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Disease Profile

HIBCH deficiency

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.



US Estimated


Europe Estimated

Age of onset





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


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.


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.


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


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.


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.


Not applicable


Other names (AKA)

Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency; 3-Hydroxyisobutyryl-CoA hydrolase deficiency; Beta-hydroxyisobutyryl-CoA deacylase deficiency;


Congenital and Genetic Diseases; Nervous System Diseases


HIBCH deficiency is a rare metabolic disease. Early symptoms include poor muscle tone, poor feeding, seizures, and a gradual loss of skills. HIBCH deficiency can cause signs and symptoms similar to another disease, called Leigh syndrome.[1] Diagnosis is aided by blood tests which show high levels of lactic acid, and imaging studies which show changes in the "globi pallidi" structure of the brain.[2][1]

HIBCH deficiency occurs when a person inherits a mutation in both copies of their HIBCH gene. This pattern of inheritance is called "autosomal recessive."[2] The HIBCH gene tells the body how to make an enzyme called 3-hyroxyisobutyryl-CoA hydrolase. When the body does not have enough working enzyme, it can not break down the amino acid valine. As a result, toxic valine metabolites build up in the body. More specifically, these toxic metabolites build up within the mitochondria of the body's cells.[3]

Currently, there is not a cure for HIBCH deficiency. Children with HIBCH deficiency require a multidisciplinary team of doctors who can assess how the deficiency is affecting each body system and recommend appropriate treatments.


Signs and symptoms of HIBCH deficiency are very similar to Leigh syndrome, and may include:[2][1][4]

  • Developmental delay (delayed motor and language skills, low muscle tone, poor feeding in infancy)
  • Deterioration of neurological functions during the first stages of life
  • Vision problems
  • Vomiting
  • Seizures
  • A blood test showing an increased lactic acid level
  • Brain lesions in the basal ganglia
  • Accumulation of several valine metabolites in the blood and urine, especially of “3-hydroxy-isobutyryl carnitine”, which is detected as “hydroxy-C4-carnitine” by tandem mass spectrometry (a screening technique that identify carnitine in blood and urine of children with a suspicion of having an inborn metabolic disease).

There are very few cases of HIBCH deficiency described until now. The long term outcome is not well defined yet, but the disease is known to progress (worsen) with time. Severity of HIBCH deficiency does vary. People with the deficiency may have some working enzyme. People with more functioning enzyme tend to have less severe symptoms, than those with little to no enzyme function.[5] Physical stress, infectious illness (such as viral infections), and fasting can trigger a sudden worsening of symptoms in all people with HIBCH deficiency.[5]

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.

Medical Terms Other Names
Learn More:
80%-99% of people have these symptoms
Motor delay
Muscular hypotonia
Low or weak muscle tone
Progressive neurologic deterioration
Worsening neurological symptoms
Throwing up
30%-79% of people have these symptoms
Abnormal vertebral morphology
Abnormality of mitochondrial metabolism
Aplasia/Hypoplasia of the corpus callosum
Eye folds
Prominent eye folds

[ more ]

Facial shape deformation
Failure to thrive
Faltering weight
Weight faltering

[ more ]

Feeding difficulties
Feeding problems
Poor feeding

[ more ]

Increased reflexes
Increased serum lactate
Infantile spasms
Metabolic acidosis
Involuntary, rapid, rhythmic eye movements
Sleep disturbance
Difficulty sleeping
Trouble sleeping

[ more ]

Squint eyes

[ more ]

Truncal ataxia
Instability or lack of coordination of central trunk muscles
5%-29% of people have these symptoms
Undescended testes
Undescended testis

[ more ]

Respiratory insufficiency
Respiratory impairment
Small basal ganglia
1%-4% of people have these symptoms
Head titubation
Tetralogy of Fallot
Percent of people who have these symptoms is not available through HPO
Abnormal facial shape
Unusual facial appearance
Abnormality of the vertebral column
Abnormal spine
Abnormal vertebral column
Abnormality of the spine

[ more ]

Agenesis of corpus callosum
High urine amino acid levels
Increased levels of animo acids in urine

[ more ]

Autosomal recessive inheritance
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood

[ more ]

Lack of coordination of movement
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

Global developmental delay
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]



HIBCH deficiency is caused by mutations in the HIBCH gene. The deficiency results in a block of the breakdown (catabolism) of valine. This leads to a build up of toxic valine metabolites within the mitochondria in the body's cells.[2] Valine is an essential amino acid, which means that it cannot be made by the body, but instead must be obtained from diet.[3]

Valine catabolism involves several steps with different enzymes acting in each step. The 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) is a mitochondrial enzyme that acts in the 5th step, therefore all the substances that are produced before this step build-up. One of the metabolites, known as methacrylyl-CoA, can react with other mitochondrial enzymes and disrupt their activities. As a result, patients with HIBCH deficiency have features similar to Leigh disease and other mitochondrial disorders.[2][1][6]

HIBCH deficiency is considered an organic acidemia. Organic acidemias are so named because they disrupt amino acid metabolism. This causes an increase in organic acid levels. In HIBCH deficiency we see an increase in lactic acid.

HIBCH deficiency can also be considered a mitochondrial disease, because it disrupts mitochondrial enzymes.

The involvement of the globi pallidi in HIBCH deficiency is one of the main features of the disease. The globi pallidi is part of the basal ganglia in the brain. The reason that the globi pallidi is affected may be due to a failure in providing energy to the brain which results in the early death of brain cells. This finding is also a feature of other mitochondrial diseases (including Leigh syndrome) and of other organic acidemias.[1]

HIBCH is also involved in a second metabolic pathway. This pathway is related to propionate metabolism. Propionate is a substance produced by the break down of some aminoacids. However, the HIBCH gene mutations do not appear to result in adverse symptoms related to this pathway.[2]


Treatment of HIBCH deficiency involves frequent carbohydrate-rich meals, along with coenzyme Q10, vitamin C, and vitamin E supplementation.[5]

People with HIBCH deficiency may also benefit from a low-valine diet with carnitine and N-acetyl-cysteine supplementation.[5]

Prompt, supportive, treatment during periods of physical stress and viral illness is vital. This may involve frequent infusions of bicarbonate, plus additional supports as required.[5]

We strongly recommend that these and other treatment options be carefully reviewed with a healthcare provider.


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

    Organizations Providing General Support

      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.

      In-Depth Information

      • 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.


        1. Reuter MS & cols. HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders. Am J Med Genet A. 2014; 164A(12):3162-9. https://www.medscape.com/medline/abstract/25251209.
        2. Petersc H & Ferdinanddussed S, Ruiterd JP & Wandersd RJA. Metabolite studies in HIBCH and ECHS1 defects: Implications for screening. Molecular Genetics and Metabolism. August, 2015; 115 (4):168–173. https://www.sciencedirect.com/science/article/pii/S1096719215300275.
        3. Jorde LB. Aminoacid Metabolism. In: Kaplan Medical, Inc. Biochemistrhy. USMLE step 1. 2016; 252-253.
        4. 3-hydroxyisobutryl-CoA hydrolase deficiency. OMIM. 2015; https://www.omim.org/entry/250620.
        5. Yamada K, Naiki M, Hoshino S et al.,. Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis. Mol Genet Metab Rep. 2014; 1:455–460. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121361/. Accessed 2/22/2017.
        6. Brown G K & cols. Beta-hydroxyisobutyryl coenzyme A deacylase deficiency: a defect in valine metabolism associated with physical malformations. Pediatrics. 1982; 70:532-538. https://www.ncbi.nlm.nih.gov/pubmed/7122152.
        7. What is Mitochondrial Disease?. United Mitochondrial Disease Foundation. https://www.umdf.org/what-is-mitochondrial-disease/. Accessed 2/21/2017.
        8. Ravenscroft G & cols. Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria. Neuromuscul Disord. November, 2016; 26(11):744-748. https://www.ncbi.nlm.nih.gov/pubmed/27751653.

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