HMG-CoA lyase deficiency

Inherited defects in the enzymes of (3-oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, and fatty hver. Defects are known in long- and short-chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of acute fetty liver of pr nancy). 3-Ketoacyl-CoA thiolase and HMG-CoA lyase deficiency also affect the degradation of leucine, a ketogenic amino acid (Chapter 30). 

HMG-CoA lyase is normally present in the mitochondrial matrix.To understand the complexity of the metabolic problems of a patient with HMG-CoA lyase deficiency, it is necessary to consider the role of this enzyme in two very distinct metabolic pathways catabolism of leucine and ketogenesis. 

For most patients with HMG-CoA lyase deficiency, strict dietary control can maintain... 

Carnitine deficiency complicates HMG-CoA lyase deficiency and other inborn errors of metabolism, which results in organic acidemia. L-Camitine or P-hydroxy-y-trimethylammonium butyrate is a carrier molecule that transports long-chain fatty acids across the inner mitochondrial membrane for subsequent P-oxi-dation. L-Carnitine also facilitates removal of toxic metabolic intermediates or xenobiotics via urinary excretion of their acyl carnitine derivatives. Indeed, individuals with HMG-CoA lyase deficiency have been shown to excrete 3-methylgluatarylcamitine (Roe et al., 1986). In the absence of ketogenesis, the formation of the acyl carnitine derivative of 3-hydroxy-3-methylglutarate from HMG-CoA also serves to regenerate free CoA in the mitochondria and permits continued P-oxidation of fatty acids. 

Individuals with HMG-CoA lyase deficiency are particularly susceptible to carnitine deficiency. With restriction of red meats and dairy products, dietary carnitine intake is quite low. Carnitine is also synthesized endogenously from the modified, methylated lysine resides of various proteins free trimethyllysine is released when the protein is degraded. Since the therapy for patients with HMG-CoA lyase deficiency must minimize their endogenous protein catabolism, they also have limited availability of trimethyllysine for carnitine synthesis. 

Nutritional therapy for HMG-CoA lyase deficiency has two major goals. First, the prescribed diet aims to provide enough total protein and calories to achieve normal growth and maintain metabolic balance in the context of a leucine-restricted diet. Equally important, the nutritional therapy focuses on preventing excess catabolism, acidosis, and hypoglycemia, especially during times of acute illness. For these patients, it is particularly important to avoid fasting at any time. 

In summary, HMG-CoA lyase deficiency is a unique inborn error of metabolism with profound effects on both amino acid catabolism and metabolic homeostasis in the fasted state. Management of these patients is difficult and requires constant attention to daily nutrition and timely intervention during acute illness. Fortunately, nutritional therapy treatment that provides a diet adequate for growth but with limited intake of leucine and prevents fasting and hypoglycemia enables individuals with HMG-CoA lyase deficiency to live normal active lives. 

Why do individuals with HMG-CoA lyase deficiency have difficulty fasting ... 

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

Glycerol kinase deficiency HMG-CoA lyase deficiency Methylmalonic aciduria Mitochondrial disorders 2-oxoadipic aciduria Propionic aciduria Additional causes Bacterial production MCT containing formulas Riboflavin deficiency (acquired)... 

C5-OH) T (3-MCC) deficiency [7] 3-OH-3-methylglutaryl-CoA (HMG CoA) lyase deficiency [6] Holocar-boxylase deficiency Biotinidase deficiency [7]... 

Note that MS/MS is unable to distinguish between isomeric acylcarnitines. Therefore, elevations of C4 can be either from accumulation of butyr-yl or isobutyryl carnitine, C5 can be either isovaleryl or 2-methylbutyryl and so on. Some individual metabolites are characteristic of more that one disease. Propionylcarnitine is markedly elevated in both propionic and methylmalonic acidemia. 3-Hydroxyisovalerylcarnitine (OH-C5) is associated with both 3-MCC deficiency and HMG-CoA-lyase deficiency. Minor elevations in either or both of these metabolites are also consistent with ho-locarboxylase deficiency or with deficiency of the cofactor biotin (or bioti-nidase). The differential diagnosis of each of these conditions is generally made from a careful analysis of urinary organic acids, performed by capillary column GC/MS in a reputable facility. This is especially important in the follow-up of abnormal newborn screening acylcarnitine results. 

The inborn errors of L-leucine catabolism present biochemically with branched-chain amino and/or organic aciduria [1]. These disorders include maple syrup disease (MSD branched-chain a-ketoacid dehydrogenase (BCKD) deficiency), isovaleric acidemia (isovaleryl-coenzyme A (CoA) dehydrogenase deficiency), isolated 3-methylcrotonyl-CoA carboxylase deficiency, the 3-methylglutaconic acidurias (3-methylglutaconyl-CoA hydratase deficiency, Barth syndrome, and other disorders in which the primary defect has not been demonstrated), and 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency). 

HMG-CoA lyase deficiency F, WBC RT-PCR genomic amplification and sequencing ASO SSCP... 

Mitchell, G.A., Ozand P.T., Robert, M.-F. et al. (1998). HMG CoA lyase deficiency Identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. Am. J. Hum. Genet. 62, 295-300. 

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