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Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical
I D Wexler1, S G Hemalatha, J McConnell
1Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-6004, USA.
Insights
Ketogenic diets improve outcomes for boys with pyruvate dehydrogenase complex (PDC) E1 deficiency. Early and strict carbohydrate restriction enhances longevity and mental development in these patients.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Inborn errors of the pyruvate dehydrogenase complex (PDC) cause severe neurological and metabolic issues.
- PDC deficiency, particularly E1 subunit mutations, presents diverse clinical phenotypes.
- Current treatments include cofactor replacement, dichloroacetate, and ketogenic diets.
Purpose of the Study:
- To evaluate the efficacy of ketogenic diet therapy in boys with pyruvate dehydrogenase E1 deficiency.
- To compare clinical outcomes based on mutation type, diet initiation timing, and carbohydrate restriction intensity.
Main Methods:
- Seven boys with E1 deficiency (R349H and R234G mutations) were treated with ketogenic diets.
- Dietary interventions varied in carbohydrate restriction levels and initiation timing.
- Clinical outcomes, including longevity and mental development, were assessed and compared.
Main Results:
- Patients with earlier diet initiation and stricter carbohydrate restriction showed improved longevity and mental development.
- Outcomes were compared within mutation groups and between siblings, highlighting the impact of dietary intensity.
- A nearly carbohydrate-free diet initiated early post-birth correlated with better outcomes.
Conclusions:
- Ketogenic diet therapy can significantly improve clinical outcomes in E1 deficiency.
- Early and stringent carbohydrate restriction is crucial for maximizing benefits.
- A nearly carbohydrate-free diet may be a valuable therapeutic strategy for E1 deficiency.
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.