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The pediatric neurotransmitter disorders are a fairly recently described group of inherited neurometabolic disorders related to defects in neurotransmitter synthesis or breakdown. These disorders may be divided into defects of γ-aminobutyric acid (GABA), glycine or monoamine metabolism, and secondary neurotransmitter deficiency states. This chapter will primarily discuss disorders of monoamine metabolism; we will focus on the diseases best characterized to date, including GTP cyclohydrolase deficiency, tyrosine hydroxylase deficiency, aromatic l-amino acid decarboxylase deficiency, and monoamine A deficiency.

The monoamine neurotransmitters include biogenic amines or catecholamines (dopamine, norepinephrine, epinephrine) and serotonin. Synthesis of dopamine and serotonin begins with tyrosine and tryptophan. Tyrosine is hydroxylated by tyrosine hydroxylase and tryptophan by tryptophan hydroxylase to form levodopa and 5-hydroxytryptophan, respectively. Levodopa and 5-hydroxytryptophan are then catalyzed to dopamine and serotonin by aromatic l-amino acid decarboxylase (AADC). See Figure 577-1.

Figure 577-1.

Synthesis and metabolism of monoamine neurotransmitters (from Pediatric Neurotransmitter Disorders, Pearl et al19). 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptophan; AADC, aromatic l-amino acid decarboxylase; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; GTP, GTP cyclohydrolase; HVA, homovanillic acid; l-dopa, levodopa; MAO, monoamine oxidase; MHPG, 3-methoxy-4-hydroxyphenylglycol; VMA, vanillylmandelic acid. BH4 is cofactor for tyrosine hydroxylase (TH) and tryptophan hydroxylase (Trp OH’ase).

Dopamine is converted to norepinephrine via dopamine β-hydroxylase; norepinephrine is then metabolized to epinephrine. Dopamine and serotonin are also deaminated by monoamine oxidase A and B to homovanillic acid and 5-hydroindoleacetic acid, respectively, metabolites that can be measured in CSF. Dopamine is also broken down by catechol-o-methyltransferase to 3-O-methyldopa, also detectable in CSF. See Figure 577-1.

Tetrahydrobiopterin serves as a cofactor for both tyrosine hydroxylase and tryptophan hydroxylase. Similarly, pyridoxine (vitamin B6) is a cofactor for AADC. Thus, impairments in tetrahydrobiopterin or pyridoxine metabolism may result in deficiencies of monoamine neurotransmitters as well.

The disorders in the pathways described above typically affect the basal ganglia due to dopamine deficiency and thus present with hyper- or hypokinetic abnormalities of movement. However, there are widespread effects across the cerebrum causing a broad range of symptoms. Patients may present subtly with global developmental or motor delays, but the presence of abnormalities of tone such as spastic diplegia, dystonia, autonomic dysfunction, or evidence of disease progression should point toward this group of disorders. Deficits in neurotransmitter metabolism should be considered in the differential diagnosis of progressive encephalopathies, particularly those with onset in infancy. The diagnosis of these conditions is often made late due to the lack of awareness of this group of diseases.

Guanosine triphosphate cyclohydrolase (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin synthesis, thus impairment of this enzyme results in deficiencies of serotonin and dopamine. GCH1 deficiency was first described by Segawa in 1971.1 Also known as Segawa disease, dopa-responsive dystonia, or hereditary progressive dystonia, the disorder is characterized by ...

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