Neurotransmitter defects and treatment of disorders of hyperphenylalaninemia

Biopterin synthesis defect. Treatment with L-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.

“…This 5-HTP-L-dopa interaction is likely to be at the level of transport (52) or aromatic amino acid decarboxylase, and reflects the structural similarity of these amino acids. Similarly, the effect of phenylalanine on the clinical response to L-dopa also probably reflects transport inhibition (52), or an inhibition by phenylalanine of monoamine synthesis from L-dopa, as has been demonstrated in PKU (7,53). Treatment of the hyperphenylalaninemia with low doses (2 mg/kg per d) of tetrahydropterins would avoid the fluctuations in plasma phenylalanine that accompany dietary therapy, and perhaps optimize the response to L-dopa replacement.…”

“…Before treatment, the concentrations of dopamine (DA), norepinephrine, epinephrine, and six monoamine metabolites were very low or undetectable in plasma, cerebrospinal fluid, or urine. L-Dopa and 5-HTP replacement was begun at age 7 mo. This therapy generally corrected the deficiency of monoamines and their metabolites, and improved neurological development until the age of 25 mo.…”

“…Although dopamine (DA) and epinephrine (E) levels were severely depressed, norepinephrine (NE) and its metabolites were normal. Other DHPR-deficient patients, in contrast, have had evidence of decreased NE synthesis (7). Documentation of the monoamine deficit in additional patients has been generally limited to one or two measurements of 5-hydroxyindoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylacetic acid (HVA) in cerebrospinal fluid (CSF) or urine (8)(9)(10)(11)(12)(13).…”

“…In some subjects, the clinical course of the disease has been favorably altered. Biochemical evaluation of this therapy, however, has been limited (6,7,13,16). In this study, we have delineated the extent of the monoamine abnormalities in a patient with a deficiency of BH4 due to a severe defect in biopterin synthesis.…”

Control of Hereditary Disorders

“…One cause of persistent hyperphenylalaninemia is biopterin deficiency in which the hyperphenylalaninemia is a secondary and perhaps an inconse quential finding, the main problem being a lack of sufficient neurotransmit ter synthesis. This leads to severe brain damage with marked mental retardation, and since patients might benefit from early treatment with neurotransmitter precursors, DOPA and 5-hydroxytryptophan, it is impor tant to identify such infants as soon as possible (29). Another cause is dihydropteridine reductase (DHPR) deficiency.…”