Dietary management of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD). A case report and survey

Abstract

Current dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxido-reductase, EC 1.1.1.211) deficiency (LCHADD) is based on avoiding fasting, and minimizing energy production from long-chain fatty acids. We report the effects of various dietary manipulations on plasma and urinary laboratory values in a child with LCHADD. In our patient, a diet restricted to 9% of total energy from long-chain fatty acids and administration of 1.5 g medium-chain triglyceride oil per kg body weight normalized plasma acylcarnitine and lactate levels, but dicarboxylic acid excretion remained approximately ten times normal. Plasma docosahexaenoic acid (DHA, 22:6n-3) was consistently low over a 2-year period; DHA deficiency may be related to the development of pigmentary retinopathy seen in this patient population. We also conducted a survey of metabolic physicians who treat children with LCHADD to determine current dietary interventions employed and the effects of these interventions on symptoms of this disease. Survey results indicate that a diet low in long-chain fatty acids, supplemented with medium-chain triclyceride oil, decreased the incidence of hypoketotic hypoglycaemia, and improved hypotonia, hepatomegaly, cardiomyopathy, and lactic acidosis. However, dietary treatment did not appear to effect peripheral neuropathy, pigmentary retinopathy or myoglobinuria.

Secondary carnitine deficiency and impaired docosahexaenoic (22:6n‐3) acid synthesis: a common denominator in the pathophysiology of diseases of oxidative phosphorylation and β‐oxidation

“…Lower levels of free carnitine would be expected to impair the carnitine‐dependent mitochondrial 22:6 n ‐3 synthesis. Significantly, recent reports indicate that defects in long chain 3‐hydroxyacyl‐CoA dehydrogenase, which induce secondary carnitine deficiency, are indeed associated with low levels of plasma 22:6 n ‐3, and supplementation with this fatty acid greatly improves the clinical condition [36–38]. Interestingly, this decrease in 22:6 n ‐3 is accompanied by normal concentrations of 22:5 n ‐3 [37], which is consistent with a compensatory up‐regulation of the microsomal desaturation–elongation pathway.…”

“…Significantly, recent reports indicate that defects in long chain 3‐hydroxyacyl‐CoA dehydrogenase, which induce secondary carnitine deficiency, are indeed associated with low levels of plasma 22:6 n ‐3, and supplementation with this fatty acid greatly improves the clinical condition [36–38]. Interestingly, this decrease in 22:6 n ‐3 is accompanied by normal concentrations of 22:5 n ‐3 [37], which is consistent with a compensatory up‐regulation of the microsomal desaturation–elongation pathway. We would also predict increased microsomal synthesis of 22:5 n ‐6, as has been observed in other disorders associated with impaired 22:6 n ‐3 synthesis [7,11].…”

Energy Contribution of Octanoate to Intact Rat Brain Metabolism Measured by13C Nuclear Magnetic Resonance Spectroscopy

“…Previous studies of fat oxidation in brain have been limited to acetate, the simplest of fats (Badar-Goffer et al, 1990;Cerdan et al, 1990;Sonnewald et al, 1996;Lebon et al, 2002); however, acetate is not a primary physiological fuel for brain (Vannucci and Hawkins, 1983;Edmond, 1992). Conversely, octanoate is a medium-chain fatty acid that composes up to 13% of the normal free fatty acid pool in humans (Mamunes et al, 1974), readily crosses the blood-brain barrier (Oldendorf, 1971(Oldendorf, , 1973, and is an important component of medium-chain triglycerides used in various clinical settings (Sulkers et al, 1989;Eckel et al, 1992;Rouis et al, 1997;Gillingham et al, 1999). Octanoate may also offer a unique approach to dissecting the glutamate-glutamine neurotransmitter cycle on the basis of evidence that fatty acid oxidation (Edmond et al, 1987) as well as glutamine synthesis (Norenberg and Martinez-Hernandez, 1979) occur predominantly in astrocytes.…”

Mitochondrial Trifunctional Protein Defects: Molecular Basis and Novel Therapeutic Approaches

“…Essential long-chain fatty acids are also precursors for the synthesis of docosahexanoic acid (DHA) and arachidonic acid, which must be present for normal neurologic and retinal development. Medium-chain fatty acids provide energy by bypassing the metabolic block and suppressing long-chain fatty acid β-oxidation, and possibly, by inhibiting the accumulation of toxic long-chain fatty acid metabolites and organic acids by a still unknown mechanism [79][80][81][82].…”

“…A follow-up of 10 patients after a year from starting a dietary regimen maintained their predicted growth patterns and 6 were healthy with no episodes of metabolic decompensation and no hospitalizations [89]. 18 patients were reported to have decreased frequency in hypoketotic hypoglycemic episodes once started on dietary therapy with 5 patients not having any metabolic decompensation since dietary treatment was started [81]. However, the long-term prognosis of patients treated by dietary modifications remains unknown.…”