Research Notes: 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency

See also 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency.

Note: According to Metagene, this is the only inborn error of metabolism in which the acylcarnitine profile shows elevated adipylcarnitine/methylglutarylcarnitine (C6-DC).

Background: 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase has a dual function in the breakdown of leucine and in regulating production of ketone bodies. It is located predominantly in mitochondria, but is also found in peroxisomes. In the last step in leucine metabolism, it cleaves 3-hydroxy-3-methylglutaryl-CoA, producing acetyl-CoA and acetoacetate, one of the ketone bodies. HMG-CoA lyase deficiency was first described in 1971 and more than 60 patients have subsequently been diagnosed.

Clinical: HMG-CoA lyase deficiency typically presents within the first week of life, though some patients have onset later in the first year. The onset of symptoms is initiated by fasting, infection, dietary protein load, or simply the stress of birth. Symptoms progress from vomiting, lethargy, trachypnea [rapid breathing] and dehydration to coma and possibly death. Hepatomegaly and neurologic abnormalities are seen on physical exam. Laboratory studies reveal non-ketotic hypoglycemia, metabolic acidosis, hyperammonemia and elevated liver transaminases. Abnormal urine organic acids are present as well as the distinctive elevated plasma acylcarnitine species.

Testing: Newborns can be screened for HMG-CoA lyase deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated six-carbon dicarboxylic acylcarnitine (C6-DC) and C5-hydroxy acylcarnitine (C5-OH), suggests the metabolic defect. To make a diagnosis, further testing is required. Urine organic acid analysis of a patient with HMG-CoA lyase deficiency will reveal elevation of 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-hydroxyisovaleric acids. A diagnosis should be confirmed by measurement of HMG-CoA lyase enzyme activity in fibroblasts or leukocytes. Prenatal diagnosis is possible by measuring 3-hydroxy-3-methylglutaric acid in amniotic fluid and by assaying HMG-CoA lyase enzyme activity in cultured amniocytes and chorionic villi cells. Mutations in the HMG-CoA lyase gene on chromosome 1 have been identified in a number of patients and prenatal diagnosis can be accomplished using DNA analysis.

Treatment: Acute symptoms of HMG-CoA lyase deficiency should be treated with IV glucose, bicarbonate for the metabolic acidosis and restriction of protein (leucine). During an acute episode, patients may require assisted ventilation. For the long-term treatment, affected patients should avoid fasting and restrict protein intake.

Because the diagnosis and therapy of HMG-CoA lyase deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patients physician.

Inheritance: This disorder most often follows an autosomal recessive inheritance pattern.

Ann Neurol. 2004 Nov.
3-hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult with leukoencephalopathy.
Bischof F, Nägele T, Wanders RJ, Trefz FK, Melms A.
Department of General Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a disorder of leucine metabolism that usually presents with recurrent episodes of life-threatening hypoglycemia during early childhood. We report on a 36-year-old woman with seizures, recurrent metabolic disturbances, and severe leukoencephalopathy. The diagnosis was made by analysis of amino acids in urine and serum and was confirmed by demonstration of the deficient enzyme in cultured skin fibroblasts. The patient improved clinically on oral L-carnitine substitution. This treatable condition can remain unrecognized in adults and should be considered a potential cause of leukoencephalopathy.

Proc Natl Acad Sci USA. 1999 Feb 2.
Mitochondrial disease in superoxide dismutase 2 mutant mice.
Melov S, Coskun P, Patel M, Tuinstra R, Cottrell B, Jun AS, Zastawny TH, Dizdaroglu M, Goodman SI, Huang TT, Miziorko H, Epstein CJ, Wallace DC.
Center for Molecular Medicine, Emory University, Atlanta, GA, USA.
[ Free full text ]

Oxidative stress has been implicated in many diseases. The chief source of reactive oxygen species within the cell is the mitochondrion. We have characterized a variety of the biochemical and metabolic effects of inactivation of the mouse gene for the mitochondrial superoxide dismutase (CD1-Sod2(tm1Cje)). The Sod2 mutant mice exhibit a tissue-specific inhibition of the respiratory chain enzymes NADH-dehydrogenase (complex I) and succinate dehydrogenase (complex II), inactivation of the tricarboxylic acid cycle enzyme aconitase, development of a urine organic aciduria in conjunction with a partial defect in 3-hydroxy-3-methylglutaryl-CoA lyase, and accumulation of oxidative DNA damage. These results indicate that the increase in mitochondrial reactive oxygen species can result in biochemical aberrations with features reminiscent of mitochondrial myopathy, Friedreich ataxia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

Arq Neuropsiquiatr. 1998 Sep.
3-Hydroxy-3-methyl-glutaryl-CoA-lyase deficiency as coma etiology in the neonatal period: case report. [Article in Portuguese]
Casella EB, Martins FR, Miura IK, Vieira MA, Porta G.
Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (FMUSP), Brasil.

We report a patient that presented two episodes of coma in the neonatal period, with severe metabolic acidosis and hypoglycemia, without ketosis. The urinary organic acid analysis showed increased amounts of 3-hydroxy-3-methyl-glutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acid. The deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase was diagnosed by the clinical and metabolic features. This disease shows autosomal recessive inheritance and the treatment is done by a diet with restriction of protein (mainly leucine) and lipids, high in carbohydrate content, and the avoidance of fasting and carnitine supplementation.

Rev Neurol. 1998 Jun.
3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome. [Article in Spanish]
Eiris J, Ribes A, Fernandez-Prieto R, Rodriguez-Garcia J, Rodriguez-Segade S, Castro-Gago M.
Servicio de Neuropediatria, Hospital General de Galicia, Santiago de Compostela.

INTRODUCTION: 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMG-CoA lyase) is an inborn error of ketogenesis and Leucine catabolism. HMG-CoA lyase catalyses the final step in leucine degradation, converting HMG-CoA to acetyl-CoA and acetoacetic acid. Clinical manifestations include hepatomegaly, lethargy or coma and apnoea. Biochemically there is a characteristic absence of ketosis with hypoglycemia, acidosis, hipertransaminasemia and variable hyperammoniemia. The urinary organic acid profile includes elevated concentrations of 3-hydroxy-3-isovaleric, 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-methylglutaric acids. CLINICAL CASE: Here, we report the case of a 17-year-old girl who presented in both ten months and five years of age a clinical picture characterized by lethargy leading to apnea and coma, hepatomegaly, hypoglycemia, metabolic acidosis, hyperammoniemia, elevated serum transaminases and absence of ketonuria. Diagnostic of Reye syndrome was suggested by hystopathologic finding of hepatic steatosis and clinical and biochemical data. As of 11 years old, laboratory investigations revealed carnitine deficiency and characteristic aciduria. Confirmatory enzyme diagnosis revealing deficiency of HMG-CoA lyase was made in cultured fibroblasts. CONCLUSION: Our report constitutes an example of the presentation of HMG-CoA lyase deficiency as recurrent Reye-like syndrome.

Eur J Pediatr. 1993 Aug.
Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria.
Ibel H, Endres W, Hadorn HB, Deufel T, Paetzke I, Duran M, Kennaway NG, Gibson KM.
University Children's Hospital, München, Germany.

In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.

Acta Paediatr Jpn. 1992 Apr.
GC/MS analysis of urine in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
Shinka T, Kuhara T, Inoue Y, Matsumoto M, Matsumoto I, Nakamura H, Irimichi H, Hasumi K, Endo A.
Division of Human Genetics, Kanazawa Medical University, Japan.

A patient with 3-hydroxy-3-methylglutaric aciduria was diagnosed using gas chromatography mass spectrometry. The patient had severe metabolic acidosis, hypoglycemia and hyperammonemia and excreted abnormal amounts of 3-methylglutaconic, 3-hydroxy-3-methylglutaric, 3-methylglutaric, 3-hydroxyisovaleric and glutaric acids in the urine. 3-Hydroxy-3-methylglutaric acid appeared as two peaks on the chromatogram after trimethylsilylation. One was a tri-trimethylsilyl and the other a di-trimethylsilyl derivative. 3-Methylglutaconic acid appeared as three peaks: cis-, trans- and cyclic cis-isomers. The structure of these derivatives was elucidated by deuterium-labeled trimethylsilyl derivatization. The di-trimethylsilyl derivative of 3-hydroxy-3-methylglutaric acid and the cyclic cis-isomer of 3-methylglutaconic acid do not appear to have been previously described. After treatment with leucine restriction milk, the excretion of leucine catabolites decreased but 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids continued to be excreted at abnormally high levels. It is concluded that these two metabolites are necessary for the chemical diagnosis of HMG-CoA lyase deficiency. This patient is the first case of HMG-CoA lyase deficiency to be reported in Japan.

An Esp Pediatr. 1990 Feb.
Sudden death of a patient with 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency. [Article in Spanish]
Vilaseca Busca MA, Ribes Rubio A, Briones Godino P, Cusi Sánchez V, Baraíbar Castelló R, Gairi Taull JM.
Instituto de Bioquímica Clínica, Diputación de Barcelona, Cerdanyola.

A new case of neonatal 3-hydroxy-3-methylglutaric aciduria is described. 3-hydroxy-3-methylglutaryl CoA lyase activities in leukocytes demonstrated the patient's homozygosity and the heterozygous character of the parents and two other members of the family. Dietetic management with low fat high carbohydrate diet together with protein restriction and carnitine resulted in a good control of the metabolic acidosis, the hypoglycemia, and the physical and neurological development. Nevertheless, sudden death occurred at the age thirteen months without any previous apparent trouble and the necropsia showed neither signs of infection nor hepatic or cardiac derangement.

Eur J Pediatr. 1988 Dec.
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients.
Gibson KM, Breuer J, Nyhan WL.
Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.

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-methyl-glutaconic, 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.

J Inherit Metab Dis. 1987.
3-Hydroxy-3-methylglutaric aciduria: response to carnitine therapy and fat and leucine restriction.
Dasouki M, Buchanan D, Mercer N, Gibson KM, Thoene J.
Department of Pediatrics, University of Michigan, Ann Arbor.

A female infant, born to first cousin parents, lapsed into coma with severe metabolic acidosis on day three of life. The gas chromatographic/mass spectrometric urinary organic acid profile showed marked elevation of the leucine metabolites 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxy-isovaleric acids. Less than 5% of the normal activity of the enzyme 3-hydroxy-3-methylglutaryl CoA lyase was detected in cultured skin fibroblasts. The patient's total and free carnitine was initially low but rose to normal levels after placing her on DL-carnitine (100 mg kg-1 d-1). On a diet providing 87 mg kg-1 d-1 of leucine and only 25% of total calories as fat and 2 g kg-1 d-1 protein, the concentration of the urinary organic acids fell markedly. She is now 15 months old with normal growth and development. This regimen appears effective in the early treatment of 3-hydroxy-3-methylglutaric aciduria.

J Clin Invest. 1986 Apr.
Identification of 3-methylglutarylcarnitine. A new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.
Roe CR, Millington DS, Maltby DA.
[ Free full text ]

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.

J Inherit Metab Dis. 1986.
3-Hydroxy-3-methylglutaryl-coenzyme a lyase deficiency: a review.
Wysocki SJ, Hähnel R.

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.

J Neurogenet. 1984 Apr.
3-Hydroxy-3-methylglutaric aciduria.
Greene CL, Cann HM, Robinson BH, Gibson KM, Sweetman L, Holm J, Nyhan WL.

3-Hydroxy-3-methylglutaric aciduria was found in a newborn infant whose parents are first cousins. The patient presented at 5 days of life with hyperammonemia, hypoglycemia, and metabolic acidosis. There was no ketonuria. Diagnosis was made by analysis of the pattern of organic acids excreted in the urine. A profound deficiency in activity of 3-hydroxy-3-methylglutaryl-coenzyme A lyase was found in cultured skin fibroblasts. The parents had intermediate levels of enzyme activity.

Neurology. 1980 Jul.
Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome.
Robinson BH, Oei J, Sherwood WG, Slyper AH, Heininger J, Mamer OA.

A 2-year-old boy had acute fever, malaise, and somnolence with hepatomegaly, increased blood ammonia content (338 microM), high SGOT, low blood glucose content, and mild acidosis. A liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes, and abnormal urinary metabolites included beta-hydroxy-beta-methyl glutarate (HMG), beta-methylglutaconate, beta-hydroxyisovalerate, and beta-methylglutaric and glutaric acids. In cultured skin fibroblasts and liver, beta-hydroxy-beta-methyl glutaryl CoA lyase activity was about 10% of normal. Therefore, a genetic deficiency of HMGCoA lyase activity can cause a clinical syndrome similar to that of Reye syndrome when the patient is stressed by an acute viral infection.

Clin Chim Acta. 1979 Jul 2.
Studies on a child suspected of having a deficiency in 3-hydroxy-3-methylglutaryl-Co A lyase.
Truscott RJ, Halpern B, Wysocki SJ, Hähnel R, Wilcken B.

The urine of a child who presented with hyperammonemia was found to contain elevated levels of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid and 3-methylglutaric acid. An increased excretion of these organic acids has been reported previously in a child with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Enzyme studies using cultured fibroblasts from this patient, however, indicated that the 3-hydroxy-3-methylglutaryl-CoA lyase activity was not markedly reduced.

Clin Chim Acta. 1978 Dec 1.
Organic acid excretion in a patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency: facts and artefacts.
Duran M, Ketting D, Wadman SK, Jakobs C, Schutgens RB, Veder HA.

The organic acid excretion in a patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency is described. In addition to 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids, substantial amounts of glutaric and adipic acids were repeatedly observed. 3-Methylcrotonic acid and possibly one of its isomers was found to be formed artificially from 3-methylglutaconic acid.