Transaldolase Deficiency: Liver Cirrhosis Associated with a New Inborn Error in the Pentose Phosphate Pathway

Abstract

This article describes the first patient with a deficiency of transaldolase (TALDO1 [E.C.2.2.1.2]). Clinically, the patient presented with liver cirrhosis and hepatosplenomegaly during early infancy. In urine and plasma, elevated concentrations of ribitol, D-arabitol, and erythritol were found. By incubating the patient's lymphoblasts and erythrocytes with ribose-5-phosphate and subsequently analyzing phosphate sugar metabolites, we discovered a deficiency of transaldolase. Sequence analysis of the transaldolase gene from this patient showed a homozygous deletion of 3 bp. This deletion results in absence of serine at position 171 of the transaldolase protein. This amino acid is invariable between species and is located in a conserved region, indicating its importance for enzyme activity. The detection of this new inborn error of pentose metabolism has implications for the diagnostic workup of liver problems of unknown etiology.

The pathogenesis of transaldolase deficiency

“…Homozygous deletion of 3 bp, coding for serine 171, of the TAL gene was initially documented in a 9-year-old girl suffering from liver cirrhosis (28). Deletion of serine 171 was found to cause misfolding, proteasome-mediated degradation and complete deficiency of TAL in fibroblasts and lymphoblasts of this patient (74).…”

“…Sedoheptulose 7-phosphate (S7P), C5-polyols D-arabitol and D-ribitol, as well as 6-phosphogluconate (6PG) levels were markedly increased in urine of TAL7/7 mice with respect to TALþ/þ and TALþ/7 littermates (80). Accumulation of S7P was detected in the blood (81) and the urine of each reported patient (28,29), suggesting that the murine model is representative of the metabolic changes in humans.…”

“…Unlike G6PD-and TK-deficient mice which are not viable (25,26), TALþ/7 or TAL7/7 mice developed normally with the exception of sperm dysmotility and infertility due to the loss of Dc m (27). TAL deficiency has been reported in patients with cirrhosis (28,29), a disease of the liver associated with increased apoptosis of hepatocytes (30). This review will delineate the potential mechanism underlying cell type-specific pathologies resulting from TAL deficiency.…”

Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum

“…TALDO deficiency was previously described in several patients, causing a severe disease of the liver, skin, and blood (Eyaid et al 2013;Verhoeven et al 2001Verhoeven et al , 2005. Fetal abnormal findings and maternal disease during pregnancy are infrequent, but were documented previously, presented by IUGR (Verhoeven et al 2001), maternal HELLP syndrome (Verhoeven et al 2005), oligohydramnios, fetal splenomegaly, and fetal distress (Wamelink et al 2008a). Here, we present a case of fetal hyperechogenic bowel, which after birth developed a multisystemic disease, eventually leading to his death.…”

The difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency

“…Glucose-6-phosphate dehydrogenase deficiency is the most common human enzyme defect and present in more than 400 million people worldwide [19]. Transaldolase deficiency, the second defect, was first described in 2001 [20] and has meanwhile been diagnosed in unrelated patients of Turkish, Arabian, Pakistani, and Polish origin [21,22]. RPI deficiency is the third defect and appears to be very rare.…”