Assessment of glycerol phenylbutyrate as a chaperone in the treatment of patients with MCAD deficiency caused by the common 985 A>G (K304E) mutation

Authors: RaeLynn Forsyth, BA, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Gerard Vockley, MD, PhD, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

Corresponding Author Contact Information: email: raf70@pitt.edu Phone: 724-984-2529

Abstract

Background: MCAD deficiency (MCADD) is the most common fatty acid oxidation disorder, and historically, caused a spectrum of sequelae including sudden death. Addition of MCADD to the newborn screening panel allowed preventative therapy from birth through dietary modifications. However, there is no pharmacological treatment for MCADD that can protect patients when fasting is unavoidable. We have previously shown that phenylbutyrate can act as a chaperonin to the misfolded MCAD protein in cells with the most common MCADD mutation (c.985A>G, p.K304E).

Methods: Four adult patients with MCADD and at least one copy of the common mutation were enrolled. Blood and urine was obtained after a twelve hour fast for metabolic and pharmacokinetic studies. After the first fast, subjects were started on study drug, and after the second and third fasts, their dose was increased pending the pharmacokinetic studies performed at the prior visit.

Results: All four subjects had improvement in one or more metabolic parameters while on phenylbutyrate. Three subjects had a decrease in acylglycine intermediates that are specific for MCADD. Other parameters were more subtly improved. Subjects were not sufficiently stressed metabolically to observe change in glucose and ketone levels. Two subjects did reach “toxic” levels of phenylbutyrate, but had no symptoms of toxicity.

Conclusions: This pilot study suggests that phenylbutyrate can improve metabolic flux through fatty acid oxidation in patients with MCADD due to the c.985A>G mutation. A phase 2 trial is currently being planned.