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Brain function depends on the capacity of neurons within interconnecting neuronal circuitry to excite or inhibit one another. Excitation and inhibition are achieved through synaptic transmission, which in turn is mediated by chemical messengers called neurotransmitters. Neurotransmission may be thought of as translation of an electrical signal to a chemical signal (mediated by the neurotransmitter) and back to an electrical signal. In the mammalian brain, the primary excitatory neurotransmitters meeting these criteria are acetylcholine and glutamic acid, whereas gamma-aminobutyric acid (GABA), together with glycine, act as the major inhibitory neurotransmitters. The biogenic amines are also critically important chemical neurotransmitters. These include the catecholamines (ie, dopamine, norepinephrine, and epinephrine) and the indoleamines (ie, serotonin and melatonin).

Neurotransmitters are involved in many brain functions, including the regulation of body temperature and pain threshold and control of behavior and motor function, memory, and a host of other processes. Alterations in glycine, GABA, glutamate, serotonin, norepinephrine, and dopamine levels have been implicated in diverse neurological disorders, including depression, dementia, schizophrenia, Parkinson disease, epilepsy, Huntington disease, and autism. Treatment by modulation of receptor function and neurotransmitter chemistry is well established in neurology and psychiatry. Experimental treatment modalities include human neuronal stem cell therapy as well as gene therapy.


Our ability to diagnose disorders of neurotransmitter metabolism has been hampered because of our limited understanding of the interplay of neurotransmitters with their multitude of receptors, and because the primary diagnostic matrix available is cerebrospinal fluid (CSF), which is only a distant mirror of the metabolic processes in the brain.

CSF analysis only mirrors the overall disturbance of neurotransmitter biosynthesis or degradation and does not necessarily reflect metabolic processes specific to localized brain structures and/or function. Differentiated functions of the brain are determined primarily by a magnitude of different receptors in contrast to the limited number of neurotransmitters. Genetic defects of neurotransmitter receptor subtypes are rapidly emerging as a new group of disorders that cause a wide range of neurological and psychiatric symptoms. The first such defect recognized was in the α1-subunit of the glycine receptor causing hyperekplexia.1 Since then, defects in the GABAA1-, GABAB1-, GABAD, and GABAG2-receptors and in the α4- and β2-subunits of the nicotinic acetylcholine receptor (CHRNA4, CHRNA2, CHRNA3) have been shown to cause familial seizure disorders. The same holds true for genetic defects of the glutamate transporter causing severe neonatal epileptic encephalopathy. Diagnosis of some of these disorders may be aided by specific abnormalities of neurotransmitter metabolites in CSF—for example, reduced levels of GABA in children suffering from hyperekplexia—but primarily, diagnosis rests on molecular analyses.

Monogenic defects of neurotransmission have become recognized as a cause of severe, progressive encephalopathies, mostly of early onset. The diagnosis is based almost exclusively on the quantitative determination of the neurotransmitters or their metabolites in CSF, that is, the amino acids glutamate, ...

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