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Two new inborn errors of metabolism occur in the reversible part of the pentose phosphate pathway. Deficiency of ribose-5-phosphate isomerase has been described in one patient who suffered from a progressive leukoencephalopathy and developmental delay. Transaldolase deficiency has been diagnosed in more than 20 patients. Patients present with a great phenotypic variability, many display the first symptoms in the neonatal or even antenatal period. The most frequent manifestations associate hemolytic anemia, hepatosplenomegaly, impaired liver function leading to liver failure and histological changes (fibrosis, cirrhosis). Both disorders are inherited in an autosomal recessive mode. Whereas essential pentosuria is a defect in the glucuronic acid pathway, the two newly discovered defects are in the reversible part of the pentose phosphate pathway.


Clinical Presentation

Ribose-5-phosphate isomerase (RPI, EC deficiency was described in a patient with speech and developmental delay1-2 (OMIM 608611). At the age of 4 years he developed epilepsy. From the age of 7 years he experienced neurological regression, with deterioration of vision, speech, hand coordination, walking, and seizures. Neurologic examination at the age of 14 years showed spasticity, bilateral optic atrophy, and nystagmus on lateral gaze; an increased masseter reflex; and mixed cerebellar/pseudobulbar dysarthria. He had prominent cerebellar ataxia and mild peripheral neuropathy. He displayed severe mental retardation, but his growth parameters were normal. He had nor organomegaly, neither internal organ dysfunction. He is now in his twenties.

Magnetic resonance imaging (MRI) at 11 and 14 years of age showed extensive abnormalities of the cerebral white matter with prominent involvement of the U-fibers. The abnormal white matter had a slightly swollen appearance with some widening of the gyri. Proton magnetic resonance spectroscopy (MRS), performed at 14 years of age, revealed abnormal resonances in the 3.5-4.0 ppm region, corresponding to arabitol and ribitol.


RPI deficiency is a block in the reversible part of the pentose phosphate pathway (PPP, Figs. 94-2 and 94-1). In theory, this defect leads to a decreased capacity to interconvert ribulose-5-phosphate (ribulose-5P) and ribose-5P. The diagnosis can be made by analysis of sugars and polyols in urine, plasma, or cerebrospinal fluid (CSF). Urinary ribitol and arabitol, as well as D-xylulose, are highly elevated (more than 10 times the upper limit of the reference ranges) (Table 94–1). These metabolites are postulated to derive from PPP intermediates (Fig.94-1). Extremely high concentrations of the pentitols are also found in CSF (>100 times higher than the upper limit of the reference range). The concentrations of ribitol and arabitol displayed a brain/CSF/plasma gradient of 70:40:1 for arabitol and 125:55:1 for ribitol. Myo-inositol concentration in CSF is decreased (two- to tenfold compared to controls)2. Erythritol is low to normal in urine, plasma and CSF.

Figure 94-1

Pentose phosphate pathway. The dashed arrows indicate conversions that have not ...

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