Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

Abstract

BH4 therapy is an advancement in the treatment of phenylketonuria, reducing blood phenylalanine (phe) levels and increasing tolerance to natural proteins of responding patients. We report the results of 16 patients undergoing long-term BH4 treatment. Responding patients to BH4 was usually based on 24-h loading tests; a !30% decrease in blood phe was considered a positive response. Weekly loading made it possible to identify an additional "slow responder." The 16 responders constitute 24.6% of patients who completed the trial (87.5% of responders in mild hyperphenylalaninemia, 38.1% in mild PKU, and 2.8% in classical PKU).Mean dose of BH4 used was 9.75 AE 0.9 mg/kg per day, during a mean of 62 months. Age at treatment start was below 4 years in seven patients; five of which begun treatment during their first month since birth. All but one patient showed good treatment compliance; six continue on BH4 monotherapy without dietary phe restriction; six showed an increase in phe tolerance of 24-55%; and in the five patients who received treatment since the neonatal period an increase in phe tolerance following the phase of maximum growth has persisted. None of the patients showed side effects except one whom vomiting at the beginning of the treatment.Testing at the time of diagnosis in the neonatal period is very appropriate, and if there is a positive response, the patient can be treated with BH4 from onset with the advantage of being able to continue breast-feeding.

Elevated Levels of Plasma Phenylalanine in Schizophrenia: A Guanosine Triphosphate Cyclohydrolase-1 Metabolic Pathway Abnormality?

“…It is important to note that even though Phe levels are elevated in schizophrenia patients, the elevated levels observed in our sample (as well as those by Rao et al [7] and Bjerkenstedt et al [6] ) are not of the same severity as in PKU. To illustrate, the patient with the highest plasma Phe in our sample had a value of 266 µmol/L, a value in the benign hyperphenylalaninemia phentotypic classification of PKU [32] . Patients with benign hyperphenylalaninemia may require Phe level monitoring, but do not need any special dietary modification as is necessary for individuals with classical PKU [30] .…”

“…To illustrate, the patient with the highest plasma Phe in our sample had a value of 266 µmol/L, a value in the benign hyperphenylalaninemia phentotypic classification of PKU [32]. Patients with benign hyperphenylalaninemia may require Phe level monitoring, but do not need any special dietary modification as is necessary for individuals with classical PKU [30].…”

The complete European guidelines on phenylketonuria: diagnosis and treatment

“…BH4, also known as sapropterin dihydrochloride (the active compound in the commercial drug) is used to treat a subset of PKU patients with PKU [ 193 , 311 , 433 , 442 – 453 ]. Patients with high residual activity of the PAH enzyme have a greater probability of BH4 response, but a minority of patients with classical PKU also may benefit from BH4 treatment [ 193 , 194 , 442 , 443 , 445 , 449 , 453 ]. Recently, efficacy and safety of BH4 has been demonstrated in children <4 years of age which has led to European approval for BH4 in this age category [ 454 – 457 ].…”

“…Several uncontrolled open-label studies and case series support a significant reduction of blood Phe levels [ 193 , 194 , 311 , 433 , 442 , 444 – 451 , 453 – 455 , 458 – 464 ] and increased Phe tolerance [ 193 , 194 , 311 , 433 , 443 – 446 , 448 – 452 , 454 , 455 , 458 , 459 , 463 – 465 ]. These benefits have also been replicated in longer-term (investigated up to 5 years) studies [ 193 , 194 , 443 , 445 , 446 , 451 , 454 , 455 , 463 , 465 ]. Furthermore, less variability in blood Phe control has been described in 3 descriptive papers [ 311 , 454 , 460 ].…”