8 Disorders of the Pentose Phosphate Pathway Mirjam M.C. Wamelink, Vassili Valayannopoulos, Cornelis Jakobs 8.1 Ribose-5-Phosphate Isomerase Deficiency – 153 8.2 Transaldolase Deficiency – 153 References – 155 J.-M. Saudubray et. al (Eds.), Inborn Metabolic Diseases, DOI 10.1007/978-3-642-15720-2_8, © Springer- Verlag Berlin Heidelberg 2012 152 Chapter 8 · Disorders of the Pentose Phosphate Pathway The Pentose Phosphate Pathway phate to a pentose-phosphate and CO2, and the sec- The pentose phosphate pathway (PPP; ⊡ Fig. 8.1) con- ond part, a nonoxidative, reversible pathway, produces sists of two distinct parts, which fulfil two specific roles: ribose for nucleotide and nucleic acid synthesis and the first part, an oxidative, nonreversible pathway, al- connects pentose phosphates to glycolytic intermedi- lows reduction of nicotinamide adenine dinucleotide ates. To date, three inborn errors in the PPP have been phosphate (NADP+) while converting glucose-6-phos- described. 8 ⊡ Fig. 8.1. The pentose phosphate pathway. The conversion of the sugar phosphates into their corresponding sugars and polyols (dot- ted arrows) has not been proven in humans. NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form; 1, glucose-6- phosphate dehydrogenase; 2, ribose-5-phosphate isomerase ; 3, transaldolase ; 4, sedoheptulokinase Three inborn errors in the pentose phosphate pathway (PPP) duced haemolytic anaemia is the main presenting symptom are known. of this defect. G6PD deficiency is an X-linked disorder. As this Glucose-6-phosphate dehydrogenase deficiency is a is a haematological disorder it is not discussed further. defect in the first, irreversible step of the pathway. As a con- Deficiency of ribose-5-phosphate isomerase has sequence, NADPH production is decreased, making erythro- been described in one patient, who presented with develop- cytes vulnerable to oxidative stress. Drug- and fava bean-in- mental delay and a slowly progressive leukoencephalopathy. 153 8.2 · Transaldolase Deficiency 8 Transaldolase deficiency has been diagnosed in ten 5-phosphate, and xylulose and arabitol from ribulose-5- unrelated families. All patients presented in the neonatal or phosphate via xylulose-5-phosphate. The concentrations antenatal period with hepatosplenomegaly, liver function of ribitol and arabitol displayed a steep descending brain/ problems, hepatic fibrosis and haemolytic anaemia. CSF/plasma gradient. Moreover, the most common, 57-kb deletion in neph- ropathic cystinosis patients, has been shown also to cause deficiency of sedoheptulokinase, resulting in urinary accu- 8.1.3 Genetics mulation of sedoheptulose [1] ( Chapter 43). Essential pentosuria is the result of a partial defi- The human RPIA gene is located at locus 2p11.2 and has ciency of L-xylulose reductase (xylitol dehydrogenase ) and nine exons. Human RPIA consists of a monomer of 311 affects the related glucuronic acid pathway . Whereas the amino acids. In the RPI-deficient patient two mutant PPP involves D-stereoisomers, glucuronic acid gives rise to alleles were demonstrated: a 1-bp deletion (c.540delG), L-xylulose , which is subsequently converted into xylitol and resulting in a frameshift at codon 181 and a predicted D-xylulose . Affected individuals excrete large amounts of truncated protein of 196 amino acids, and a missense L-xylulose in urine. Pentosuria occurs almost exclusively in mutation c.182C>T, resulting in an ala-to-val substitution Jewish people. This is a benign disorder and is not discussed (p.A61V). The finding of two mutant alleles in the patient further here. and apparently healthy parents suggests autosomal reces- sive inheritance. 8.1 Ribose-5-Phosphate Isomerase Deficiency 8.1.4 Diagnostic Tests 8.1.1 Clinical Presentation The diagnosis of RPI deficiency can be made by the analysis of sugars and polyols in urine, plasma or CSF. The one patient recorded with ribose-5-phosphate Urinary ribitol and arabitol, as well as xylulose, are ele- isomerase (RPI) deficiency, a boy, was born after an un- vated (more than 10 times the upper limit of the reference complicated pregnancy as the only child of healthy, unre- ranges). Extremely high concentrations of these pentitols lated parents [2, 3]. He had psychomotor retardation from are also found in CSF. The myo-inositol concentration early in life and developed epilepsy at the age of 4 years. in CSF is decreased. In vivo brain MRS reveals elevated From the age of 7 years a slow neurological regression oc- peaks in the 3.5- to 4.0-ppm region, which correspond to curred, with prominent cerebellar ataxia, some spasticity, arabitol and ribitol. optic atrophy and a mild sensorimotor neuropathy. Neither The diagnosis can be confirmed by an enzyme assay organomegaly nor dysfunction of the internal organs was in fibroblasts or lymphoblasts, and by sequence analysis present. His growth parameters were normal. He is now of the RPIA gene. in his twenties. Magnetic resonance imaging (MRI) of the brain at 11 and 14 years showed extensive abnormalities of the cerebral white matter with prominent involvement of 8.1.5 Treatment and Prognosis the U-fibres and a slightly swollen appearance with some widening of the gyri. He has a slowly progressive leuko- Therapeutic options for RPI deficiency have not yet been encephalopathy. Magnetic resonance spectroscopy (MRS) identified. The prognosis is unclear. revealed highly elevated peaks in the 3.5-4.0 ppm region, or the sugar and polyol region of the spectrum, which were identified as representing ribitol and d-arabitol. 8.2 Transaldolase Deficiency 8.2.1 Clinical Presentation 8.1.2 Metabolic Derangement Transaldolase (TALDO) deficiency was first described RPI is an enzyme of the reversible part of the PPP. In in 2001 [4] in a single patient presenting with cirrhosis, theory, this defect leads to a decreased capacity to in- with nine additional patients reported from five different terconvert ribulose-5-phosphate and ribose-5-phosphate families [4-9]. and results in the accumulation of sugars and polyols: The patients were each born to consanguineous ribose and ribitol from ribose-5-phosphate or ribulose- couples native to Turkey, the United Arabic Emirates, 154 Chapter 8 · Disorders of the Pentose Phosphate Pathway Pakistan or Poland, suggesting rare alleles in the human in the majority in whom assessment was possible (three population. patients died before the age of 6 months). In contrast to Wide phenotypic variability has been reported in those with RPI deficiency, brain MRI and MRS did not TALDO-deficient patients (⊡ Table 8.1) [4-7, 9, 10]. Most reveal abnormalities in patients with TALDO deficiency. patients display the first symptoms of the disease in the neonatal or antenatal period, when intrauterine growth retardation, oligohydramnios and hydrops fetalis have 8.2.2 Metabolic Derangement been described, leading to a medical termination of preg- nancy in the case of a 28-week fetus presenting also with TALDO is located in the reversible part of the PPP a polymalformative syndrome [6]. Neonates present with and recycles pentose phosphates into glycolytic inter- hepatosplenomegaly, bleeding, abnormal liver function mediates in concerted action with transketolase. Its tests, cholestatic jaundice and elevated liver enzymes. deficiency results in the accumulation of polyols derived Hepatic fibrosis and cirrhosis (in older patients) are the from the pathway intermediates and seven-carbon sug- pathological liver hallmarks. Haemolytic anaemia is also ars from sedoheptulose-7-phosphate . In a majority of a constant feature found in all patients. TALDO-deficient patients elevated urinary concentra- Most patients showed dysmorphic features (antimon- tion of the citric acid cycle intermediates 2-oxoglutaric goloid slant, low-set ears and cutis laxa, hypertrichosis), acid and fumaric acid were detected, indicating a pos- neonatal oedema and congenital heart defects (septal sible disturbed mitochondrial metabolism in TALDO defects, cardiomyopathy, tetralogy of Fallot). deficiency [11]. 8 Renal manifestations (tubulopathy, renal failure, nephrocalcinosis) and endocrine disorders have fre- quently been reported, leading to intermittent hypogly- 8.2.3 Genetics caemia, and testicular or ovarian insufficiency leading to cryptorchidism, clitoris enlargement, intermittent hy- The human TALDO gene (TALDO1) is located on chro- poglycaemia and bone development abnormalities with mosome 11p15.5-p15.4, and a pseudogene, on chromo- rickets. some 1p34.1-p33. The mode of inheritance is autosomal Mild transient hypotonia was described in several recessive. Mutations detected in the TALDO1 gene in- patients, but mental and motor development were normal clude missense mutations, deletions and a duplication. ⊡ Table 8.1. Principal clinical manifestations in reported patients with TALDO deficiency Patient no. [ref.] 1 [4] 2 [5] 3 [6] 4 [6] 5 [6] 6 [6] 7 [8] 8 [10] 9 [9] 10 [9] Dysmorphism or cutis laxa - +++++++- - Consanguinity ++++++++++ IUGR + - +++++++- Neonatal oedema/oligoamnios - + - ++ - + + - + - Liver + + + + + + + + + + – function + + + + + + + + + + – fibrosis/cirrhosis Anaemia +++- +++- ++ Cardiac +++++++- - - Renal +++? +++- - - Endocrine - ? + ? - + ---- Psychomotor development n† ?† n† ?† n n Mild Mild nn delay delay IUGR, intrauterine growth retardation; +, presence; -, absence; ?, unknown; †, deceased patient 155 References 8 8.2.4 Diagnostic Tests References Diagnosis of TALDO deficiency is achieved by detecting [1] Wamelink MM, Struys EA, Jansen EE et al. (2008) Sedoheptuloki-