Transaldolase (TALDO, EC 126.96.36.199) deficiency (OMIM 606003) (Table 73S-2)has been diagnosed in more than 20 patients [4-11 and unpublished].
A great phenotypic variability has been reported in TALDO deficient patients. Most patients displayed the first symptoms of the disease in the neonatal or antenatal period. Prenatally intra-uterine growth retardation, oligohydramnios and hydrops foetalis have been described . Neonates present with hepatosplenomegaly, bleeding diathesis, abnormal liver function tests, cholestatic jaundice and elevated liver enzymes. Hepatic fibrosis or cirrhosis (in older patients) is the pathological liver hallmark. Most patients showed hemolytic anemia, dysmorphic features, neonatal oedema and congenital heart defects (septal defects, cardiomyopathy, tetralogy of Fallot).
Table 73S-2 |Favorite Table|Download (.pdf) Table 73S-2
Concentrations of elevated metabolites in body fluids of patients affected with TALDO deficiency
| ||TALDO deficiency ||Controls |
| Urine (mmol/mol creatinine) || n=20 || |
|Erythritol ||90 – 1131 ||<209 # |
|Ribitol ||43 – 722 ||<25 # |
|Arabitol ||99 – 588 ||<151 # |
|Sedoheptulose ||70 – 5300 ||<40 # |
|Mannoheptulose ||6 – 112 ||<3 |
|Sedoheptitol ||2 – 27 ||<1 |
|Perseitol ||3 – 67 ||<1 |
|Sedoheptulose-7-P ||0.5 – 23.8 ||<0.07 |
|Erythronic acid ||350 - 2900 ||<120 # |
| Plasma (μmol/L)  || n=11 || |
|Erythritol ||10-18 ||<5 |
|Ribitol ||6-12 ||<5 |
|Arabitol ||15-32 ||<5 |
| CSF (μmol/L)  || n=1 || |
|Erythritol ||27 ||12-33 |
|Ribitol ||19 ||<5 |
|Arabitol ||34 ||9-39 |
Renal manifestations and endocrine disorders (hypothyroidism, adrenal insufficiency, hyperinsulinism, microphallus and cryptorchidism or clitoris hypertrophy) have been frequently reported. Mild transient hypotonia was described in several patients but mental and motor development was normal in most patients.
Unlike RPI deficiency, brain MRI and MRS did not reveal abnormalities in patients with TALDO deficiency. Liver pathology includes hepatocellular damage and degeneration of hepatocytes or hyperplastic and enlarged hepatocytes with fibrosis and cirrhosis.
Transaldolase, located in the reversible part of the pentose phosphate pathway (Figs 73-2 and 73S-1), recycles pentose phosphates into glycolytic intermediates in concert with transketolase. Its deficiency results in the accumulation of seven-carbon sugars (sedoheptulose, mannoheptulose), sedoheptulose-7P, polyols (erythritol, arabitol, ribitol, sedoheptitol, perseitol) and erythronic acid derived from the pathway intermediates [4,5,12-15].(2). Elevations are most striking in the neonatal period and are more subtle in older patients. In plasma and CSF, there are no or minor elevations of polyols. In amniotic fluid from one affected fetus elevated ribitol and sedoheptulose were retrospectively detected . MRS is not informative in this disorder. Confirmation of this defect can be achieved by measuring TALDO activity in fibroblasts, erythrocytes, lymphocytes and lymphoblasts and by sequence analysis of the TALDO gene.
The human TALDO gene (TALDO1; GenBank #NM_006755; gi 5803186) is located on chromosome 11p15.5-p15.4 and a pseudogene is positioned on chromosome 1p34.1-p33. The gene consists of 8 exons . Human TALDO is a monomer of 337 amino acids. The core structure is an eight-stranded alpha/beta barrel comprised of 8 parallel beta-strands and 14 alpha-helical regions . In the crystal structure, human TALDO is operative as a dimer. Several mutations have been detected, including missence mutations, small and large deletions and duplications. Allelic homozygosity and inheritance pattern suggest autosomal recessive inheritance.
Therapeutic options have not yet been identified. For TALDO deficiency treatment is symptomatic and focused on liver disease, which is the main cause of morbidity and mortality of this condition. Liver transplantation may be considered in patients with severe liver cirrhosis. Correction of anaemia and low clotting factors may require transfusions of packed red cells and fresh frozen plasma. Surgical correction of heart septal defects and medical treatment of tubulopathy, arterial hypertension and endocrine disorders may be required. To date, patients with transaldolase deficiency display normal intellectual and neurological development.
In transaldolase deficiency accumulation of sedoheptulose-7P and a failure to recycle ribose-5P through the non-oxidative branch, results in diminished production of NADPH which leads to secondary depletion of GSH and oxidative stress, as well as the loss of the mitochondrial transmembrane potential and mitochondrial mass . A further decrease of NADPH is probably caused by the conversion of C5 sugar phosphates to C5 polyols by aldose reductase at the expense of NADPH levels . In some earlier diagnosed TALDO deficient patients low levels of cholesterol, estradiol, testosterone or vitamin D were detected, indicating decreased NADPH/NADP+, leading to decreased activity of NADPH-dependent reactions (i.e. cholesterol biosynthesis, hormone metabolism) . Haemolytic anaemia was also observed in most patients, probably related to the decreased NADPH production in erythrocytes.
The clinical picture of TALDO deficiency is dominated by liver fibrosis/cirrhosis, resulting in permanent scar tissue. Since TALDO has been recognized as a regulator of apoptotic signal-processing , this might have relevance for the pathogenesis of the liver disease. Finally, accumulation of the metabolite sedoheptulose-7P has been suggested to be involved in the pathophysiology of the liver cirrhosis .