Disorders of the Pentose Phosphate Pathway and Polyol Metabolism

Five inborn errors in the pentose phosphate pathway (PPP) have been described of which Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a defect in the first, irreversible step of the pathway. As a consequence, nicotinamide adenine dinucleotide phosphate (NADPH) production is decreased, making erythrocytes vulnerable to oxidative stress. Drug- and fava bean-induced haemolytic anaemia is the main presenting symptom of this defect. G6PD deficiency is an X-linked disorder. This haematological disorder is not further discussed. Three other defects with associated clinical pictures are: Deficiency of ribose-5-phosphate isomerase has to date been described in three cases, who presented with psychomotor developmental delay, visual impairment, spasticity and leukoencephalopathy. Transaldolase deficiency presents with hepato- and splenomegaly, cardiac abnormalities, liver function problems, anaemia, thrombocytopenia and abnormal skin (e.g. cutis laxa) in most patients. Transketolase deficiency was identified by whole exome sequencing (WES) in five patients of three families with common clinical findings: short stature, developmental delay and congenital heart defects. Four other inborn errors with polyol abnormalities without a clear suspected clinical phenotype are: Sedoheptulokinase deficiency results in urinary accumulation of sedoheptulose and erythritol and is the result of mutations in the SHPK gene. A 57-kb-deletion, the most common cause of nephropathic cystinosis, also results in SHPK deficiency. Two unrelated patients with isolated SHPK deficiency have been described with completely different clinical pictures suggesting the clinical phenotype may not be related to sedoheptulokinase deficiency. L-xylulose reductase deficiency, a defect of the glucuronic oxidation pathway with the biochemical feature of pentosuria, is a benign condition. L-arabinosuria has been documented in only one patient. The defect has not been fully elucidated in humans. Sorbitol dehydrogenase is an enzyme that participates in fructose and mannose metabolism. Deficiency is associated with cataract, although no direct relation has been confirmed of this enzyme deficiency and (congenital) cataract.