Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency–related leukodystrophy

Abstract

Background: Multiple acyl-CoA dehydrogenase deficiency-(MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein-and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. Administration of ketone bodies was described as a promising adjunct, but has only been documented once. Methods:We describe a Portuguese boy of consanguineous parents who developed progressive muscle weakness at 2.5 y of age, followed by severe metabolic decompensation with hypoglycaemia and coma triggered by a viral infection. Magnetic resonance (MR) imaging showed diffuse leukodystrophy. MADD was diagnosed by biochemical and molecular analyses. Clinical deterioration continued despite conventional treatment. Enteral sodium D,L-3-hydroxybutyrate (NaHB) was progressively introduced and maintained at 600 mg/kg BW/d (≈3% caloric need). Follow up was 3 y and included regular clinical examinations, biochemical studies, and imaging. results: During follow up, the initial GMFC-MLD (motor function classification system, 0 = normal, 6 = maximum impairment) level of 5-6 gradually improved to 1 after 5 mo. Social functioning and quality of life recovered remarkably. We found considerable improvement of MR imaging and spectroscopy during follow up, with a certain lag behind clinical recovery. There was some persistent residual developmental delay. conclusion: NaHB is a highly effective and safe treatment that needs further controlled studies.

Oral β-hydroxybutyrate increases ketonemia, decreases visceral adipocyte volume and improves serum lipid profile in Wistar rats

“…Oral βHB salts intake has already been reported in some previous studies: It was already effective and safely used for the treatment of 1 year-old child with hypoketotic hypoglycemia caused by a fatty acid oxidation disorder [9]; to increase blood and cerebrospinal fluid ketone concentrations in two infant patients with persistent hyperinsulinemic hypoglycemia [10]; in the treatment of multiple acyl-CoA dehydrogenase deficiency (MADD) in three infants (a child with leukodystrophy and two infants with cardiomyopathy) [11]; and more recently, in a case of MADD-related leukodystrophy during 3 years of treatment [12]. All of that circumstances evidence the capacity of absorption and utilization of oral βHB salts, at least in humans.…”

“…Therefore, considering the previous studies cited above [9–12], we decided to retest the hypothesis that βHB mineral salts could increase ketonemia in a different animal model (Wistar rats) and assess whether supplemented oral βHB mineral salts could be a model of chronic ketosis. Also, we intended to describe whether βHB mineral salts could influence others parameters improved by ketogenic diets, as body fat and adiponectinemia, as well blood glucose and lipid profile.…”

Ketogenic diets: Opportunities and limitations in practical application (LITERATURE REVIEW)

“…To date, there is no data on market volume of preparations based on βHB and other co-products. Scientifically relevant monitoring of general values of vital functions such as levels of blood (βHB, glucose) and concentrations of acetone in outbreathed air could be performed during KD (183,184).…”

Orphan drugs in development for long-chain fatty acid oxidation disorders: challenges and progress

“…49 Improvements in extensive leukodystrophy in a Portuguese patient without cardiomyopathy have also been reported, with a dose of 900 mg/kg/day. 50 While these cases are promising, this literature shows the clear need for larger, systematic studies to investigate the full effectiveness of D,L-3-hydroxybutyrate.…”