Phenotypes and Genotypes of Inherited Disorders of Biogenic Amine Neurotransmitter Metabolism

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.

Automated summary

Inherited disorders of biogenic amine metabolism are genetically determined conditions that result in dysfunctions or lack of enzymes involved in the synthesis, degradation, or transport of certain neurotransmitters. They present as a group of treatable diseases characterized by complex movement disorders, developmental delay, and autonomic dysregulation. Diagnosis relies on measuring neurotransmitter metabolites in cerebrospinal fluid, and traditional pharmacological strategies are not effective in modifying the disease. Gene therapy has shown promising results in certain types of these disorders. However, the rarity of these diseases and limited knowledge often lead to misdiagnosis or diagnostic delays.