Rare Nephrology News

Disease Profile

HMG CoA lyase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

All ages

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ICD-10

E71.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

3-hydroxy-3-methylglutaryl-CoA lyase deficiency; Defect in leucine metabolism; HMG-CoA lyase deficiency;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

Summary

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]

Symptoms

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]

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.

Diagnosis

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.

    Treatment

    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.
      Medical Terms Other Names
      Learn More:
      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
      Excessive daytime sleepiness
      More than typical sleepiness during day

      [ more ]

      0001262
      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.

      Organizations

      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

        Learn more

        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.

            References

            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; https://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; https://www.newbornscreening.info/Parents/organicaciddisorders/HMGCoA.html#4.

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