Neurotransmitters include the catecholamines (dopamine, norepinephrine, and epinephrine) and the indoleamines (serotonin and melatonin). They are chemical messengers, which mediate, amplify, or modulate synaptic transmission between neurons in the brain. Consequently, neurotransmitters are involved in central brain functions including control of movements and behavior, neuronal excitation and inhibition, the regulation of body temperature, pain threshold, memory, and a host of other processes. Inherited deficiencies of neurotransmitters encompass defects of neurotransmitter biosynthesis and catabolism, as well as defects of neurotransmitter transporters. They result in a wide variety of clinical signs and symptoms. This chapter will focus on primary disorders of serotonin and dopamine metabolism. Described defects are deficiencies of tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), dopamine ß-hydroxylase (DßH), monoamine oxidase A, as well as the hereditary dopamine transporter and the dopamin-serotonin vesicular transport defect.
Neurotransmitter disorders are important to recognize because early diagnosis and prompt therapeutic intervention seem to improve motor and cognitive outcome. The disease predominantly starts during infancy and early childhood. The specific clinical presentation of individual neurotransmitter diseases is determined by the type and severity of the underlying disorder. The clinical phenotype is not characteristic but can mimic that of other neurological disorders. Although a detailed clinical history and physical examination are essential, the diagnosis is almost exclusively based on the quantitative determination of neurotransmitters or their metabolites in cerebrospinal fluid (CSF). The additional determination of pterin metabolites is needed for the differentiation from deficiencies of BH4 metabolism. Every diagnosis must be confirmed by molecular testing. The aim of their treatment is to restore neurotransmitter homeostasis. Bypassing the metabolic block using levodopa/carbidopa together with dopamine agonists has led to remarkable clinical improvement in TH deficiency. In patients with AADC deficiency and with dopamine receptor deficiency, syndrome treatment options are limited and in many cases not satisfactory. Patients with DβH deficiency benefit from dihydroxyphenylserine (DOPS) administration. A specific therapy with sustained effect for MAO-A deficiency or dopamine transporter deficiency has not yet been described.
KeywordsTyrosine Hydroxylase Dopamine Agonist Biogenic Amine Homovanillic Acid COMT Inhibitor
- Brunner HG, Nelen MR, van Zandvoort P, Abeling NG, van Gennip AH, Wolters EC, Kuiper MA, Ropers HH, van Oost BA (1993b) X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet 52(6):1032–1039PubMedCentralPubMedGoogle Scholar
- Edelstein SB, Breakefield XO (1986) Monoamine oxidases A and B are differentially regulated by glucocorticoids and “aging” in human skin fibroblasts. Cell Mol Neurobiol 6(2):121–150Google Scholar
- Kurian MA, Zhen J, Cheng SY, Li Y, Mordekar SR, Jardine P, Morgan NV, Meyer E, Tee L, Pasha S, Wassmer E, Heales SJ, Gissen P, Reith ME, Maher ER (2009) Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J Clin Invest 119(6):1595–1603. doi: 10.1172/JCI39060, 39060 [pii]PubMedCentralPubMedGoogle Scholar
- Kurian MA, Li Y, Zhen J, Meyer E, Hai N, Christen H-J, Hoffmann GF, Jardine P, von Moers A, Mordekar SR, O’Callaghan F, Wassmer E, Wraige E, Dietrich C, Lewis T, Hyland K, Heales SJR, Sanger T, Gissen P, Assmann BE, Reith MEA, Maher ER (2011b) Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. The Lancet Neurology 10(1):54–62CrossRefGoogle Scholar
- Robertson D, Goldberg MR, Onrot J, Hollister AS, Wiley R, Thompson JG Jr, Robertson RM (1986) Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired beta-hydroxylation of dopamine. N Engl J Med 314(23):1494–1497. doi: 10.1056/NEJM198606053142307 PubMedCrossRefGoogle Scholar
- Surtees R, Hyland K (1990) L-3,4-dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans. J Neurol Neurosurg Psychiatry 53:569–72Google Scholar
- Willemsen MA, Verbeek MM, Kamsteeg EJ, de Rijk-van Andel JF, Aeby A, Blau N, Burlina A, Donati MA, Geurtz B, Grattan-Smith PJ, Haeussler M, Hoffmann GF, Jung H, de Klerk JB, van der Knaap MS, Kok F, Leuzzi V, de Lonlay P, Megarbane A, Monaghan H, Renier WO, Rondot P, Ryan MM, Seeger J, Smeitink JA, Steenbergen-Spanjers GC, Wassmer E, Weschke B, Wijburg FA, Wilcken B, Zafeiriou DI, Wevers RA (2010) Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain 133(Pt 6):1810–1822. doi: 10.1093/brain/awq087, awq087 [pii]PubMedCrossRefGoogle Scholar