Disorders of Ketogenesis and Ketolysis

Zusammenfassung

Disorders of ketone body metabolism present either in the first few days of life or later in childhood, during an infection or some other metabolic stress. There are two defects of ketogenesis, 3-hydroxy-3-methylglutaryl (HMG)-CoA lyase deficiency and HMG-CoA synthase deficiency. In these, decompensation leads to encephalopathy, with vomiting and a reduced level of consciousness, often accompanied by hepatomegaly. The biochemical features – hypoketotic hypoglycaemia, with or without hyperammonaemia – resemble those seen in fatty acid oxidation disorders. The organic acids are diagnostic in HMG-CoA lyase deficiency. In HMG-CoA synthase deficiency, the organic acids are characteristic during decompensation but normal at other times. Ketone body utilisation is catalysed bysuccinyl-CoA:3-ketoacid CoA transferase (SCOT)and mitochondrial acetoacetyl-CoA thiolase (T2). Deficiencies of SCOT, T2 or the monocarboxylate transporter 1 (MCT1) present with episodes of ketoacidosis. This is often accompanied by dehydration and decreased consciousness. The organic acids usually show characteristic abnormalities in T2 deficiency but there are no specific findings in SCOT or MCT1 deficiencies and diagnosis relies on molecular analysis. In all these disorders, the primary aim of treatment is to prevent decompensation. Fasting is avoided and a high glucose intake is maintained at times of metabolic stress, such as infections. This chapter also briefly discusses the use of ketogenic diets in inherited metabolic disease.