National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

HIBCH deficiency


Other Names:
Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency; 3-Hydroxyisobutyryl-CoA hydrolase deficiency; Beta-hydroxyisobutyryl-CoA deacylase deficiency; Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency; 3-Hydroxyisobutyryl-CoA hydrolase deficiency; Beta-hydroxyisobutyryl-CoA deacylase deficiency; Methacrylic aciduria; Methacrylic acid toxicity; Valine metabolic defect See More
Categories:
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.
Last updated: 2/17/2017
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]
Last updated: 2/17/2017

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.

Showing of 42 |
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HPO ID
80%-99% of people have these symptoms
Dystonia 0001332
Motor delay 0001270
Muscular hypotonia
Low or weak muscle tone
0001252
Progressive neurologic deterioration
Worsening neurological symptoms
0002344
Vomiting
Throwing up
0002013
30%-79% of people have these symptoms
Abnormal vertebral morphology 0003468
Abnormality of mitochondrial metabolism 0003287
Aplasia/Hypoplasia of the corpus callosum 0007370
Epicanthus
Eye folds
Prominent eye folds
[ more ] 		0000286
Facial shape deformation 0011334
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Feeding difficulties
Feeding problems
Poor feeding
[ more ] 		0011968
Hyperreflexia
Increased reflexes
0001347
Hypsarrhythmia 0002521
Increased serum lactate 0002151
Infantile spasms 0012469
Metabolic acidosis 0001942
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Sleep disturbance
Difficulty sleeping
Trouble sleeping
[ more ] 		0002360
Strabismus
Cross-eyed
Squint
Squint eyes
[ more ] 		0000486
Truncal ataxia
Instability or lack of coordination of central trunk muscles
0002078
Ventriculomegaly 0002119
5%-29% of people have these symptoms
Cryptorchidism
Undescended testes
Undescended testis
[ more ] 		0000028
Encephalopathy 0001298
Irritability
Irritable
0000737
Leukoencephalopathy 0002352
Respiratory insufficiency
Respiratory impairment
0002093
Small basal ganglia 0012697
1%-4% of people have these symptoms
Head titubation 0002599
Tetralogy of Fallot 0001636
Percent of people who have these symptoms is not available through HPO
Abnormal facial shape
Unusual facial appearance
0001999
Abnormality of the vertebral column
Abnormal spine
Abnormal vertebral column
Abnormality of the spine
[ more ] 		0000925
Agenesis of corpus callosum 0001274
Aminoaciduria
High urine amino acid levels
Increased levels of animo acids in urine
[ more ] 		0003355
Autosomal recessive inheritance 0000007
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood
[ more ] 		0002376
Dysmetria
Lack of coordination of movement
0001310
Generalized hypotonia
Decreased muscle tone
Low muscle tone
[ more ] 		0001290
Global developmental delay 0001263
Infantile onset
Onset in first year of life
Onset in infancy
[ more ] 		0003593
Myoclonus 0001336
Seizure 0001250
Showing of 42 |
Last updated: 7/1/2020
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]
Last updated: 2/17/2017
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.
Last updated: 2/22/2017

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

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.

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.

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  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. http://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. http://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. http://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.