HMG-CoA lyase deficiency …

Jorn Oliver Sass Dr rer nat

Neurogenetic Disorders

Updated 12.27.2023
Released 03.30.1995
Expires For CME 12.27.2026

HMG-CoA lyase deficiency

Author: Jorn Oliver Sass Dr rer nat

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Editor: Barry Wolf MD PhD

HMG-CoA lyase deficiency

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Introduction

Overview

HMG-CoA lyase deficiency is an inborn error of metabolism resulting in impaired ketogenesis. The catabolism of leucine is also affected, and several metabolites accumulate that probably have toxic potential. The disease is characterized by life-threatening metabolic derangements with hypoketotic hypoglycemia and metabolic acidosis, often manifesting within the early neonatal period; the remainder of patients typically present within the first year of life. As with many other organic acidurias, in HMG-CoA lyase deficiency, early diagnosis and early initiation of appropriate treatment appear important for a good outcome.

Key points

	• Deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase (HMG-CoA lyase) is an organic aciduria with impaired ketogenesis and leucine catabolism.
	• HMG-CoA lyase deficiency is characterized by life-threatening metabolic derangement with hypoketotic hypoglycemia and metabolic acidosis.
	• HMG-CoA lyase deficiency is an autosomal recessive disorder due to mutations in the HMGCL gene.
	• Complications can probably be minimized by early diagnosis and appropriate treatment, including avoidance of prolonged fasting.

Historical note and terminology

3-hydroxy-3-methylglutaryl coenzyme A lyase (HMG-CoA lyase) catalyzes the final step of ketogenesis and leucine metabolism, the cleavage of HMG-CoA yielding acetyl-CoA and acetoacetate (33). Inborn deficiency of HMG-CoA lyase results in 3-hydroxy-3-methylglutaric aciduria. The first patient reported with HMG-CoA lyase deficiency was a boy who presented at 7 months of age with diarrhea and vomiting that were associated with lethargy, pallor, dehydration, and events of cyanosis and apnea (09). Metabolic acidosis and hypoglycemia were noted and Reye syndrome was suspected. Urine samples obtained after clinical onset showed a pattern of organic acids with highly elevated concentrations of 3-hydroxy-iso-valeric, 3-methylglutaric, 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids. The patient recovered completely after intensive care and several days of intravenous fluids. Several aspects of his metabolic disease (including confirmation of HMG-CoA lyase deficiency in skin fibroblasts and in leukocytes) and his further development have been addressed in several subsequent reports (10; 46; 42; 43; 44; 45; 34). At the age of 10 years, he has been considered healthy on a self-regulated diet high in potatoes and citrus cordials. However, the boy lacked attention at school, required special teaching, and has broken both arms a total of nine times. Occasional attacks with lethargy, pallor, nausea, and vomiting occur and are managed by supplementing glucose intake (45).

Clinical manifestations

Presentation and course

HMG-CoA lyase deficiency is characterized by life-threatening metabolic derangement with hypoketotic hypoglycemia and metabolic acidosis. Lethargy, vomiting, tachypnea, hyperammonemia, and moderate hepatomegaly with elevated serum transaminases and lactate values are frequent findings. Grünert and Sass performed a systematic literature review to identify all published cases (14). They analyzed 211 individuals for whom relevant clinical data were available. More than 95% presented with acute metabolic decompensation. Most patients manifested symptoms within the first year of life (42.4% as newborns), whereas very few individuals remained asymptomatic. The neurologic long-term outcome was favorable, with 62.6% of patients showing normal development. Metabolic decompensations can be prompted by catabolic situations resulting in protein breakdown and increased ketogenesis, such as the fetal-neonatal transition, fasting, infections, and excessive protein intake resulting in an increased leucine load.

Between episodes of metabolic decompensation, patients often appear normal. However, residual neurologic deficits caused during metabolic decompensation may be severe.

Several individuals with HMG-CoA lyase deficiency have white matter abnormalities (13; 38). The combination of multifocal severe white matter abnormalities on a background of a diffuse and mild signal abnormality of almost the entire cerebral white matter has been considered unique. Strikingly, even in clinically normal patients, extensive white matter abnormalities can be observed (38).

Cerebral infarction/stroke-like encephalopathy and pancreatitis have been noted as complications in HMG-CoA lyase deficiency (40; 17; 26). Dilated cardiomyopathy has been reported in a 7-month-old boy (with a fatal course) and in a 23-year-old man (12; 21). A girl with this metabolic disease in association with retinitis pigmentosa and intellectual impairment has also been reported (18).

This metabolic disease has also been diagnosed in a 36-year-old woman with a history of recurrent episodes of somnolence and hypoglycemia starting at day 3 after birth (04). She suffered from seizures, a mild right-sided spastic hemiparesis, cerebellar ataxia, tremor, and mild dysarthria. Her IQ values were 60 or lower, and she received special education intervention. A 29-year-old Portuguese man with no prior indication of HMG-CoA lyase deficiency in the medical history has been described as an adult-onset case of this disease (30). A 54-year-old female presented with cervical dystonia and head tremor from the age of 48 years (05). Her past medical history included an unexplained coma episode for 3 days at the age of 3 years, followed by childhood epilepsy.

Prognosis and complications

As with many other organic acidurias, early diagnosis and initiation of appropriate treatment are essential, but not sufficient, for a good outcome in HMG-CoA lyase deficiency. Although some patients have died during metabolic decompensations, with appropriate treatment, most individuals recover from their initial metabolic crisis. A number of patients suffer from neurologic sequelae, including seizures, hemiparesis, and cognitive impairment; dilated cardiomyopathy has been reported twice. Pancreatitis is another well-known complication. However, long-term follow-up information is limited.

Clinical vignette

The first reported patient with HMG-CoA lyase deficiency (09) presented at 7 months of age. During a gastrointestinal illness with diarrhea and vomiting the boy developed lethargy, pallor and dehydration as well as cyanosis and apnea. Metabolic acidosis and hypoglycemia were noted, and Reye syndrome was suspected. Urinary organic acid analysis revealed highly elevated concentrations of 3-hydroxy-iso-valeric, 3-methylglutaric, 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids. The patient recovered completely after intensive care and several days of intravenous fluids. At the age of 10 years, he was considered healthy on a self-regulated diet high in potatoes and citrus cordials (45). However, the boy lacked attention at school, required special teaching, and has broken both arms a total of nine times. Occasional attacks of lethargy, pallor, nausea, and vomiting were managed by supplementing glucose intake.

Biological basis

Etiology and pathogenesis

HMG-CoA lyase (EC 4.1.3.4) is a mitochondrial enzyme involved in leucine catabolism. It is expressed in all tissues studied (23). In the liver, HMG-CoA lyase also catalyzes the final step of ketogenesis, the formation of acetoacetate and acetyl-CoA from HMG-CoA. Although the brain cannot use fatty acids directly for energy when glucose levels become compromised, acetoacetate and its reduction product 3-hydroxybutyric acid can provide about 2/3 of the brain’s energy requirements during periods of prolonged fasting and starvation (19). Another role for ketone bodies in the brain is the provision of substrates for the synthesis of molecules such as cholesterol in myelin (25).

Pathophysiology. The deficiency of HMG-CoA lyase may result in a lack of energy and the accumulation of HMG-CoA. The latter may result in increased concentrations of alternative metabolites, including upstream catabolites in leucine degradation. This is reflected by the distinctive pattern of leucine metabolites in urinary organic acids, including elevated 3-hydroxy-3-methylglutaric, 3-hydroxy-iso-valeric, 3-methylglutaconic and 3-methylglutaric acids. Especially during episodes of metabolic decompensation, 3-methylcrotonylglycine and elevated concentrations of several dicarboxylic acids (glutaric, adipic, sebacic, and suberic acids) can also be present in increased concentrations. Notably, although hypoketotic hypoglycemia is typical for HMG-CoA lyase deficiency, ketone bodies may still be detectable in the urine by gas-chromatography with mass-selective detection. In blood, C5-hydroxyacylcarnitine and C6-dicarboxylic monocarnitine are metabolites that can be of diagnostic value. Secondary deficiency of free carnitine may occur. Václavík and colleagues have identified diagnostic biomarkers or HMG-CoA lyase deficiency and have applied them using dried blood spots as they are used in neonatal screening (37).

Increased dietary intake of fat or leucine and a catabolic state result in increased oxidation of endogenous fatty acids and protein and may trigger a metabolic decompensation in HMG-CoA lyase deficiency.

The precise mechanism by which accumulating metabolites contribute to the disease’s course is unknown. It has been reported that the pancreas is, after the liver, the tissue with most HMG-CoA lyase activity (29). This has prompted the authors to suggest that pancreatitis should be considered as a possible complication in HMG-CoA lyase deficiency, especially during acute decompensations.

Genetics. HMG-CoA lyase deficiency is an autosomal recessive disorder due to mutations in the HMGCL gene on human chromosome 1 (24). There is no genotype-phenotype correlation in HMG-CoA lyase deficiency; residual deficiency of HMG-CoA lyase alone does not determine the clinical manifestation (23). Afadhel and colleagues have presented a retrospective study of 62 Saudi individuals with HMG-CoA lyase deficiency from 54 different families, with a HMGCL founder variant (c.122G> A; p.[Arg41Gln]), in the majority of the cases (01).

The crystal structure of the human enzyme provides a useful model for the decrease in HMG-CoA lyase activity associated with pathologic mutations that affect active site function or enzyme stability (11).

References

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31: Ruesch S, Krahenbuhl S, Kleinle S, et al. Combined 3-methylglutaconic and 3-hydroxy-3-methylglutaric aciduria with endocardial fibroelastosis and dilatative cardiomyopathy in male and female siblings with partial deficiency of complex II/III in fibroblasts. Enzyme Protein 1996;49(5-6):321-9. PMID 9252790
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36: Truscott RJ, Halpern B, Wysocki SJ, Hahnel R, Wilcken B. Studies on a child suspected of having a deficiency in 3-hydroxy-3-methylglutaryl-CoA lyase. Clin Chim Acta 1979;95:11. PMID 509721
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38: van der Knaap MS, Bakker HD, Valk J. MR imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency. AJNR Am J Neuroradiol 1998;19:378-82. PMID 9504498
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40: Wilson WG, Cass MB, Sovik O, Gibson MK, Sweetman L. A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Eur J Pediatr 1984;142:289. PMID 6489380
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Contributors

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

Author

Jorn Oliver Sass Dr rer nat

Dr. Sass of Bonn-Rhein Sieg University of Applied Sciences received honorariums from Immedica Pharma AB and consulting fees from CoA Therapeutics.
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Editor

Barry Wolf MD PhD

Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.
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Former Authors

Johannes Zschocke MD PhD
Robert Rust MD (original author)

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: Panethnic

Portuguese

Saudi Arabian

Turkish
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Disturbances of branched-chain amino-acid metabolism: 270.3
ICD-10: Disturbances of branched-chain amino-acid metabolism: E71.1
OMIM: HMG-CoA lyase deficiency: #246450

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HMG-CoA lyase deficiency

Associated Disorders

Intellectual disability
Pancreatitis
Reye-like syndrome

Differential Diagnosis

inborn errors of fatty acid oxidation
other heritable organic acidurias
pancreatitis
3-methylglutaconic aciduria type I
3-methylglutaconic aciduria type II
- 3-methylglutaconic aciduria type III
- 3-methylglutaconic aciduria type IV
- urea cycle defects

HMG-CoA lyase deficiency …

HMG-CoA lyase 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

Diagnostic workup

Management

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

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

HMG-CoA lyase 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

Diagnostic workup

Management

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

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

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