3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMG-CoA lyase) is an inborn error of leucine catabolism which often leads to life-threatening illness in the neonatal period. The cardinal clinical features include severe infantile hypoglycemia, metabolic acidosis, hepatomegaly, lethargy or coma and apnea. Hyperammonemia is variable. There is a characteristic absence of ketosis. Considerable heterogeneity has been observed in clinical and biochemical presentation. Acute episodes of illness have been mistaken for Reye syndrome. The pattern of organic acids in the urine includes large amounts of 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids. Smaller, but appreciable levels of glutaric, adipic and other dicarboxylic acids may also be excreted in the urine. Lactic acid may be present in sizable amounts at times of acute illness. The primary defect is a deficiency of 3-hydroxy-3-methylglutaryl-coenzyme A lyase, a key enzyme in the cycle of ketogenesis.

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients.

There are now nine inherited diseases that have been identified in the pathway of mitochondrial fatty acid oxidation, including LCAD, MCAD, SCAD, and HMG-CoA lyase deficiencies, two forms each of CPT and MAD deficiencies and an incompletely characterized disorder of primary carnitine deficiency. The varied range of clinical manifestations in this new group of diseases should attract the attention not only of general pediatricians (coma, hypoglycemia) but also of pediatric subspecialists in neurology (myopathy), cardiology (cardiomyopathy), and gastroenterology (fatty liver), as well as genetics and metabolism. The presenting features of the genetic defects in fatty acid oxidation fit well with the concept that fatty acid oxidation plays a major role in energy production during prolonged fasting and in working cardiac and skeletal muscle. Life-threatening episodes of coma and hypoglycemia induced by fasting are a common presenting feature in most of the fatty acid oxidation disorders (MCAD, LCAD, and HMG-CoA lyase deficiencies, the infantile form of CPT deficiency, the mild form of MAD deficiency, and in some cases of primary carnitine deficiency). The hypoglycemia in these disorders is most easily explained by the inability of affected patients to use fatty acids as a fuel as a substitute for glucose. It should be stressed, however, that the coma in these disorders may occur from direct toxic effects of fatty acids or fatty acid intermediates before plasma glucose concentrations reach hypoglycemic levels. Severe disturbances of muscle function are a feature in several of the disorders; hypertrophic cardiomyopathy and chronic skeletal muscle weakness occur in both the mild and severe forms of MAD deficiency, in primary carnitine deficiency, and in some patients with LCAD deficiency. In contrast, patients with the adult form of CPT deficiency have normal muscle strength but are prone to episodes of painful rhabdomyolysis induced by prolonged exercise. These manifestations presumably reflect the requirement of working cardiac and skeletal muscle for energy supplied from fatty acid oxidation. In two of the disorders, SCAD deficiency and the severe form of MAD deficiency, chronic CNS toxicity is a dominant feature. The severe effects on the brain in these two disorders may reflect the fact that short-chain fatty acids more readily cross the blood-brain barrier than longer-chain fatty acids. Since the presence of an underlying defect in fatty acid oxidation is unlikely to be appreciated with routine laboratory tests, the genetic defects in fatty oxidation are easily and often misdiagnosed as other diseases, such as Reye's syndrome and sudden infant death syndrome. The possibility of a defect in fatty acid oxidation should be considered in all patients with coma and hypoglycemia associated with fasting and in patients with skeletal muscle weakness or cardiomyopathy. The demonstration of inappropriately low urinary ketones (i.e., anything less than large) at a time of illness is a simple clue to the diagnosis. The most powerful tool in the diagnosis of the defects in fatty acid oxidation is an examination of the urinary organic acid profile by gas chromatography or gas chromatography-mass spectroscopy. It is most likely to be revealing with a urine sample obtained at a time of illness. Additional diagnostic information may be obtained from studies of plasma and tissue carnitine levels, the identification of abnormal urinary acyl-carnitine esters, and studies of fatty acid oxidation in cultured skin fibroblasts. Specific enzyme deficiencies for most of the disorders can be demonstrated in peripheral blood leukocytes or cultured skin fibroblasts. Clinical studies of fasting adaptation can be useful in demonstrating an impairment in fatty acid oxidation but should be done only with great caution since fasting may provoke a life-threatening illness in these patients. It is likely that additional genetic defects in mitochondrial fatty acid oxidation will be added to this group of disorders in the future. Potential sites for other enzyme defects in the pathway include HMG-CoA synthase, hydroxyacyl-CoA dehydrogenase, and at least two chain-length specific enzymes each for the acyl-CoA hydratase and β-keto thiolase steps in the β-oxidation cycle. A syndrome of primary carnitine deficiency is included in the present list of the genetic defects in fatty acid oxidation. However, because of the recognition that many of the enzyme defects in fatty acid and amino acid oxidation have an associated secondary carnitine deficiency, further work is needed to clarify the basic underlying abnormality in this syndrome. The possibility of an acquired defect in fatty acid oxidation due to a deficiency of carnitine has been suggested in several different clinical situations, including newborn infants who have been fed carnitine-free formulas. Functional consequences due to lowered carnitine levels in these situations have not yet been clearly demonstrated, however, and the need for a dietary supply of carnitine in the newborn infant remains to be established. 

New Genetic Defects in Mitochondrial Fatty Acid Oxidation and Carnitine Deficiency

Deficiency of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) lyase affects the metabolism of leucine as well as ketogenesis. This disorder is one of an increasing list of inborn errors of metabolism that presents clinically like Reye's Syndrome or nonketotic hypoglycemia. Four patients with proven 3-hydroxy-3-methylglutaryl-CoA lyase deficiency were shown to excrete a new diagnostically specific metabolite. The technique of fast atom bombardment and tandem mass spectrometry revealed that only 3-methylglutaryl-CoA is a substrate for acylcarnitine formation. Neither 3-methylglutaconyl-CoA nor 3-hydroxy-3-methylglutaryl-CoA are excreted as acylcarnitines. The excretion of 3-methylglutarylcarnitine may explain, in part, the apparent secondary carnitine deficiency in this disorder. Carnitine supplementation with moderate dietary restrictions may be a useful treatment strategy for this disorder.

/pdf/identification-of-3-methylglutarylcarnitine-a-new-diagnostic-txcfwy826c.pdf

Identification of 3-methylglutarylcarnitine. A new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.

Five new patients are reported and the pathogenesis of the hypoglycaemia without ketogenesis is discussed. This report extends a recent review.J. Inher. Metab. Dis. 9, 225–233.

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients.

signs. In the light of these new risk figures which give a median onset age of 49 years, the section on the use of age of onset in genetic counselling should be revised. However, Dr Hayden is right to emphasise that there is more to the duties of a genetic counsellor than the provision of genetic risks. The last chapters describe the management of patients with Huntington's chorea, including some precise drug regimens, and discuss new prospects in research. The book thus provides a comprehensive review of Huntington's chorea, written by someone with wide experience of and sympathy towards the disease. It is an excellent monograph, interesting and stimulating, and I also found a it valuable source of reference. S BUNDEY

https://jmg.bmj.com/content/jmedgenet/20/2/159.2.full.pdf

Organic Acids in Man. The Analytical Chemistry, Biochemistry and Diagnosis of the Organic Acidurias

A 4-month-old infant with hypotonia and macrocephaly was diagnosed as having 3-hydroxy-3-methylglutaric aciduria, using gas chromatography and mass spectrometry and confirmatory enzyme studies. The same diagnosis was made on his asymptomatic non-indentical twin. Examination of the pedigree is consistent with an autosomal recessive mode of inheritance. Dietary treatment improved the symptoms of the propositus, but did not prevent episodes similar to Reye's syndrome in both twins. One such episode closely followed immunisation and our experience suggests that children with this disorder should be observed carefully following immunisation. These episodes were accompanied by an overflow of a wide range of abnormal metabolites. Examination of the urine for organic acids should be considered in infants with unexplained hypotonia and macrocephaly, especially if accompanied by abnormal biochemical indices.

Dizygotic twins with 3-hydroxy-3-methylglutaric aciduria; unusual presentation, family studies and dietary management

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Dizygotic twins with 3-hydroxy-3-methylglutaric aciduria; unusual presentation, family studies and dietary management