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29 Disorders of Neurotransmission 29 Disorders of Neurotransmission Jaak Jaeken, Cornelis Jakobs, Peter T. Clayton, Ron A. Wevers 29.1 Inborn Errors of Gamma Amino Butyric Acid Metabolism – 361 29.1.1 Gamma Amino Butyric Acid Transaminase Deficiency – 361 29.1.2 Succinic Semialdehyde Dehydrogenase Deficiency – 362 29.2 Inborn Defects of Receptors and Transporters of Neurotransmitters – 362 29.2.1 Hyperekplexia – 362 29.2.2 GABA Receptor Mutation – 363 29.2.3 Mitochondrial Glutamate Transporter Defect – 363 29.3 Inborn Errors of Monoamine Metabolism – 365 29.3.1 Tyrosine Hydroxylase Deficiency – 365 29.3.2 Aromatic L-Aminoacid Decarboxylase Deficiency – 365 29.3.3 Dopamine β-Hydroxylase Deficiency – 366 29.3.4 Monoamine Oxidase-A Deficiency – 366 29.3.5 Guanosine Triphosphate Cyclohydrolase-I Deficiency – 367 29.4 Inborn Disorders Involving Pyridoxine and Pyridoxal Phosphate – 369 29.4.1 Pyridoxine-Responsive Epilepsy – 369 29.4.2 Pyridox(am)ine 5’-Phosphate Oxidase Deficiency – 370 References – 371 360 Chapter 29 · Disorders of Neurotransmission Neurotransmitters The neurotransmitter systems can be divided into and serotonin (. Fig. 29.2), and in many other pathways mainly inhibitory aminoacidergic [J-aminobutyric acid including the glycine cleavage system. A major inhibi- (GABA) and glycine], excitatory aminoacidergic (as- tory neurotransmitter, GABA is present in high concen- partate and glutamate), cholinergic (acetylcholine), tration in the central nervous system, predominantly in monoaminergic (mainly adrenaline, noradrenaline, the gray matter. GABA modulates brain activity by dopamine, and serotonin), and purinergic (adenosine binding to sodium-independent, high-affinity, mostly and adenosine mono-, di-, and triphosphate). A rapidly GABAA receptors. growing list of peptides are also considered putative GLYCINE, a non-essential amino acid, is an inter- neurotransmitters. mediate in many metabolic processes but also one of the GABA is formed from glutamic acid by glutamic major inhibitory neurotransmitters in the central nerv- acid decarboxylase (. Fig. 29.1). It is catabolized into ous system. The inhibitory glycine receptors are mostly succinic acid through the sequential action of two mi- found in the brain stem and spinal cord. tochondrial enzymes, GABA transaminase and suc- GLUTAMATE is the major excitatory neurotrans- VI cinic semialdehyde dehydrogenase. All these enzymes mitter in the brain. Its function requires rapid uptake to require pyridoxal phosphate as a coenzyme. Pyridoxal replenish intracellular neuronal pools following extra- phosphate also intervenes in the synthesis of dopamine cellular release. Fig. 29.1. Brain metabolism of γ-aminobutyric acid (GABA). Dotted arrow indicates reactions postulated. Enzyme defects are B6, pyridoxal phosphate. 1, Glutamic acid decarboxylase; 2, GABA depicted by solid bars transaminase; 3, succinic semialdehyde dehydrogenase. 361 29 29.1 · Inborn Errors of Gamma Amino Butyric Acid Metabolism 29.1.1 Gamma Amino Butyric Acid This chapter deals mainly with inborn errors of neuro- Transaminase Deficiency transmitter metabolism. Defects of their receptors and transporters, and disorders involving pyridoxine (vita- GABA transaminase deficiency was reported in 1984 in a min B6) and its derivative, pyridoxal phosphate, a co- brother and sister from a Flemish family >1@. No other pa- factor required for the synthesis of several neurotrans- tients have been identified. mitters, are also discussed. Two defects of GABA metabolism are known: the Clinical Presentation very rare, severe, and untreatable GABA transaminase The two siblings showed feeding difficulties from birth, deficiency, and the much more frequent succinic semial- often necessitating gavage feeding. They had a pronounced dehyde dehydrogenase (SSADH) deficiency which, to some axial hypotonia and generalized convulsions. A high-pitched extent, responds to GABA transaminase inhibition. cry and hyperreflexia were present during the first 6–8 Hyperekplexia is a dominantly inherited defect of the α1 months. Further evolution was characterized by lethargy subunit of the glycine receptor which causes excessive and psychomotor retardation (the developmental level of startle responses, and is treatable with clo nazepam. 4 weeks was never attained). Corneal reflexes and the reac- Mutations in the γ2-subunit of the GABAA receptor are a tion of the pupils to light remained normal. A remarkable, cause of dominantly inherited epilepsy. Disorders of the continued acceleration of length growth was noted from metabolism of glycine are discusssed in 7 Chap. 24. birth until death. This was explained by increased fasting Five disorders of monoamine metabolism are dis- plasma growth hormone levels; these could be suppressed cussed: Tyrosine hydroxylase (TH) deficiency impairs by oral glucose. In one of the patients, head circumference synthesis of dihydroxyphenylalanine (L-dopa), and showed a rapid increase during the last 6 weeks of life (from causes an extrapyramidal disorder which responds to the 50th to the 97th percentiles). Postmortem examination the latter compound. The clinical hallmark of dopamine of the brain showed a spongiform leukodystrophy. β-hydroxylase deficiency is severe orthostatic hypo- tension with sympathetic failure. The other disorders of Metabolic Derangement monoamine metabolism involve both catecholamine The cerebrospinal (CSF) and plasma concentrations of and serotonin metabolism. Aromatic L-amino acid de- GABA, GABA conjugates, and E-alanine were increased. carboxylase (AADC) is located upstream of these inter- Liver GABA and E-alanine concentrations were normal. mediates. Treatment of its deficiency is more difficult This metabolite pattern could be explained by a decrease in and less effective. Monoamine-oxidase A (MAO-A) defi- GABA transaminase activity in the liver (and lymphocytes). ciency, located downstream, mainly causes behavioral Intermediate levels were found in the healthy sibling, the disturbances; no effective treatment is known. Guano- father, and the mother. It can be assumed that the same sine triphosphate cyclohydrolase-I (GTPCH-I) deficiency is enzymatic defect exists in the brain, since GABA transami- a defect upstream of L-dopa and 5-hydroxytryptophan nases of human brain and of peripheral tissues have the (5-HTP) and, therefore, can be effectively treated with same kinetic and molecular properties. E-Alanine is an these compounds. alternative substrate for GABA transaminase, hence its in- Pyridoxine-responsive convulsions, a rare form of crease in this disease. In this context, it can be mentioned early or late infantile seizures, has been recently found that the antiepileptic drug J-vinyl-GABA (Vigabatrin) to be caused by mutations of antiquitin, an enzyme causes an irreversible inhibition of GABA transaminase, intervening in the degradation of lysine (. Fig. 23.1). leading to two- to threefold increases in CSF free GABA. Recently also, defective conversion of pyridoxine to Interestingly, this drug also significantly decreases serum pyridoxal phosphate, due to pyridox(am)ine 5’-phos- glutamic pyruvic transaminase but not glutamic oxaloacetic phate oxidase (PNPO) deficiency, has been identified transaminase activity. as a cause of neonatal epilepsy. Genetics The gene for GABA transaminase maps to 16p13.3 and inheritance is autosomal recessive. The patients were com- 29.1 Inborn Errors of Gamma Amino pound heterozygotes for two missense mutations. Butyric Acid Metabolism Diagnostic Tests Two genetic diseases due to a defect in brain gamma amino The diagnosis requires analysis of the relevant amino acids butyric acid (GABA) catabolism have been reported: GABA in CSF. Due to enzymatic homocarnosine degradation, free transaminase deficiency and succinic semialdehyde dehy- GABA levels in the CSF show artifactual increases unless drogenase (SSADH) deficiency (. Fig. 29.1). samples are deep-frozen (at –20 °C) within a few minutes 362 Chapter 29 · Disorders of Neurotransmission when analysis is performed within a few weeks, and at Diagnostic Tests –70 °C if the time until analysis is longer. Control CSF free Diagnosis is made by organic acid analysis of urine, plasma, GABA levels range from about 40 nmol/l to 150 nmol/l after and/or CSF. Pitfalls in this diagnosis are the instability of the age of 1 year and are lower in younger children. Because J-hydroxybutyrate in urine and the variable excretion pat- of these low levels, sensitive techniques, such as ion-ex- tern of this compound which, in some patients, is only mar- change chromatography and fluorescence detection >2@ or ginally increased. The enzyme deficiency can be demons- a stable-isotope-dilution technique >3@, must be used. Enzy- trated in lymphocytes and lymphoblasts. Residual SSADH matic confirmation can be obtained in lymphocytes, lym- activity measured in extracts of cultured cells has been less phoblasts, and liver. As for prenatal diagnosis, GABA trans- than 5% of control values in all patients, and parents have aminase activity is not expressed in fibroblasts, but activity intermediate levels of enzyme activity >6@. SSADH activity is present in chorionic villus tissue >4@. is expressed in normal human fibroblasts, although with low activity, and in liver, kidney, and brain, and SSADH Treatment and Prognosis deficiency in these tissues has been demonstrated. Prenatal No clinical or biochemical response was obtained after diagnosis can be accurately performed using both isotope- administration of either pharmacological doses of pyrid- dilution mass spectrometry
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