Phenotypes and Genotypes of Inherited Disorders of Biogenic Amine Neurotransmitter Metabolism

Abstract

Inherited disorders of biogenic amine metabolism are genetically determined conditions resulting in dysfunctions or lack of enzymes involved in the synthesis, degradation, or transport of dopamine, serotonin, adrenaline/noradrenaline, and their metabolites or defects of their cofactor or chaperone biosynthesis. They represent a group of treatable diseases presenting with complex patterns of movement disorders (dystonia, oculogyric crises, severe/hypokinetic syndrome, myoclonic jerks, and tremors) associated with a delay in the emergence of postural reactions, global development delay, and autonomic dysregulation. The earlier the disease manifests, the more severe and widespread the impaired motor functions. Diagnosis mainly depends on measuring neurotransmitter metabolites in cerebrospinal fluid that may address the genetic confirmation. Correlations between the severity of phenotypes and genotypes may vary remarkably among the different diseases. Traditional pharmacological strategies are not disease-modifying in most cases. Gene therapy has provided promising results in patients with DYT-DDC and in vitro models of DYT/PARK-SLC6A3. The rarity of these diseases, combined with limited knowledge of their clinical, biochemical, and molecular genetic features, frequently leads to misdiagnosis or significant diagnostic delays. This review provides updates on these aspects with a final outlook on future perspectives.

Keywords: dystonia; encephalopathy; movement disorders; neurotransmitter disorders; parkinsonism.

Figure 1

Biogenic amine and pterin metabolism. LEGEND: 5-HIAA, 5-hydroxyindoleacetic acid; 5-HIAL, 5-hydroxyindoleacetaldehyde; BH4, tetrahydrobiopterin; DHPR, dihydropterine reductase; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-dihydroxyphenylacetaldehyde; DAT, dopamine transporter; GTP, guanosine-5′-triphosphate; HVA, homovanillic acid; MOPG, methoxylhydroxyphenylglycol; PLP, pyridoxal 5′-phosphate; PNMT, phenylethanolamine N-methyltransferase; PTP, 6-pyruvoyltetrahydropterin; qBH2, quinonoid dihydrobiopterin; VLA, vanillyllactic acid; VMA, vanillylmandelic acid; VMAT 2, vesicular monoamine transporter.

Figure 2

Suggested diagnostic work-up in patients with suspected defects of inherited monoamine neurotransmitter disorders. LEGEND: 3OMD, 3-O-methyldopa; 5-HIAA, 5-hydroxyindoleacetic acid; AADC, aromatic l-amino acid decarboxylase; AD, autosomal dominant; ALDH7A1, aldehyde dehydrogenase 7 family member A1; AR, autosomal recessive; CSF, cerebrospinal fluid; DDC, DOPA decarboxylase gene; GCH1, GTP cyclohydrolase 1 gene; PTS, 6-pyruvoyltetrahydropterin synthase gene; QDPR, quinoid dihydropteridine reductase gene; SLC6A3, solute carrier family 6 member A3, dopamine transporter gene; SLC18A2, solute carrier family 18 member A2, vesicular monoamine transporter 2 gene; SPR, sepiapterin reductase gene; TH, tyrosine hydroxylase gene; HVA, homovanillic acid; MAO, monoamine oxidase gene; MHPG, 3-methoxy-4-hydroxyphwnylglycol; NBIA, neurodegeneration with brain iron accumulation; PNPO, pyridoxamine 5’-phosphate oxidase gene.