 2019 • Confirmation of a Rare Genetic Leukoencephalopathy due to a Novel Bi-allelic Variant in RPIA. PMID:31247379
• Journal of molecular medicine (Berlin, Germany) • 2010 • The difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency. PMID:20499043

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