47.1 Clinical Features
and Laboratory Investigations 3-Phosphoglycerate dehydrogenase deficiency is a rare neurological disorder with a prenatal onset. All patients known so far have presented with congenital microcephaly. Some have contractures at birth. Dur- ing the first months of life a severe psychomotor retardation becomes apparent. Between 2 and 14 months epilepsy starts, which is difficult to control with antiepileptic medication. Different types of seizures may be seen, including West syndrome and tonic, atonic, and myoclonic seizures. The patients de- velop spastic tetraparesis. Other features that may be seen are nystagmus, cataract, and hypogonadism.
Low levels of
L-serine and glycine are found in the CSF and plasma in the fasting state. The levels are rel- atively lower in CSF than in plasma. Urinary amino acids are not informative. Another finding is a low level of 5-methyltetrahydrofolate in CSF without an elevated homocysteine concentration in plasma.
Megaloblastic anemia and thrombocytopenia are variably present. The diagnosis is confirmed by demonstration of deficient 3-phosphoglycerate dehy- drogenase activity in cultured fibroblasts. Prenatal diagnosis is possible by means of both enzyme as- sessment and DNA analysis.
47.2 Pathology
At present, no autopsy reports are available.
47.3 Pathogenetic Considerations
Deficiency of 3-phosphoglycerate dehydrogenase is a disease with an autosomal recessive mode of inheri- tance. The related gene, PHGDH, is located on chromo- some 1q12. Different mutations have been described.
L
-Serine is derived from four possible sources: di- etary intake, biosynthesis from 3-phosphoglycerate, biosynthesis from glycine, and degradation of protein and phospholipids. It is likely that the predominant source of
L-serine is different for different tissues and different stages of development. 3-Phosphoglycerate dehydrogenase catalyzes the first step in the synthesis of
L-serine from the glycolytic intermediate 3-phos- phoglycerate.
L
-serine has a central role as a precursor for sulfur amino acids. It is a major source of one-carbon groups, providing formyl groups for purine synthesis and methyl groups for pyrimidine synthesis, the remethylation of homocysteine, and many other methylation reactions necessary in cellular metabo- lism. It is a precursor for the synthesis of phosphoglyc- erides and complex macromolecules such as sphin- golipids and glycolipids. Serine can be converted to glycine, which has important neurotransmitter func- tions as an NMDA receptor agonist. The conversion of
L
-serine to glycine is accompanied by the conversion of tetrahydrofolate to 5,10-methylenetetrahydrofolate, which is subsequently reduced to 5-methyltetrahydro- folate. The latter is a methyl donor for the remethyla- tion of homocysteine to methionine.
L-serine can also be converted to
D-serine, and
D-serine is an even more potent NMDA receptor agonist than glycine.
L-Serine is utilized in gluconeogenesis, but its role here is quan- titatively of minor importance.
It is likely that, as soon as the blood–brain barrier is established, the CNS has to rely on its own synthe- sis of
L-serine. 3-Phosphoglycerate dehydrogenase is highly expressed in fetal tissues including the CNS, especially in the ventricular and subventricular zone of the neural tube. This is the zone where the prolifer- ation of neural cells takes place. It is likely that im- pairment of neuronal proliferation is responsible for the microcephaly observed in patients at birth. The role of
L-serine in the CNS is not restricted to provid- ing nucleotide precursors needed for cell prolifera- tion. Serine has also a trophic effect on neurons and stimulates dendritogenesis and axon length.
The hypomyelination observed on MRI in patients with 3-phosphoglycerate dehydrogenase deficiency may be secondary to low concentrations of folate metabolites. Hypomyelination has been described in patients suffering from other inborn errors with a low CSF level of 5-methyltetrahydrofolate. Low levels of S-adenosylmethionine may be important in the white matter abnormalities observed in folate deficiency.
47.4 Therapy
Treatment with high doses of
L-serine is usually very effective in controlling the seizures. Some patients need additional treatment with glycine to stop the seizures. There is some developmental progress after
Serine Synthesis Defect Caused
by 3-Phosphoglycerate Dehydrogenase Deficiency
Chapter 47
047_Valk_Serine_Synthesis 08.04.2005 16:04 Uhr Seite 369
onset of treatment, but the children remain seriously handicapped. The biochemical abnormalities nor- malize during treatment. The problem with treating children diagnosed some time after birth is that irre- versible brain damage is already present, which can- not be reversed by treatment. There is preliminary evidence that treatment of mothers pregnant of an affected fetus with
L-serine may prevent all or most of the clinical problems.
47.5 Magnetic Resonance Imaging
MRI in untreated patients shows a reduced volume of the cerebral white matter with enlarged subarachnoid spaces (Fig. 47.1). The sulci almost touch the walls of the lateral ventricles. The corpus callosum is thin and short (Fig. 47.2). The cerebral white matter is defi- cient in myelination, also in older children.
Chapter 47 Serine Synthesis Defect Caused by 3-Phosphoglycerate Dehydrogenase Deficiency 370
Fig. 47.1. Female patient with 3-phosphoglycerate dehydro- genase deficiency at the age of 12 months before the start of treatment (first row), and at the ages of 18 (second row) and 22 months (third row), both after treatment started. At 12 months there is serious myelin deficiency and atrophy of the cerebral
white matter. Under treatment the myelin content and the volume of the cerebral white matter increase, although they do not become normal. Courtesy of Dr. M. Pineda, Department of Neuropediatrics, Hospital Sant Joan de Déu, Barcelona, Spain
047_Valk_Serine_Synthesis 08.04.2005 16:04 Uhr Seite 370
Once treatment has been started, the white matter volume increases (Fig. 47.1). In some patients myeli- nation progresses, but not in all. In the patients in whom myelination progresses, it still remains defi- cient and does not seem to reach completion. Longer follow-up is needed to document the long-term effects of treatment.
47.5 Magnetic Resonance Imaging 371
Fig. 47.2. Midsagittal image of two brothers with 3-phosphoglycerate dehydrogenase deficiency, showing the short and thin corpus callosum
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