Case Report of Pyruvate Dehydrogenase Deficiency With Unusual Increase of Fats During Ketogenic Diet Treatment

Abstract

This article describes a case of pyruvate dehydrogenase deficiency in a 3-year-old boy who presented generalized hypotonia, severe psychomotor development delay, and generalized and partial seizures and was refractory to antiepileptic drugs. After the diagnosis, the patient was put on a ketogenic diet. Six months later, seizure frequency was reduced and psychomotor development had improved. At the same time he presented some side effects, such as 2 episodes of significant increases in cholesterol and triglycerides associated with viral respiratory infections. The latter decreased with a supplementation of ω-3 fatty acids and an increase in caloric intake.

Severe Hypertriglyceridemia in Glut1D on Ketogenic Diet

“…Blood lipids were lowered by increased caloric intake and polyunsaturated fatty acids. 10 Our patient was asymptomatic, but the fact that the only death of a Glut1D patient reported in the literature was associated with severe acute pancreatitis caused significant concern. 11 Our report highlights that regular laboratory investigations were unhelpful to determine valid pancreatic and liver enzymes in serum as lipid apheresis was required, a method not readily available in many hospitals.…”

Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency

“…The efficacy of the ketogenic diet for PDC deficiency is based on two considerations: (i) the ketogenic diet results in increased circulating plasma levels of free fatty acids and ketone bodies (β-hydroxybutyrate and acetoacetate) providing alternate sources of acetyl-CoA for energy production and biosynthetic process in the brain (ketone bodies only) and other tissues and (ii) the reduction in blood and intracellular levels of lactate and pyruvate due to the reduction or removal of dietary carbohydrates. In this regard, ketogenic diets with reduced level of carbohydrate intake or with little or no carbohydrates have been used with variable success to control lactic acidosis with little or some clinical improvement [8] , [18] , [20] , [22] , [24] , [25] , [51] , [52] . This is due largely to several variables introduced in each case such as the variability in mutations expressed, age at the initiation of the treatment, level of fat content in the diet, quality of dietary fats, length of treatment, acceptability/adherence to the diet, etc.…”

“…Several strategies have been employed to treat PDC-deficient patients, with variable and often limited success [18] , [19] , [20] , [21] . They include three major therapies (and often in some combination) [5] , [8] : (i) the use of a ketogenic diet to provide ketone bodies as an alternate fuel for brain metabolism (by-passing PDC reaction) [18] , [20] , [21] , [22] , [23] , [24] , [25] (ii) supplementation of high doses of thiamine, presumably to meet the increased Km requirement for thiamine pyrophosphate associated with some PDHA1 mutations and/or for enzyme stability [26] , [27] , [28] , [29] , [30] , [31] , and (iii) administration of dichloroacetate which is known to inhibit PDH kinases decreased blood cerebrospinal fluid lactate concentrations in a large number of PDC-deficient children [19] , [32] . Beneficial effect of phenylbutyrate on residual ‘active’ PDC activity was shown in skin fibroblast cell lines from PDC-deficient patients caring PDHA1 missense mutations [33] , [34] .…”

“…Unfortunately, none of these approaches have been evaluated in a controlled manner with a sufficient number of subjects or duration to establish their efficacy. Several studies suggest that an early postnatal implementation of a ketogenic diet severely restricted in its carbohydrate content may be beneficial; however, this remains to be further evaluated [18] , [20] , [21] , [22] , [36] . The efficacy of ketogenic substrates was tested using a zebrafish model for PDC deficiency (due to deletion of the dihydrolipoamide acetyltransferase gene, Dlat ) [36] .…”

Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency

“…An improvement in lactic acidosis as a clinical benefit of a ketogenic diet was first described more than four decades ago [ 4 ]. Increasingly, a ketogenic diet is being recognized as an effective therapy for epilepsy, delayed psychomotor development, sleep disturbance, and so on [ 2 , 3 , [5] , [6] , [7] , [8] , [9] ]. However, it has remained unknown how the ketogenic diet affects metabolism within the TCA cycle, which is the source of cellular energy production, and energetics in multiple organ systems.…”