3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: A review

Children with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA-LD; McKusick 24645), have inherited two areas of metabolic weakness. Firstly, they are unable to metabolize fully the carbon skeleton of leucine, and secondly, they cannot make ketone bodies in response to prolonged fasting. In the first year of life infants with HMG-CoA-LD run a high risk of developing severe hypoglycaemia which can lead to death if prompt intervention does not occur. The metabolic crisis develops when the infant is first introduced to dietary protein soon after birth, or later, when a reduced intake of glucose, often during a viral infection, results in a drain on the infant's circulating glucose levels. However, where diets are adequately adjusted to limit protein and fat intake, the metabolic handicaps of individuals with HMG-CoA-LD are not exposed and they are virtually symptomless. As children with HMG-CoA-LD grow older the incidence of hypoglycaemic attacks diminishes and they usually develop normally. This article reviews literature on cases of HMG-CoA-LD and interprets data on altered metabolism in these children.     

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia

Summary Deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase has been studied in 11 Saudi infants. The diagnosis was established by the measurement of enzyme activity in lymphocytes, in fibroblasts and, in seven patients, by the gas chromatography/mass spectrometer pattern of excreted organic acids in the urine. In seven infants the disease caused a devastating acidotic attack within the first day of life, while in two the crisis occurred by the third day of life. In two infants from one family the disease appeared later in infancy. The clinical presentation of an acidotic attack is lethargy, hyperpnoea, tachypnoea and seizures, either at birth (two infants), following first feeding (in five infants), or following vomiting or refusal of food in later infancy. The acidotic attacks recurred later in life following minor illness or refusal to eat. The acidosis of this enzyme deficiency progresses rapidly, leading to cardiopulmonary arrest and death within hours of onset unless treated promptly. In four surviving infants diagnosed and treated early, development is normal. Magnetic resonance and computerized tomography brain scans in these infants, however, show white matter lesions and mild atrophy.     

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Biochemical studies and family investigation of four generations

Summary 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase activity was determined by the recently described spectrophotometric method of Wanderset al. (1988a) in polymorphonuclear leukocytes and lymphocytes obtained from 33 members of a highly consanguineous Arab-Bedouin family belonging to four generations. Seven subjects were obligatory heterozygotes (parents and grandparents of three propositi); in seven additional subjects enzyme activity in both cell types was in the heterozygote range. No asymptomatic homozygotes were found. The results support the proposed autosomal recessive mode of inheritance of this disorder.     

3-hydroxy-3-methylglutaryl-coenzyme a lyase deficiency: Report of five new patients

Summary 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.     

Glucose metabolism in a child with 3-hydroxy-3-methylglutaryl-coenzyme a lyase deficiency

A child with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency suffered from fasting hypoglycaemia and impaired ketone body formation.     

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency in a boy with VATER association

Journal of Inherited Metabolic Disease -     

3-Hydroxy-3-methylglutaryl-CoA-lyase deficiency

Journal of Inherited Metabolic Disease -     

3-Hydroxy-3-methylglutaryl-coenzyme A reductase is present in peroxisomes in normal rat liver cells.

The location inside rat liver parenchymal cells of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34), the key regulatory enzyme in cholesterol biosynthesis, has been examined by immunoelectron microscopy and by subcellular fractionation. Although HMG-CoA reductase is generally thought to be exclusively a microsomal enzyme, we find that a substantial portion of cellular HMG-CoA reductase is localized in peroxisomes. Immunoelectron microscopic labeling of ultrathin frozen sections of normal rat liver, using two monoclonal antibodies to purified HMG-CoA reductase, showed that the enzyme is present in the peroxisomes at a higher concentration than at any other site inside the hepatocytes. Subcellular fractionation studies using Percoll and metrizamide gradients demonstrated a close correspondence of peaks of HMG-CoA reductase activity and of catalase activity, again revealing the presence of the reductase enzyme in peroxisomes. HMG-CoA reductase is therefore localized in peroxisomes in addition to being in the microsomal fraction.     

3-Hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency

Summary: A boy now 8 years old presented at 21 months of age with developmental arrest, followed by regression, cortical blindness and myoclonic seizures. Urine organic acid analysis revealed 3-hydroxy-2-methylbutyric acid and tiglyglycine; 3-ketothiolase enzyme activity was normal and he was subsequently found to have 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency.     

3-Hydroxy-3-methylglutaryl-coenzyme A reductase from Arabidopsis thaliana is structurally distinct from the yeast and animal enzymes.

We have isolated the Arabidopsis thaliana gene (HMG1) encoding 3-hydroxy-3-methylglutaryl-CoA reductase [HMG-CoA reductase; (S)-mevalonate:NAD+ oxido-reductase (CoA-acylating), EC 1.1.1.88], the catalyst of the first committed step in isoprenoid biosynthesis. cDNA copies of the plant gene were identified by hybridization with a short, highly conserved segment of yeast HMG-CoA reductase as probe. DNA sequence analysis reveals that the COOH-terminal domain of the Arabidopsis HMG-CoA reductase (containing the catalytic site of the enzyme) is highly conserved with respect to the yeast, mammalian, and Drosophila enzymes, whereas the membrane-bound amino terminus of the Arabidopsis protein is truncated and lacks the complex membrane-spanning architecture of the yeast and animal reductases. Expression of the Arabidopsis gene from the yeast GAL1 promoter in a yeast mutant lacking HMG-CoA reductase activity suppresses the growth defect of the yeast mutant. Taken together, the sequence similarity to other cloned HMG-CoA reductase genes and the suppression of the yeast hmg- mutant provide strong evidence that the novel Arabidopsis gene we have cloned encodes a functional HMG-CoA reductase enzyme.