| #246450 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 3-HYDROXY-3-METHYLGLUTARYL-CoA LYASE DEFICIENCY; HMGCLD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HMG-CoA LYASE DEFICIENCY HMGCL DEFICIENCY HL DEFICIENCY HYDROXYMETHYLGLUTARIC ACIDURIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because HMG-CoA lyase deficiency is caused by homozygous or compound heterozygous mutation in the HMGCL gene (613898) on chromosome 1p. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency 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, which include 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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) observed a Moroccan family with 4 of 7 sibs affected. 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 HGM-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. The results supported autosomal recessive inheritance. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HMG-CoA lyase deficiency is an autosomal recessive disorder (Mitchell et al., 1992). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Population Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. (1992) reported that the disorder in Saudi Arabian patients is particularly severe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Faull et al. (1976); Mitchell et al. (1998); Ozand et al. (1991); Shutgens et al. (1979) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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