Alternative titles; symbols
SNOMEDCT: 124611007; ORPHA: 20;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.11 | HMG-CoA lyase deficiency | 246450 | Autosomal recessive | 3 | HMGCL | 613898 |
A number sign (#) is used with this entry because of evidence that 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is caused by homozygous or compound heterozygous mutation in the HMGCL gene (613898) on chromosome 1p36.
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988).
Faull et al. (1976) reported a 7-month-old male infant from Australia with metabolic acidosis and hypoglycemia, who excreted organic acids suggestive of a defect in 3-hydroxy-3-methylglutaryl CoA lyase, the enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. The profile of urinary organic acids was different from that of 3 previously identified defects of leucine degradation--maple syrup urine disease (248600), isovaleric acidemia (243500), and methylcrotonylglycinemia (210200). Wysocki and Hahnel (1976) demonstrated marked deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase activity in leukocytes from the infant reported by Faull et al. (1976). Both parents had reduced levels of HMG-CoA lyase in leukocytes. The biochemical diagnosis is made by the finding of abnormal organic aciduria with greatly increased urinary excretion of 3-hydroxy-3-methylglutaric acid and related substances. The enzyme can be measured in leukocytes and fibroblasts. Shilkin et al. (1981) provided further follow-up on this patient. At the age of 4 years and 7 months, he appeared to be well and developing satisfactorily. His diet had been difficult to control and the biochemical defect was exceedingly sensitive to small amounts of leucine in the diet.
Duran et al. (1979) reported a Moroccan family in which 4 of 7 sibs had HMG-CoA lyase deficiency. Prenatal diagnosis was possible by demonstration of HMG acid in the mother's urine. Recessive inheritance was supported by intermediate levels of lyase activity in both parents.
Leonard et al. (1979) reported a patient with HMG-CoA lyase deficiency presenting as Reye syndrome.
Robinson et al. (1980) described the case of a 2-year-old boy with acute fever, malaise, and somnolence with hepatomegaly, hyperammonemia, high SGOT, hypoglycemia and mild acidosis. Liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes. Abnormal urinary metabolites included beta-hydroxy-beta-methyl-glutarate (HMG). In liver and cultured skin fibroblasts, HMG-CoA lyase activity was about 10% of normal. The urine had an odor resembling that of a cat. The child's parents were unrelated and came from San Miguel in the Azores. Robinson et al. (1980) noted features resembling Reye syndrome.
Wilson et al. (1984) stated that acute pancreatitis is found at autopsy in over 7% of cases of Reye syndrome. They reported a 5-year-old child with a history of recurrent hypoglycemia who presented with a Reye-like syndrome and acute pancreatitis. HMG-CoA lyase deficiency was established by enzymatic analysis of skin fibroblasts and lymphocytes. This disorder is one of an increasing list of inborn errors of metabolism that clinically present as Reye syndrome or nonketotic hypoglycemia.
Berry et al. (1981) found deficiency of 3-hydroxy-3-methylglutarate CoA lyase in liver and cultured fibroblasts of 2 related children ascertained because of abnormal metabolites in the urine: 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. A shortage of glucose-sparing ketone bodies normally produced during fasting was thought to be responsible for the hypoglycemia that characterizes this metabolic defect. The absence of ketonuria in this disorder is a direct consequence of the metabolic lesion. HMG-CoA lyase is involved in ketogenesis, and the patient with the deficiency is compromised in the ability to generate ketone bodies.
Despite the clinical heterogeneity observed with HMG-CoA lyase deficiency, Sovik et al. (1984) could find no evidence of biochemical heterogeneity (residual enzyme activity in cultured fibroblasts was equally low in all 7 cases studied) or genetic heterogeneity (no complementation was observed in heterokaryons).
Roe et al. (1986) demonstrated 3-methylglutarylcarnitine in the urine of 4 patients with this disorder and suggested this as the cause of an apparently secondary carnitine deficiency. They suggested that dietary supplementation with carnitine may be warranted.
Wysocki and Hahnel (1986) reviewed 12 patients, and Gibson et al. (1988) reported 5 others. Gibson et al. (1988) reviewed 18 reported cases.
Ribes et al. (1990) described sudden death in a 13-month-old boy with HMG-CoA lyase deficiency.
Barash et al. (1990) determined HMG-CoA lyase activity by the spectrophotometric method of Wanders et al. (1988) in polymorphonuclear leukocytes and lymphocytes obtained from 33 persons in 4 generations of a highly consanguineous Arab-Bedouin family. Seven subjects were obligatory heterozygotes, being parents and grandparents of 3 propositi; in 7 additional subjects, enzyme activities in both cell types were in the heterozygous range. No asymptomatic homozygotes were found.
Grunert et al. (2017) reviewed the clinical presentation and outcome in a series of 37 patients with HMGCLD, including 30 patients from Turkey and the rest from Belgium, Germany, The Netherlands, and Switzerland. Most patients (94%) presented with an acute metabolic decompensation in the first year of life, approximately half in the neonatal period. The most common clinical symptoms were recurrent vomiting, seizures, and impaired vigilance. The most common laboratory findings were hypoglycemia, acidosis, an increased anion gap, hyperammonemia, and elevated transaminase activities. Of 32 patients, 10 had no further metabolic decompensations after diagnosis, and 22 had at least one more metabolic crisis, most often associated with infections, especially gastroenteritis or respiratory tract infections. Half of the patients had normal cognitive development, and the remainder had psychomotor deficits of variable severity. Six of the patients had died at a mean age of 11 years (range, 4 months to 40 years).
HMG-CoA lyase deficiency is treatable by diet and avoidance of prolonged fasting. Leucine is restricted and supplementary glucose given to prevent hypoglycemia. Without treatment, death occurs early (Duran et al., 1979; Gibson et al., 1988).
HMG-CoA lyase deficiency is an autosomal recessive disorder (Mitchell et al., 1992).
Muroi et al. (2000) stated that the incidence of HMG-CoA lyase deficiency is low, except in Saudi Arabia where the deficiency comprises 16% of all organic acidemia (Ozand et al., 1992). Otherwise, only 41 cases had been reported in the English literature and only 5 cases had been reported from Japan. Ozand et al. (1991, 1992) reported that the disorder in Saudi Arabian patients is particularly severe.
Mitchell et al. (1993) characterized mutation in the HMGCL gene causing human HL deficiency; see 613898.0001-613898.0002.
By genomic Southern blot analysis and exonic PCR, Wang et al. (1996) found that 2 of 33 HMGCL-deficient patient probands were homozygous for different large deletions in the gene (see, e.g., 613898.0003).
Muroi et al. (2000) presented the results of a molecular analysis of all known 5 Japanese cases of HMG-CoA lyase deficiency together with their clinical phenotypes. Five different mutations were identified: 1 large deletion, 1 nonsense mutation, 1 missense mutation, and 2 splice mutations. A glu279-to-lys (613898.0005) mutation was found in homozygous state in 1 patient and in heterozygous state in a second; all of the other mutations were unique to each family.
By gene targeting, Wang et al. (1998) created a strain of HL-deficient mice. Heterozygous HL-deficient mice were clinically normal, and fibroblasts from homozygous HL-deficient embryos grew normally despite absence of HL activity. In contrast, homozygous HL-deficient embryos died at approximately 11.5 days postcoitum. Histologically, HL-deficient embryos showed marked vacuolization, particularly in the liver. Ultrastructural studies of hepatocytes obtained before death from HL-deficient embryos showed abnormal dilated mitochondria. HL-deficient mice are the first mammalian example of a disease primarily affecting CoA ester metabolism with abnormal prenatal development.
In a review of redox homeostasis abnormalities in HL deficiency, Leipnitz et al. (2015) discussed that 3-hydroxy-3-methylglutaryl-CoA (HMG), 3-methylglutaric acid, 3-methyglutaconic acid, and 3-hydroxyisovaleric acid lead to lipid peroxidation in the rat cerebral cortex. HMG has the most significant effects. Only HMG caused lipid peroxidation in the rat liver.
Yang et al. (2022) developed a cardiomyocyte-specific HL-deficient mouse. The mutant mice developed left ventricular cardiac hypertrophy by 9 months of age. After injection of 2-ketoisocaproic acid (a leucine metabolite), the mutant mice developed transient left ventricular dysfunction and elevated leucine-associated acyl-CoA metabolites in the heart compared to wildtype mice. Acyl-CoA profiles in the liver of the mutant mice were the same as those in wildtype mice. Yang et al. (2022) demonstrated further that in liver-specific HL-deficient mice, the cardiac acyl-CoA levels were the same as those in wildtype mice. Yang et al. (2022) concluded that abnormal acyl-CoA metabolites occur in an organ-autonomous manner in the heart and liver in HL deficiency.
Barash, V., Mandel, H., Sella, S., Geiger, R. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: biochemical studies and family investigation of four generations. J. Inherit. Metab. Dis. 13: 156-164, 1990. [PubMed: 2116546] [Full Text: https://doi.org/10.1007/BF01799678]
Berry, H. K., Suchy, F. J., Norman, E. J. HMG CoA lyase deficiency in double first cousins: relation of leucine defect to fat metabolism. (Abstract) Am. J. Hum. Genet. 33: 37A, 1981.
Duran, M., Schutgens, R. B. H., Ketel, A., Heymans, H., Bertssen, M. W. J., Ketting, D., Wadman, S. K. 3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: postnatal management following prenatal diagnosis by analysis of maternal urine. J. Pediat. 95: 1004-1007, 1979. [PubMed: 91680] [Full Text: https://doi.org/10.1016/s0022-3476(79)80297-8]
Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysocki, S. J., Masters, P. L. Patient with defect in leucine metabolism. (Letter) New Eng. J. Med. 294: 1013, 1976. [PubMed: 1256504] [Full Text: https://doi.org/10.1056/nejm197604292941823]
Faull, K. F., Bolton, P. D., Halpern, B., Hammond, J., Danks, D. M. The urinary organic acid profile associated with 3-hydroxy-3-methylglutaric aciduria. Clin. Chim. Acta 73: 553-559, 1976. [PubMed: 1000872] [Full Text: https://doi.org/10.1016/0009-8981(76)90160-1]
Gibson, K. M., Breuer, J., Kaiser, K., Nyhan, W. L., McCoy, E. E., Ferreira, P., Greene, C. L., Blitzer, M. G., Shapira, E., Reverte, F., Conde, C., Bagnell, P., Cole, D. E. C. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients. J. Inherit. Metab. Dis. 11: 76-87, 1988. [PubMed: 3128690] [Full Text: https://doi.org/10.1007/BF01800058]
Gibson, K. M., Breuer, J., Nyhan, W. L. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Europ. J. Pediat. 148: 180-186, 1988. [PubMed: 3063529] [Full Text: https://doi.org/10.1007/BF00441397]
Grunert, S. C., Schlatter, S. M., Schmitt, R. N., Gemperle-Britschgi, C., Mrazova, L., Balci, M. C., Bischof, F., Coker, M., Das, A. M., Dermirkol, M., de Vries, M., Gokcay, G., and 12 others. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: clinical presentation and outcome in a series of 37 patients. Molec. Genet. Metab. 121: 206-215, 2017. [PubMed: 28583327] [Full Text: https://doi.org/10.1016/j.ymgme.2017.05.014]
Leipnitz, G., Vargas, C. R., Wajner, M. Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. J. Inherit. Metab. Dis. 38: 1021-1028, 2015. [PubMed: 26041581] [Full Text: https://doi.org/10.1007/s10545-015-9863-3]
Leonard, J. V., Seakins, J. W. T., Griffin, N. K. Beta-hydroxy-methylglutaricaciduria presenting as Reye's syndrome. (Letter) Lancet 313: 680 only, 1979. Note: Originally Volume I. [PubMed: 85928] [Full Text: https://doi.org/10.1016/s0140-6736(79)91137-1]
Mitchell, G. A., Ozand, P. T., Robert, M.-F., Ashmarina, L., Roberts, J., Gibson, K. M., Wanders, R. J., Wang, S., Chevalier, I., Plochl, R., Miziorko, H. 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, 1998. [PubMed: 9463337] [Full Text: https://doi.org/10.1086/301730]
Mitchell, G. A., Robert, M.-F., Fontaine, G., Wang, S., Lambert, M., Cole, D., Lee, C., Gibson, M., Miziorko, H. HMG CoA lyase (HL) deficiency: detection of a causal mutation in an affected French-Canadian sibship. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A173, 1992.
Mitchell, G. A., Robert, M.-F., Hruz, P. W., Wang, S., Fontaine, G., Behnke, C. E., Mende-Mueller, L. M., Schappert, K., Lee, C., Gibson, K. M., Miziorko, H. M. 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency. J. Biol. Chem. 268: 4376-4381, 1993. [PubMed: 8440722]
Muroi, J., Yorifuji, T., Uematsu, A., Shigematsu, Y., Onigata, K., Maruyama, H., Nobutoki, T., Kitamura, A., Nakahata, T. Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. Hum. Genet. 107: 320-326, 2000. [PubMed: 11129331] [Full Text: https://doi.org/10.1007/s004390000363]
Ozand, P. T., Al Aqeel, A., Gascon, G., Brismar, J., Thomas, E., Gleispach, H. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia. J. Inherit. Metab. Dis. 14: 174-188, 1991. [PubMed: 1886403] [Full Text: https://doi.org/10.1007/BF01800590]
Ozand, P. T., Devol, E. B., Gascon, G. G. Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J. Child Neurol. 7 (suppl.): S4-S11, 1992. [PubMed: 1588014] [Full Text: https://doi.org/10.1177/08830738920070010211]
Ribes, A., Briones, P., Vilaseca, M. A., Baraibar, R., Gairi, J. M. Sudden death in an infant with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. J. Inherit. Metab. Dis. 13: 752-753, 1990. [PubMed: 2246860] [Full Text: https://doi.org/10.1007/BF01799579]
Robinson, B. H., Oei, J., Sherwood, W. G., Slyper, A. H., Heininger, J., Mamer, O. A. Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome. Neurology 30: 714-718, 1980. [PubMed: 6156427] [Full Text: https://doi.org/10.1212/wnl.30.7.714]
Roe, C. R., Millington, D. S., Maltby, D. A. Identification of 3-methylglutarylcarnitine: a new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. J. Clin. Invest. 77: 1391-1394, 1986. [PubMed: 3958190] [Full Text: https://doi.org/10.1172/JCI112446]
Schutgens, R. B. H., Heymans, H., Ketel, A., Veder, H. A., Duran, M., Ketting, D., Wadman, S. K. Lethal hypoglycemia in a child with a deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase. J. Pediat. 94: 89-91, 1979. [PubMed: 758433] [Full Text: https://doi.org/10.1016/s0022-3476(79)80364-9]
Shilkin, R., Wilson, G., Owles, E. 3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: follow-up of first described case. Acta Paediat. Scand. 70: 265-268, 1981. [PubMed: 6112838] [Full Text: https://doi.org/10.1111/j.1651-2227.1981.tb05555.x]
Sovik, O., Sweetman, L., Gibson, K. M., Nyhan, W. L. Genetic complementation analysis of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency in cultured fibroblasts. Am. J. Hum. Genet. 36: 791-801, 1984. [PubMed: 6475954]
Wanders, R. J. A., Schutgens, R. B. H., Zoeters, P. H. M. 3-Hydroxy-3-methylglutaryl-CoA lyase in human skin fibroblasts: study of its properties and deficient activity in 3-hydroxy-3-methylglutaric aciduria patients using a simple spectrophotometric method. Clin. Chim. Acta 171: 95-102, 1988. [PubMed: 2450702] [Full Text: https://doi.org/10.1016/0009-8981(88)90294-x]
Wang, S. P., Marth, J. D., Oligny, L. L., Vachon, M., Robert, M.-F., Ashmarina, L., Mitchell, G. A. 3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice. Hum. Molec. Genet. 7: 2057-2062, 1998. [PubMed: 9817922] [Full Text: https://doi.org/10.1093/hmg/7.13.2057]
Wang, S. P., Robert, M.-F., Gibson, K. M., Wanders, R. J. A., Mitchell, G. A. 3-Hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients. Genomics 33: 99-104, 1996. [PubMed: 8617516] [Full Text: https://doi.org/10.1006/geno.1996.0164]
Wilson, W. G., Cass, M. B., Sovik, O., Gibson, K. M., Sweetman, L. A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Europ. J. Pediat. 142: 289-291, 1984. [PubMed: 6489380] [Full Text: https://doi.org/10.1007/BF00540255]
Wysocki, S. J., Hahnel, R. 3-Hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaryl-coenzyme A lyase levels in leucocytes. Clin. Chim. Acta 73: 373-375, 1976. [PubMed: 1000856] [Full Text: https://doi.org/10.1016/0009-8981(76)90186-8]
Wysocki, S. J., Hahnel, R. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: a review. J. Inherit. Metab. Dis. 9: 225-233, 1986. [PubMed: 3099065] [Full Text: https://doi.org/10.1007/BF01799652]
Yang, H., Wang, Y., Tang, M. C., Waters, P., Wang, S., Allard, P., Ryan, R. O., Nuyt, A. M., Paradis, P., Schiffrin, E. L., Furtos, A., Mitchell, G. A. Cardiac-specific deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase in mice causes cardiomyopathy and a distinct pattern of acyl-coenzyme A-related biomarkers. Molec. Genet. Metab. 137: 257-264, 2022. [PubMed: 36228350] [Full Text: https://doi.org/10.1016/j.ymgme.2022.09.008]