Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride

Abstract

We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake.

Phenylalanine Tolerance over Time in Phenylketonuria: A Systematic Review and Meta-Analysis

“…The studies followed variable target therapeutic ranges for blood Phe levels. Thirteen studies [ 25 , 26 , 28 , 29 , 30 , 31 , 35 , 36 , 40 , 41 , 52 , 53 , 56 , 58 ] used similar targets to the European PKU guidelines [ 12 ]. Another three studies aimed for blood Phe levels <360 µmol/L, (<6 y), <480 (6–10 y), and <600 (>10 y) [ 32 , 33 , 34 ].…”

Complex patterns of inheritance, including synergistic heterozygosity, in inborn errors of metabolism: Implications for precision medicine driven diagnosis and treatment

“…Interestingly, extensive published clinical experience demonstrates otherwise [52,53]. Even in the clinical trials leading to approval of the medication, variability in response independent of genotype was reported except for null mutations leading to complete loss of PAH protein [54,55]. Similarly, patients with PKU, even siblings, show variable responses to treatment with pegvaliase, an enzyme substitution therapy given to patients subcutaneously [56,57].…”

The financial and time burden associated with phenylketonuria treatment in the United States

“…However, the drug therapy is expensive and patient response, in terms of metabolic control, is variable [10,11]. Those with mild PKU or non-PKU HPA are more responsive to BH4 (24%–100% response rate) than those with more severe PKU (10%–40% response rate) [9,12,13].…”