Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets

Abstract

Inborn errors of the pyruvate dehydrogenase complex (PDC) are associated with lactic acidosis, neuroanatomic defects, developmental delay, and early death. PDC deficiency is a clinically heterogeneous disorder, with most mutations located in the coding region of the X-linked alpha subunit of the first catalytic component, pyruvate dehydrogenase (E1). Treatment of E1 deficiency hs included cofactor replacement, activation of PDC with dichloroacetate, and ketogenic diets. In this report, we describe the outcome of ketogenic diet treatment in seven boys with E1 deficiency. These patients were divided into two groups based on their mutations (R349H, three patients; and R234G, four patients, two sibling pairs). All seven patients received ketogenic diets with varying degrees of carbohydrate restriction. Clinical outcome was compared within each group and between siblings as related to the intensity and duration of dietary intervention. Subjects who either had the diet initiated earlier in life or who were placed on greater carbohydrate restriction had increased longevity and improved mental development. Based on the improved outcomes of patients with identical mutations, it appears that a nearly carbohydrate-free diet initiated shortly after birth may be useful in the treatment of E1 deficiency.

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

“…It leads to decreased blood lactate and pyruvate concentrations and provides an alternative source of energy in the form of ketones (Wexler et al 1997) and has been shown to be helpful in reducing childhood onset epilepsy and paroxysmal dystonia (Barnerias et al 2010). However, its efficacy has been variable (Weber et al 2001).…”

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

“…There are no proven treatments for PDH complex deficiency. Anecdotal studies have reported beneficial effects from the use of high-fat, ketogenic diets, which provide an alternative energy source to carbohydrate [7] and dichloroacetate (DCA), which inhibits PDH kinase and maintains E1α in its unphosphorylated, catalytically active form [8]. Neither intervention has been rigorously evaluated as a treatment for PDH deficiency in a controlled clinical trial.…”

A zebrafish model for pyruvate dehydrogenase deficiency: Rescue of neurological dysfunction and embryonic lethality using a ketogenic diet

“…Current treatments for PDH deficiency, which include the activation of residual PDH with dichloroacetate (6), the administration of cofactors (lipoic acid and thiamine) (7,8), and the provision of ketogenic diets (9,10), have yielded only limited or variable success (see Fig. 1).…”

“…1). The technical challenges of working with small numbers of human patients has made it difficult to include all of the necessary controls and to systematically evaluate therapeutic agents and diets with varying proportions of calories from fat, carbohydrate, and protein (9,11). Furthermore, preexisting neurological disorders compound the difficulty of evaluating treatments.…”