Energy metabolism and clinical symptoms in beta-oxidation defects, especially long-chain 3-hydroxyacyl-coenzyme a dehydrogenase deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) is a severe inborn error in the beta-oxidation of long-chain fatty acids. The disease presents during the first years of life. Hypoglycemia, hepatic manifestations, muscle hypotonia and episodes of rhabdomyolysis, cardiomyopathy and even sudden death are common symptoms. Despite life-long complicated treatment with a low fat diet and fasting avoidance, episodes of rhabdomyolysis and liver abnormalities may still occur. Patients with LCHAD develop chorioretinopathy, not seen in any other beta-oxidation deficiencies. The aim of this thesis was to describe the clinical outcome for patients with LCHAD, and investigate the energy metabolism with particular emphasis on the dynamics of fasting. Ten patients were included in the studies. The patients had rapid weight gain after diagnosis and initiation of dietary treatment. The nutritional surplus caused overweight and accelerated linear growth in the majority of the children, however not affecting final height. Patients with LCHAD had a decreased fasting tolerance with increased lipolysis. Fat and carbohydrate metabolism during fasting was investigated by stable isotope technique, microdialysis, and biochemical measurements. Despite normal blood glucose and normal glucose production rate (19.6 ± 3.4 umol/kg/min), lipolysis was induced after 3–4 hours, shown by increased glycerol production rate (7.7 ± 1.6 umol/kg/min). Fatty acid intermediates, plasma and microdialysate glycerol levels were increased. Indirect calorimetry showed increased respiratory quotient, indicating mainly glucose oxidation. Our results imply that frequent meals are essential in order to avoid lipolysis and diminish accumulation of the incompletely degraded toxic fatty acid metabolites. All patients developed ocular changes with retinal pigmentations and chorioretinopathy. Early diagnosis and treatment may delay but not prevent the ocular outcome. Neuropsychological deficits were more common than expected, and demonstrated a specific cognitive pattern. The patients either had normal IQ scores with a particular weakness in auditive verbal memory and executive functions, or developmental delay and autistic behaviors. In conclusion, this thesis shows that patients with LCHAD have an increased lipolysis with considerably impaired fasting tolerance. Shorter fasting intervals than has been advocated are thus crucial to reduce the accumulation of fatty acid metabolites and improve the metabolic control. The shorter fasting tolerance should be weighed against the increased the risk for overweight. All patients develop retinal and cognitive symptoms; however, these symptoms may be improved with good adherence to the complicated diet. Neuropsychological screening is important for the identification of special needs early on