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.
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 ...