Diagnosis of Biogenic Amines Synthesis Defects

Defects of biogenic amines synthesis encompass a group of rare genetic disorders that have been described during the last few decades. They include tyrosine hydroxylase deficiency, aromatic L-amino acid decarboxylase deficiency, and pterin defects such as 6-pyruvoyl-tetrahydropterin synthase deficiency, dihydropteridine reductase deficiency, guanosine triphosphate cyclohydrolase-I deficiency, and sepiapterin reductase deficiency. These diseases cause low brain concentrations of catecholamines (dopamine and norepinephrine) and serotonin, which may affect motor, cognitive, and autonomic nervous system. Although most patients have recognizable phenotypes, and share a collection of overlapping symptoms, presentations vary widely and may appear to be nonclassic for the specific disorder. In general, the spectrum of clinical manifestations range from benign forms such as L-3,4-dihydroxyphenylalanine responsive movement disorders to severe encephalopathies that are difficult to treat. These conditions require the specialized analysis of the cerebrospinal fluid because every defect has a very suggestive profile in regard to monoamine and pterin metabolites. However, secondary deficiencies of these metabolites in the cerebrospinal fluid can also be found in a wide variety of neurological disorders. Owing to the still existing challenges of the diagnostic approach, it is important to highlight some of the most relevant clinical and biochemical signatures, as well as to propose practical algorithms that may help clinicians to detect and treat these patients.