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3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase Deficiency.


3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare autosomal recessive congenital defect of ketone body synthesis and leucine degradation. The HMG-CoA lyase enzyme is localized in the mitochondria and peroxisomes and converts HMG-CoA to acetyl CoA and acetoacetate at the last step of leucine catabolism (Figure 1) (1).

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency leads to a reduced ability to synthesize ketones, which are the primary energy source of the brain when glucose is unavailable. In 1976, Faull et al. (2) first described the disorder in a 7-month-old boy with metabolic acidosis and hypoglycemia.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is usually clinically evident during infancy and is characterized by vomiting, hypotonia, lethargy, metabolic acidosis, non-ketotic hypoglycemia, and Reyelike syndrome. Patients with this disorder are usually normal except for recurrent metabolic attacks that can be triggered by infection, starvation, and excessive physical exercise (1, 3). These attacks can cause deaths in 20% of cases and serious long-term morbidities such as psychomotor retardation, epilepsy, hepatic steatosis, pancreatitis, or dilated cardiomyopathy (3, 4).

Although the organic acid profile is essentially diagnostic, enzyme deficiency can be detected in cultured fibroblasts, or the diagnosis can be confirmed by molecular genetic analysis of the HMGCL gene (1). There are a few reports that demonstrate the clinical findings of this condition (2-6).


A 3-month-old girl presented with vomiting and drowsiness. She was born after an uneventful pregnancy by spontaneous vaginal delivery. She weighed 3000 g. Her prenatal, obstetric, and family histories were unremarkable.

She was hospitalized owing to hypoglycemia and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 1 month ago prior to the last hospital admission. She was discharged after her symptoms improved with supportive treatment.

Her body weight, height, and head circumference were 5.2 kg (10% to 25% percentile), 58 cm (10% to 25% percentile), and 40 cm (50% percentile), respectively. She was hypotonic, hypoactive, and lethargic, and she had hepatomegaly. Her liver edge was 5 cm below the right costal margin.

Metabolic tests were analyzed for inborn error of metabolism due to metabolic acidosis, hypoketotic hypoglycemia, hyperammonemia, and elevated liver enzymes. Plasma amino acid and blood acylcarnitine levels were quantified using liquid chromatographytandem mass spectrometry, and urinary organic acid was analyzed using gas chromatography-mass spectrometry. Table 1 shows the laboratory findings of the patient.

The patient was diagnosed with HMG-CoA lyase deficiency according to the symptoms and laboratory findings. Sodium bicarbonate and fluid therapy with high dextrose were started for hypoglycemia and metabolic acidosis. Carnitine treatment (100 mg/kg/day) and carbohydrate-rich and protein- and fat-restricted diet were started. Liver function tests were normal on day 20 after hospitalization.

The patient was hospitalized due to infections three times after the diagnosis, but Reye-like syndrome did not develop. Molecular genetic analysis could not be performed due to familial reasons. The patient is 4 years old now, and her intelligence is normal.


3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare inborn error of leucine catabolism. The patient was admitted to the hospital with Reye-like syndrome and diagnosed with HMG-CoA lyase deficiency using organic acid analysis. Reyelike syndrome can be caused due to sepsis, intoxication, and various metabolic diseases. Inborn error of metabolism was considered in this patient because of lethargy, hepatomegaly, hypoglycemia, metabolic acidosis, elevated ALT and AST levels, and history of previous attack.

Patients with HMG-CoA lyase deficiency present with infectionor starvation-induced metabolic acidosis, hypoglycemia, vomiting, hyperammonemia, consciousness, hypotony, convulsions, hepatomegaly, and elevated ALT and AST levels (5, 6). Left ventricular cardiomyopathy and macrocephaly can be observed, but not frequently (4). Classical symptoms of the disorder were seen in our patient and were induced by infection.

Hyperinsulinism, endocrine deficiencies, and fatty acid oxidation defects can present along with hypoketotic hypoglycemia (7). Endocrine causes of hypoglycemia and fatty acid oxidation defects were ruled out in our patient.

White matter abnormalities, cerebral atrophy, mental retardation, and neurological disorders may occur due to prolonged hypoglycemia and convulsions (8). The neurological development of our patient was normal, and she did not have any convulsion.

Some treatment options for patients with HMG-CoA lyase deficiency include intravenous fluid, sodium bicarbonate therapy, diet, and carnitine supplementation. Leucine- and oil-restricted and valine-, isoleucine-, and carbohydrate-supplemented diet are recommended (9). The blood brain barrier is less selective during the early stages of development and can be more affected by neurotoxic metabolites. Ribas et al. (10) suggested that considering the ability of L-carnitine to easily cross the blood brain barrier, L-carnitine supplementation may also be beneficial in preventing neurological damage derived from oxidative injury. L-Carnitine with leucine-restricted diet appears to play an important role in preventing neurological damage.

Although HMG-CoA lyase deficiency is a defined disorder among the causes of hypoglycemia in the infancy period, it has been observed to manifest in very few patients and is rarely considered in the differential diagnosis of hypoglycemia.

Informed Consent: Written informed consent was obtained from the parents of the patient who participated in this study.

Peer-review: Externally peer-reviewed.

Author Contributions: Conceived and designed the experiments or case: PSU, MK. Analyzed the data: FK, SG. Wrote the paper: PSU. All authors have read and approved the final manuscript.

Conflict of Interest: The authors have no conflict of interest to declare.

Financial Disclosure: The authors declared that this study has received no financial support.


(1.) Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis 2014; 37(4): 541-51. [CrossRef]

(2.) Faull KF, Bolton PD, Halpern B, Hammond J, Danks DM, Hahnel R et al. Letter: Patient with defect in leucine metabolism. New Engl J Med 1976; 294(18): 1013. [CrossRef]

(3.) Munoz-Bonet JI, Ortega-Sanchez MD, Le[delta]n Guijarro JL. Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Ital J Pediatr 2017; 43(1): 12. [CrossRef]

(4.) K[delta]ksal T, GundUz M, Ozaydin E, Azak E. HMG coenzyme a lyase deficiency: macrocephaly and left ventricular noncompaction with a novel mutation. Indian J Pediatr 2015; 82(7): 645-8. [CrossRef]

(5.) Yalaki Z, Arikan F1, Tapgi E, Altan B, Dallar BY. 3-OH-3-methyl glutaric aciduria: A metabolic disease that could be confused with Reye's syndrome. Ege J Med 2013; 52(2): 111-3.

(6.) Ipek MS, Ugar S, Zorlu P, Ciftci A, Okur 1. 3-Hidroksi-3-MetilglutarilCoA liyaz eksikligi: Bir olgu. Yeni Tip Dergisi 2007; 24(3): 180-2.

(7.) Saudubray JM. Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Berghe G V, Walter JH (Eds); Inborn Metabolic Diseases. Diagnosis and Treatment. 5th edition. SpringerVerlag; Berlin Heidelberg; 2012; p. 4-54. [CrossRef]

(8.) Dodelson de Kremer R, Kelley RI, Depetris de Boldini C, Paschini de Capra A, Corbella L, Givogri I, et al. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency as a cause of severe neurological damage. Medicina 1992; 52(1): 30-6.

(9.) Dausoki M, Buchanan D, Mercer N, Gibson KM, Thoene J. 3-Hydroxy3-methylglutaric aciduria: Response to carnitin therapy and fat and leucine restriction. J Inher Metab Dis 1987; 10(2): 142-6. [CrossRef]

(10.) Ribas GS, Vargas CR, Wajner M. L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 2014; 533(2): 469-76. [CrossRef]

Pembe Soylu Ustkoyuncu, Mustafa Kendirci, Songul Gokay, Fatih Kardas

Department of Pediatrics, Division of Pediatric Nutrition and Metabolism, Erciyes University Faculty of Medicine, Kayseri, Turkey


Pembe Soylu Ustkoyuncu

Department of Pediatrics, Division of Pediatric Nutrition and Metabolism, Erciyes University Faculty of Medicine, Kayseri, Turkey

Phone: +90 3522076666

Cite this article as: Soylu Ustkoyuncu P Kendirci M, Gokay S, Kardas F. 3-Hydroxy3-methylglutaryl-CoA (HMG-CoA) lyase deficiency. Erciyes Med J 2018; 40(3): 169-71.





Available Online Date


DOI: 10.5152/etd.2018.0128
Table 1. Laboratory findings of the patient

Non-specific tests                 Metabolic tests

Hb (g/dL)                 9.5      Ammonia (mmol/L)
WBC [(mm.sup.3)]       5930        3-Methylglutaric acid (mmol/mol
PLT [(mm.sup.3)]    112,000        3-Methylglutaconic acid (mmol/mol
Glucose (mmol/L)          1.1      3-OH isovaleric acid (mmol/mol
ALT (IU/L)              534        Glutaric acid (mmol/mol creatinine)
AST (IU/L)              788        3-Hydroxy-3-methylglutaric acid
                                   (mmol/mol creatinine)
Total/direct              1.6/1.3  C5OH acylcarnitine ([micro]mol/L)
bilirubin (mg/dL)
Urinary ketone      (-)

Non-specific tests           Blood gas analysis

Hb (g/dL)            200     Blood pH              7.26
WBC [(mm.sup.3)]     536     Bicarbonate level     9.4
PLT [(mm.sup.3)]    3049     Base deficit         -9
Glucose (mmol/L)    4026
ALT (IU/L)           494
AST (IU/L)          4210
Total/direct           1.7
bilirubin (mg/dL)
Urinary ketone

Hb: hemoglobin, WBC: white blood cell, PLT: platelet, ALT: alanine
aminotransferase, AST: aspartate aminotransferase
ALT level (n:10-49), AST level (n:0-34), ammonia level (n:11.2-35.4),
C5OH acylcarnitine level (n:0-0.9), 3-methylglutaric acid level (n:0-9),
3-methylglutaconic acid level (n:0-9), 3-OH isovaleric acid level
(n:0-46), glutaric acid level (N<2), and 3-hydroxy-3-methylglutaric
acid level (n:11-36)
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Title Annotation:CASE REPORT
Author:Ustkoyuncu, Pembe Soylu; Kendirci, Mustafa; Gokay, Songul; Kardas, Fatih
Publication:Erciyes Medical Journal
Date:Sep 1, 2018
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