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HMG CoA lyase deficiency


Other Names:
3-hydroxy-3-methylglutaryl-CoA lyase deficiency; Defect in leucine metabolism; HMG-CoA lyase deficiency; 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; Defect in leucine metabolism; HMG-CoA lyase deficiency; 3-hydroxy-3-methylglutaric aciduria; Hydroxymethylglutaric aciduria See More
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HMG CoA lyase deficiency is an inherited disorder in which the body cannot process a protein called leucine or make ketones. Ketones are used for energy during periods of fasting. The signs and symptoms of condition usually appear within the first year of life and include episodes of vomiting, diarrhea, dehydration, extreme tiredness (lethargy), and weak muscle tone (hypotonia). During an episode, blood sugar levels can become dangerously low (hypoglycemia), and a buildup of harmful compounds can cause the blood to become too acidic (metabolic acidosis). If untreated, the disorder can lead to breathing problems, convulsions, coma, and death. Episodes are often triggered by an infection, fasting, strenuous exercise, or other types of stress. Mutations in the HMGCL gene cause HMG-CoA lyase deficiency, and this condition is inherited in an autosomal recessive pattern.[1][2] Treatment usually involves a team of specialists including a metabolics and/or genetics specialist and a dietician and may include avoidance of fasting, a low leucine diet, and supplementation with L-carnitine.[3]
Last updated: 1/19/2017
The signs and symptoms of HMG CoA lyase deficiency usually appear within the first year of life. The condition causes episodes of vomiting, diarrhea, dehydration, extreme tiredness (lethargy), and weak muscle tone (hypotonia). During one of these episodes, blood sugar levels can become dangerously low (hypoglycemia), and a buildup of harmful compounds can cause the blood to become too acidic (metabolic acidosis). If untreated, the disorder can lead to breathing problems, convulsions (seizures), coma, and death. Episodes are often triggered by an infection, fasting (not eating enough), strenuous exercise, or other types of stress.[1]
Last updated: 1/19/2017

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
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HPO ID
80%-99% of people have these symptoms
3-Methylglutaric aciduria 0003344
Hyperammonemia
High blood ammonia levels
0001987
Metabolic acidosis 0001942
Nonketotic hypoglycemia 0001958
30%-79% of people have these symptoms
Anemia
Low number of red blood cells or hemoglobin
0001903
Anorexia 0002039
Apathy
Lack of feeling, emotion, interest
0000741
Elevated hepatic transaminase
High liver enzymes
0002910
Episodic vomiting 0002572
Hepatomegaly
Enlarged liver
0002240
Hyperuricemia
High blood uric acid level
0002149
Increased serum lactate 0002151
Lethargy 0001254
Lipid accumulation in hepatocytes 0006561
Muscular hypotonia
Low or weak muscle tone
0001252
Prolonged prothrombin time 0008151
Recurrent hypoglycemia
Recurrent low blood sugar levels
0001988
Reye syndrome-like episodes 0006582
Seizure 0001250
Tachypnea
Increased respiratory rate or depth of breathing
0002789
5%-29% of people have these symptoms
Apnea 0002104
Dehydration 0001944
Diarrhea
Watery stool
0002014
Edema
Fluid retention
Water retention
[ more ] 		0000969
Encephalopathy 0001298
Fatigue
Tired
Tiredness
[ more ] 		0012378
Fever 0001945
Hyporeflexia
Decreased reflex response
Decreased reflexes
[ more ] 		0001265
Hypotension
Low blood pressure
0002615
Hypsarrhythmia 0002521
Intellectual disability, mild
Mental retardation, borderline-mild
Mild and nonprogressive mental retardation
Mild mental retardation
[ more ] 		0001256
Intellectual disability, moderate
IQ between 34 and 49
0002342
Intellectual disability, severe
Early and severe mental retardation
Mental retardation, severe
Severe mental retardation
[ more ] 		0010864
Jaundice
Yellow skin
Yellowing of the skin
[ more ] 		0000952
Ketonuria 0002919
Leukocytosis
Elevated white blood count
High white blood count
Increased blood leukocyte number
[ more ] 		0001974
Leukopenia
Decreased blood leukocyte number
Low white blood cell count
[ more ] 		0001882
Myoclonus 0001336
Pallor 0000980
Thrombocytosis
Increased number of platelets in blood
0001894
Weight loss 0001824
1%-4% of people have these symptoms
Acute pancreatitis
Acute pancreatic inflammation
0001735
Ataxia 0001251
Cardiac arrest
Heart stops beating
0001695
Dilated cardiomyopathy
Stretched and thinned heart muscle
0001644
Dysarthria
Difficulty articulating speech
0001260
Global developmental delay 0001263
Hypoglycemic coma
Coma caused by low blood sugar
0001325
Hypothermia
Abnormally low body temperature
0002045
Leukoencephalopathy 0002352
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ] 		0000252
Psychomotor retardation 0025356
Spastic hemiparesis 0011099
Percent of people who have these symptoms is not available through HPO
Abnormality of the cerebral white matter 0002500
Autosomal recessive inheritance 0000007
Coma 0001259
Death in childhood 0003819
Decreased plasma carnitine 0003234
Decreased prothrombin time 0032198
EEG abnormality 0002353
Excessive daytime somnolence
More than typical sleepiness during day
0001262
Glutaric aciduria 0003150
Hypoglycemia
Low blood sugar
0001943
Increased level of 3-hydroxy-3-methylglutaric acid in urine 0410051
Increased level of hippuric acid in urine 0410066
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Vomiting
Throwing up
0002013
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Last updated: 7/1/2020
HMG CoA lyase deficiency is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene (and are referred to as carriers), but they typically do not show signs and symptoms of the condition. When parents who are both carriers of an autosomal recessive condition have a child, there is a 1 in 4 (25%) chance for each child to have the condition, a 1 in 2 (50%) chance for each child to be a carrier like each of the parents, and a 1 in 4 (25%) chance for the child not to have the condition and not be a carrier.[1]

Last updated: 1/19/2017

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Newborn Screening

  • The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.
  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.

The resources below provide information about treatment options for this condition. If you have questions about which treatment is right for you, talk to your healthcare professional.

Management Guidelines

  • Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition.  

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes sepsis, fatty acid oxidation disorders, organic acidurias and Reye's syndrome.
Visit the Orphanet disease page for more information.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on HMG CoA lyase deficiency. This website is maintained by the National Library of Medicine.
  • The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • The New England Consortium of Metabolic Program has written medical guidelines called acute care protocols for HMG CoA lyase deficiency for health care professionals. 
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss HMG CoA lyase deficiency. Click on the link to view a sample search on this topic.

News

Other Conferences

  • The International Network for Fatty Acid Oxidation Research and Management (INFORM) was formed in order to promote research and discussion into the cause, diagnosis, and management of fatty acid oxidation disorders (FAODs). They offer several learning opportunities throughout the year for patients, families, and researchers. INFORM's Annual Meeting will be held on August 30th and 31st, 2020 in Freiberg, Germany preceding the Society for the Study of Inborn Errors of Metabolism (SSIEM). The Network also continues to provide a collaborative framework for ongoing communication and research regarding FAODs.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • My daughter has been diagnosed with this condition. I have low platelet and white blood cell counts and have been told my marrow does not properly store iron. Is it possible that I have the condition also, and may not be just a carrier? See answer

  • Are there any active protocols researching this disorder? We would like to make a donation for research. See answer


  1. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Genetics Home Reference. October 2008; https://ghr.nlm.nih.gov/condition/3-hydroxy-3-methylglutaryl-coa-lyase-deficiency.
  2. Bandeira A, Vilarinho L. 3-hydroxy-3-methylglutaric aciduria. Orphanet. August 2014; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=20.
  3. Organic Acid Oxidation Disorders: 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Screening, Technology and Research in Genetics (STAR-G). April 20, 2016; http://www.newbornscreening.info/Parents/organicaciddisorders/HMGCoA.html#4.