Neurotransmitter Defects and Related Disorders

Monogenic defects of neurotransmission have become recognized as causes of severe, progressive encephalopathies mostly of early onset. The clinical presentation can be quite distinctive. Patients suffering from nonketotic hyperglycinemia or defects of glutamate transport or gamma-aminobutyrate (GABA)-transaminase deficiency usually present with early-onset severe encephalopathy, dominated by seizures refractory to treatment. Defects in pyridoxine metabolism present similarly; however, rational therapies have been developed with satisfactory or even excellent success. Defects in the biosynthesis of dopamine generally result in progressive extrapyramidal movement disorders, especially parkinsonism–dystonia and chorea. The spectrum of individual symptoms and course of disease, however, is wide, ranging from intermittent focal dystonia to severe, lethal infantile encephalopathies. Investigations for neurotransmitter disorders cannot and should not be separated from the broader scope of cerebrospinal fluid (CSF) investigations for neurometabolic disorders. The diagnosis of neurotransmitter defects is based almost exclusively on the quantitative determination of the neurotransmitters and their metabolites in CSF. This should be considered in children with neurological problems when basic metabolic investigations are normal. Next-generation sequencing is starting to complement CSF analysis and will take a greater role in primary diagnostics in the future.