Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Johannes Zschocke MD PhD

Neurogenetic Disorders

Updated 10.17.2023
Released 08.20.2005
Expires For CME 10.17.2026

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Author: Johannes Zschocke MD PhD

See Contributor Disclosures

Editor: Deepa S Rajan MD

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

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Introduction

Overview

Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, the rate-limiting enzyme in hepatic ketogenesis, causes potentially life-threatening hypoglycemic hypoketotic coma during fasting periods. In the normal, nonfasting state, most patients are asymptomatic and show no abnormalities in standard metabolic tests. Cases with acute severe metabolic acidosis, fatty liver, and dyslipidemia without hypoglycemia have been reported. The author explains that the disease should be easy to recognize when adequate samples are obtained for metabolic analyses in the acute crisis. The diagnosis is confirmed through sequence analysis of the HMGCS2 gene on chromosome 1p12.

Key points

	• Mitochondrial HMG-CoA synthase is required for the generation of ketone bodies that provide chemical energy to the brain and other organs at times of fasting.
	• The genetic deficiency of mitochondrial HMG-CoA synthase can lead to hypoketotic hypoglycemia, coma, and death at times of fasting and metabolic stress. Some patients may show acute severe metabolic acidosis, fatty liver, and dyslipidemia sometimes without hypoglycemia.
	• There are usually no known adverse effects outside catabolic periods.
	• The diagnosis is based on biochemical findings during fasting periods and molecular genetics analysis.
	• Treatment is mostly based on the avoidance of prolonged fasting periods; no other (drug) treatment is necessary in most patients.

Historical note and terminology

A genetic deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2, EC 2.3.3.10) as a cause of fasting hypoketotic coma in a child was first recognized in 1997 (15) and has since been reported in approximately 50 patients (16). Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase has to be distinguished from its cytosolic isoform, which catalyzes the rate-limiting first step of cholesterol biosynthesis and is encoded by a different gene. The HMGCS2 gene for mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase is located on chromosome 1p12. The full cDNA sequence and gene structure were identified by 1997 (03; 04). The crystal structure of human mitochondrial HMG-CoA synthase was published in 2010 (14). Guidelines for the diagnosis of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency were published in 2002 (17).

Clinical manifestations

Presentation and course

Clinical symptoms caused by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency are usually those of acute hypoglycemia. Patients show unexpected deterioration of consciousness and rapidly deepening coma leading to respiratory arrest during prolonged periods of poor food intake or fasting. Hepatomegaly with liver steatosis, severe metabolic acidosis, hyperammonemia, and dyslipidemia sometimes without hypoglycemia have been reported in several children (08; 06; 16). Very severe cases may be associated with complete loss of enzyme function due to HGCS2 null variants (09; 16). The condition may present at any age but the first symptomatic episode is usually in late infancy due to greater intervals between meals in conjunction with a higher incidence of common infections with fever, vomiting, and reduced food intake. Variable manifestations were documented in one highly consanguineous family from Turkey with several affected individuals homozygous for a pathogenic splice variant c.725-2A>C (07). One child presented in infancy and has been well since, and one child died in a metabolic decompensation at two years of age, whereas four individuals including an adult were asymptomatic, with a history of hepatosteatosis in two individuals.

Prognosis and complications

Irreversible brain damage after an acute decompensation, prolonged metabolic acidosis, and death have been reported. Unrecognized lethal manifestations may have occurred in some individuals. The prognosis after diagnosis is usually excellent if fasting is avoided.

Clinical vignette

An affected boy was the first child of unrelated German parents (01). After an unremarkable neonatal and early infantile period, at 11 months of age, he developed gastroenteritis with vomiting and poor feeding. On the third day of this illness, he suddenly deteriorated with coma and respiratory arrest. Blood glucose after resuscitation was 1.2 mmol/l (norm: > 3 mmol/l). Apart from elevated transaminases (aspartate aminotransferase 283 U/l, norm: 10-27 U/l; alanine aminotransferase 138 U/l, norm: 5-23 U/l) and lactate dehydrogenase (1502 U/l, norm: 200-500 U/l), there were no abnormalities in routine clinical chemical analysis. Urinary organic acid analysis revealed massive dicarboxylic aciduria without adequate ketonuria. Acylcarnitine analyses in dried blood spots were normal. The patient recovered well with intravenous glucose infusion.

Enzyme studies in fibroblasts showed normal beta-oxidation capacity. Unfortunately, free fatty acids and ketone bodies had not been measured at the time of the acute decompensation, and it was felt necessary to perform a monitored fasting test under controlled conditions in a metabolic hospital unit. During this test the boy developed hypoglycemia (blood glucose 2.3 mmol/l) much earlier than envisaged, 12 hours after the last meal. At this time there was massive elevation of plasma free fatty acids (3290 µmol/l, norm: < 300) without concomitant elevation of total plasma ketones (174 µmol/l, norm: < 150, in prolonged fasting: > 1500). Blood lactate, insulin and transaminases were within normal ranges. Urinary organic acids again showed massive dicarboxylic aciduria without adequate ketonuria. Acylcarnitines in dried blood spots were normal.

The diagnosis was later confirmed by molecular studies that revealed compound heterozygosity for the pathogenic variants p.G212R (c.634G> A) in exon 3 and p.R500H (c.1499G> A) in exon 9 of the HMGCS2 gene. The family was advised to avoid fasting periods of more than 6 to 8 hours. There were no subsequent hypoglycemic episodes, and the child has developed normally with no residual neurologic impairment.

Biological basis

Etiology and pathogenesis

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency is an autosomal recessive disorder caused by pathogenic variants in the HMGCS2 gene. This gene stretches over 20 kb on chromosome 1p13-p12 and contains 10 exons. Greater than 30 pathogenic and likely pathogenic variants and numerous variants of uncertain significance are listed in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar); the majority of predicted pathogenic variants are missense. Functional analyses showed complete loss of protein or protein function in most pathogenic variants studied (12). Correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and, therefore, the activity of the enzyme (11). Most pathogenic variants reported so far are rare. Exceptions are p.Phe174Leu (c. 520T> C), which was reported in an affected boy of Chinese descent and has an allele frequency of approximately one of 700 in East Asians, and p.G212R (c.634G> A, exon 3), which was reported in three European patient families and has an allele frequency of approximately one of 2000 in Europeans. Variant p.Arg501Pro (c.1502G> C) may be prevalent in Thai patients (13). A stop variant p.Tyr242Ter has an allele frequency of one in 1560 in Africans/African Americans but has not yet been reported in patients. Frequency data can be accessed at the following database: http://gnomad.broadinstitute.org. In line with the fasting-dependent clinical presentation and the diagnostic challenges, the available allele frequency data indicate that some individuals with biallelic pathogenic HMGCS2 variants may stay asymptomatic, or they may remain undiagnosed after manifestation.

Fasting is accompanied by an increased breakdown of fatty acid stores for provision of energy to peripheral tissues. Humans are unable to convert even-chain fatty acids into glucose, and organs such as the brain and muscle that do not have the enzymes for complete fatty acid oxidation rely on the utilization of the ketone bodies acetoacetate and 3-hydroxybutyrate during fasting. The hepatic biosynthesis of acetoacetate from acetoacetyl-CoA involves a 2-step process catalyzed by the enzymes 3-hydroxy-3-methylglutaryl-CoA synthase and 3-hydroxy-3-methylglutaryl-CoA lyase. The latter enzyme is also required for the breakdown of the amino acid leucine, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency usually presents as an organic aciduria with acute metabolic (keto-) acidosis, hypoglycemia, liver disease, and sometimes fatal Reye syndrome-like crisis. In contrast, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase appears to be required mainly for ketogenesis during fasting. A deficiency of this enzyme, therefore, leads to symptoms or metabolic abnormalities during fasting or poor food intake. In mice, Hmgcs2 knockout was reported to cause spontaneous fatty liver during postnatal development, which was rescued by a shift to a low-fat dietary composition via early weaning. Heterozygous adult mice, which exhibited lower ketogenic activity, were more susceptible to diet-induced NAFLD development (02). It remains to be seen whether altered HMGCS2 function influences the manifestation of multifactorial liver disease in humans.

Diagnostic workup

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency may be easily recognized through examination of appropriate laboratory tests in samples obtained during hypoglycemia (17). Most patients are now identified through undirected massive parallel sequencing. For biochemical diagnosis, it is essential to recognize deficient conversion of free fatty acids to ketones by measuring these substances in serum. 3-hydroxybutyrate is sufficient for the assessment of ketogenesis capacity as it usually accounts for over two-thirds of total ketones and is more stable than acetoacetate. During prolonged fasting, free fatty acids and total ketones typically reach concentrations of 1500 µmol/ml or higher, with ketones usually exceeding free fatty acids. Insufficient ketogenesis in this situation (eg, ratio free fatty acids / ketones > 2) is pathognomonic for a deficiency of mitochondrial beta-oxidation or ketogenesis even if ketones are elevated compared to the fed state. The discrepancy between highly elevated free fatty acids and low ketones is most pronounced in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency where the ratio may exceed 20. Urinary stix tests may show apparent elevations of ketones; however, the ketone concentration is far less than expected for the fasting state. In line with increased fatty acid mobilization, blood triglyceride concentrations may be elevated (05).

Once hypoketosis is recognized, the combination of normal or nonspecific acylcarnitines in dried blood spots (some compounds may be elevated as is normal during fasting) and a “fasting pattern without ketones” in urinary organic acids during the acute episode is highly suggestive of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency. Although acylcarnitine profiles in most patients were normal, elevation of C2-carnitine and other carnitine species may be observed (09). Careful examination of the urinary organic acid profile obtained from the acute presentation may show highly increased concentrations of 4-hydroxy-6-methyl-2-pyrone. Although this metabolite may also be elevated in some ketotic patients, it is highly suggestive of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency. This observation led to the diagnosis of seven additional patients from various parts of the world in a single Australian center (10).

Molecular studies are used for the confirmation of the diagnosis. DNA analysis should involve full sequencing of the coding region as well as genomic quantification as the disease has been caused by larger deletions in several patients (10). No metabolic abnormalities are usually present in the fed state in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency, and enzyme studies not only require liver biopsy but are hampered by the cytosolic isoenzyme. A fasting test may be helpful in exceptional cases with equivocal genetic findings. This is potentially dangerous and must be carried out in a specialist hospital setting only.

References

01: Aledo R, Zschocke J, Pie J, et al. Genetic basis of mitochondrial HMG-CoA synthase deficiency. Hum Genet 2001;109(1):19-23. PMID 11479731
02: Asif S, Kim RY, Fatica T, et al. Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis. Mol Metab 2022;61:101494. PMID 35421611
03: Boukaftane Y, Duncan A, Wang S, et al. Human mitochondrial HMG CoA synthase: liver cDNA and partial genomic cloning, chromosome mapping to 1p12-p13, and possible role in vertebrate evolution. Genomics 1994;23(3):552-9. PMID 7851882
04: Boukaftane Y, Mitchell GA. Cloning and characterization of the human mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase gene. Gene 1997;195(2):121-6. PMID 9305755
05: Conboy E, Vairo F, Schultz M, et al. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: unique presenting laboratory values and a review of biochemical and clinical features. JIMD Rep 2018;40:63-9. PMID 29030856
06: Conlon TA, Fitzsimons PE, Borovickova I, et al. Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: further evidence of specific biochemical markers which may aid diagnosis. JIMD Rep 2020;55(1):26-31. PMID 32905056
07: Kılıç M, Dorum S, Topak A, Yazıcı MU, Ezgu FS, Coskun T. Expanding the clinical spectrum of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review. Am J Med Genet A 2020;182(7):1608-14. PMID 32259399
08: Lee T, Takami Y, Yamada K, et al. A Japanese case of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency who presented with severe metabolic acidosis and fatty liver without hypoglycemia. JIMD Rep 2019;48(1):19-25. PMID 31392109
09: Liu H, Miao JK, Yu CW, et al. Severe clinical manifestation of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency associated with two novel mutations: a case report. BMC Pediatr 2019;19(1):344. PMID 31597564
10: Pitt JJ, Peters H, Boneh A, et al. Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations. J Inherit Metab Dis 2015;38(3):459-66. PMID 25511235
11: Puisac B, Marcos-Alcalde I, Hernández-Marcos M, et al. Human mitochondrial HMG-CoA synthase deficiency: role of enzyme dimerization surface and characterization of three new patients. Int J Mol Sci 2018;19(4). PMID 29597274
12: Ramos M, Menao S, Arnedo M, et al. New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. Eur J Med Genet 2013;56(8):411-5. PMID 23751782
13: Rojnueangnit K, Maneechai P, Thaweekul P, et al. Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency. Eur J Med Genet 2020;63(12):104086. PMID 33045405
14: Shafqat N, Turnbull A, Zschocke J, Oppermann U, Yue WW. Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. J Mol Biol 2010;398(4):497-506. PMID 20346956
15: Thompson GN, Hsu BY, Pitt JJ, Treacy E, Stanley CA. Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. N Engl J Med 1997;337(17):1203-7. PMID 9337379
16: Wu S, Shen L, Chen Q, et al. Clinical, biochemical, molecular, and outcome features of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency in 10 Chinese patients. Front Genet 2022;12:816779. PMID 35308163
17: Zschocke J, Penzien JM, Bielen R, et al. The diagnosis of mitochondrial HMG-CoA synthase deficiency. J Pediatr 2002;140(6):778-80. PMID 12072887

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Johannes Zschocke MD PhD

Dr. Zschocke of the Medical University of Innsbruck has no relevant financial relationships to disclose.
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Editor

Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Former Authors

Jennifer Friedman MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none

ICD & OMIM codes

ICD-9: Unspecified disorder of metabolism: 277.9
ICD-10: Metabolic disorder, unspecified: E88.9
OMIM: 3-hydroxy-3-methylglutaryl-CoA synthase 2, mitochondrial: *600234

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Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Associated Disorders

coma
hypoglycemia

Differential Diagnosis

disorders of mitochondrial fatty acid oxidation
medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
disorders of long-chain fatty acid oxidation
cardiomyopathy
muscle disease
- liver disease

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Hypermethioninemia

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Nonketotic hyperglycinemia

Leukodystrophies

Mucopolysaccharidoses

Alexander disease

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hypermethioninemia

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Nonketotic hyperglycinemia

Leukodystrophies

Mucopolysaccharidoses

Alexander disease

This is an article preview.
Start a Free Account
to access the full version.