8 Disorders of the Pentose Phosphate
Pathway
Nanda M. Verhoeven, Cornelis Jakobs
8.1
Ribose-5-Phosphate Isomerase Deficiency – 133
8.1.1
8.1.2
8.1.3
8.1.4
8.1.5
Clinical Presentation – 133
Metabolic Derangement – 133
Genetics – 133
Diagnostic Tests – 133
Treatment and Prognosis – 133
8.2
Transaldolase Deficiency
8.2.1
8.2.2
8.2.3
8.2.4
8.2.5
Clinical Presentation – 133
Metabolic Derangement – 134
Genetics – 134
Diagnostic Tests – 134
Treatment and Prognosis – 134
References
– 134
– 133
132
Chapter 8 · Disorders of the Pentose Phosphate Pathway
The Pentose Phosphate Pathway
II
The pentose phosphate pathway (. Fig. 8.1) is present
in most cell types. Its function is twofold: the provision of ribose-5-phosphate (ribose-5-P) for ribonucleic
acid synthesis and the reduction of nicotinamide
adenine dinucleotide phosphate (NADP) into NADPH,
a cofactor in many biosynthetic processes. To date, three
inborn errors in the pentose phosphate pathway have
been described.
. Fig. 8.1. The pentose phosphate pathway. All sugars are D
stereoisomers. The conversion of the sugar phosphates into their
corresponding sugars and polyols (italics) has not been proven in
humans. NADP, nicotinamide adenine dinucleotide phosphate;
NADPH, reduced form; P, phosphate. 1, glucose-6-phosphate
dehydrogenase; 2, ribulose-5-phosphate epimerase; 3, ribose-5phosphate isomerase; 4, transketolase 5, transaldolase. Enzyme
defects are depicted by solid bars across the arrows.
133
8.2 · Transaldolase Deficiency
Three inborn errors in the pentose phosphate pathway
are known. In glucose-6-phosphate dehydrogenase
deficiency, there is a defect in the first, irreversible step
of the pathway. As a consequence 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.
As this is a haematological disorder it is not discussed
further.
Deficiency of ribose-5-phosphate isomerase has
been described in one patient who suffered from a
progressive leucoencephalopathy and developmental
delay.
Transaldolase deficiency has been diagnosed in
three unrelated families. All patients presented in the
newborn period with liver problems. One of the patients died soon after birth from liver failure and cardiomyopathy, whereas another patient is now 15 years old
and suffers from liver cirrhosis. Her neurological and
intellectual development has been normal.
Essential pentosuria, due to a defect in the enzyme
xylitol dehydrogenase, affects the related glucuronic
acid pathway. Whereas the pentose phosphate pathway involves D stereoisomers, glucuronic acid gives
rise to L-xylulose which is subsequently converted into
xylitol and D-xylulose. Affected individuals excrete large
amounts of L-xylulose in urine. This is a benign disorder
and not discussed further.
8.1
Ribose-5-Phosphate Isomerase
Deficiency
8.1.1 Clinical Presentation
The patient with ribose-5-phosphate isomerase deficiency
[1] presented with developmental and speech delay. At the
age of 4 years he developed epilepsy. From the age of 7 years
he regressed, with deterioration of vision, speech, hand coordination, walking and seizure control. At 20 years of age
he had no organomegaly or internal organ dysfunction.
Neurological examination showed some spasticity, bilateral
optic atrophy, nystagmus on lateral gaze, an increased
masseter reflex, and mixed cerebellar/pseudobulbar dysarthria. He had prominent cerebellar ataxia in his arms and
legs and mild peripheral neuropathy. He suffered from learning difficulties but his growth parameters were normal.
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. On proton magnetic resonance spectroscopy (MRS), performed at 14 years of age,
there were abnormal resonances in the 3.5–4.0 ppm region,
corresponding to arabitol and ribitol.
8.1.2 Metabolic Derangement
Ribose-5-phosphate isomerase deficiency is a block in the
reversible part of the pentose phosphate pathway. In theory,
this defect leads to a decreased capacity to interconvert
ribulose-5-phosphate and ribose-5-phosphate and results
in the formation of sugars and polyols: ribose and ribitol
from ribose-5-phosphate and xylulose and arabitol from
ribulose-5-phosphate via xylulose-5-phosphate.
8.1.3 Genetics
The presence of two mutant alleles in the ribose-5-phosphate isomerase gene with one of these in the patient’s
mother (the father could not be investigated) suggest autosomal recessive inheritance.
8.1.4 Diagnostic Tests
Ribose-5-phosphate isomerase deficiency can be diagnosed
by analysis of sugars and polyols in a random urine sample.
Urinary ribitol and arabitol, as well as D-xylulose and
ribose are highly elevated. Extremely high concentrations
of these pentitols are also found in cerebrospinal fluid
(CSF). Myoinositol concentration in CSF is decreased.
On in vivo MRS of the brain there are abnormal high
peaks in the 3.5–4.0 ppm region. The diagnosis can be confirmed by an enzyme assay in fibroblasts or lymphoblasts,
and by sequence analysis of the ribose-5-phosphate isomerase gene.
8.1.5 Treatment and Prognosis
No treatment for this defect is available hitherto. The prognosis is unclear.
8.2
Transaldolase Deficiency
8.2.1 Clinical Presentation
Transaldolase deficiency has been diagnosed in 3 families
[2–4]. Clinical symptoms among these families vary, but
liver disease has been present in all. All patients are from
consanguineous Turkish parents. The first patient had low
birth weight and presented in the neonatal period with an
aortic coarctation. After surgical intervention, she had mild
bleeding problems. An enlarged clitoris was noted. In the
8
134
II
Chapter 8 · Disorders of the Pentose Phosphate Pathway
first months of life she developed hepatosplenomegaly with
normal JGT and transaminases but mildly prolonged prothrombin time (PT) and activated partial prothrombin
time (APTT). At the age of two years, a liver biopsy showed
micronodular liver cirrhosis but without specific characteristics. At the age of ten years, her height was at the 10th
percentile and her weight for height at the 2nd percentile.
Her liver was 7 cm below the costal margin and her spleen
size 14.5 cm. She had trombocytopenia, probably due to
splenic pooling. Her J-GT was raised on one occasion. Bile
acids were elevated but bilirubin was normal. Ammonia
was intermittently raised. Her neurological and intellectual
development has been normal. MRI and MRS of the brain
did not show abnormalities.
The second patient was born after caesarean section
because of maternal HELLP syndrome (hemolysis, elevated
liver enzymes and low platelet count). Birth weight was
on the 50th percentile. She displayed generalized edema,
moderate hypotonia and dysmorphic signs (down-slanting
palpebral fissures, low-set ears and increased intermamillar
distance). She had a severe coagulopathy unresponsive to
intraveneous vitamin K, an elevated ammonia, unconjugated hyperbilirubinemia, hypoglycemia and low transaminases. Liver size was decreased whereas the spleen was
moderately increased. The kidneys appeared normal but
there was glomerular proteinuria. The heart was enlarged
with marked myocardial thickening. The patient showed
intractable liver failure, progressive myocardial hypertrophy, and developed respiratory failure and severe lactic
acidosis. She died from bradycardic heart failure.
In the third family, three affected children with variable
symptoms were diagnosed. The first child died at the age of
4 months from liver failure. The second child had hepatomegaly during the first 8 months of life with fibrosis and
steatosis. At the age of 5 years his liver is still palpable but
liver function has normalized. He suffers from chronic
renal failure. The third child had neonatal liver problems
with high transaminases and a prolonged APTT and PT,
cardiomyopathy and transient renal failure. All four patients had transient dysmorphic features, cutis laxa and increased hair growth and in addition suffered from haemolytic anemia and pancytopenia. In the same family, there
has been one abortion because of severe hydrops foetalis
with oligohydramnios. Transaldolase in tissues of this fetus
was deficient [4].
To date all children diagnosed with transaldolase deficiency have been of normal intellectual and neurological
development.
8.2.2 Metabolic Derangement
Transaldolase, located in the reversible part of the pentose
phosphate pathway, recycles pentose phosphates into hexose
phosphates in concerted action with transketolase. Its deficiency results in the accumulation of polyols derived from
the pathway intermediates: erythritol, arabitol and ribitol.
8.2.3 Genetics
The same mutation was found in the first and third families,
but was different in the second family. All patients were
homozygous for these specific mutations, suggesting autosomal recessive inheritance.
8.2.4 Diagnostic Tests
The diagnosis of transaldolase deficiency is suggested by
elevated concentrations of erythritol, arabitol and ribitol in
urine. 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. Transaldolase
activity can be determined in fibroblasts, erythrocytes and
lymphoblasts. Mutation analysis is also available.
8.2.5 Treatment and Prognosis
To date, no therapeutic options have been investigated.
Liver transplantation may be performed in patients with
severe liver cirrhosis.
References
1. Huck JHJ, Verhoeven NM, Struys EA et al (2004) Ribose-5-phosphate
isomerase deficiency: new inborn error in the pentose phosphate
pathway associated with a slowly progressive leukoencephalopathy.
Am J Hum Genet 74: 745-51
2. Verhoeven NM, Huck JH, Roos B et al (2001) Transaldolase deficiency:
liver cirrhosis associated with a new inborn error in the pentose
phosphate pathway. Am J Hum Genet 68: 1086-1092
3. Verhoeven NM, Wallot M, Huck JHJ et al (2005) A newborn with
severe liver failure, cardiomyopathy and transaldolase deficiency.
J Inherit Metab Dis 28: 169-179
4. Valayannopoulos V, Verhoeven N, Salomons GS et al (2005) Transaldolase deficiency: an inborn error of the pentose phosphate pathway associated with a severe phenotype and multiorgan involvement including hydrops foetalis, cutis laxa, hepatic failure and
haemolytic anaemia. J Inherit Metab Dis 28:217