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

3-Hydroxyisobutyric aciduria


Other Names:
Disorder of valine metabolism
Categories:
3-Hydroxyisobutyric aciduria is a rare metabolic condition in which the body is unable to breakdown certain amino acids (the building blocks of protein). This leads to a toxic buildup of particular acids known as organic acids in the blood (organic acidemia), tissues and urine (organic aciduria). Signs and symptoms of 3-hydroxyisobutyric aciduria include developmental delay, characteristic facial features and brain abnormalities. The exact underlying cause is not well understood; however, researchers believe some cases are caused by changes (mutations) in the ALDH6A1 gene and inherited in an autosomal recessive manner. Because it is so rare, there is limited evidence to support the effectiveness of treatment, but a protein-restricted diet and carnitine supplementation have been tried with varying degrees of success.[1][2][3][4]
Last updated: 1/28/2015
The signs and symptoms of 3-hydroxyisobutyric aciduria vary but may include:[1][2][3]
  • Developmental delay
  • Intellectual disability
  • Failure to thrive
  • Characteristic facial features including a long philtrum and small, low-set ears
  • Unusually small head (microcephaly)
  • Congenital brain abnormalities
  • Nausea
  • Diarrhea
  • Dehydration
  • Lethargy

The severity of the condition can also vary significantly from person to person. Some affected people may only experience mild attacks of vomiting with normal development, while others experience failure to thrive with severe intellectual disability and early death.[2]
Last updated: 1/28/2015

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
Learn More:
HPO ID
80%-99% of people have these symptoms
Hypogonadotropic hypogonadism 0000044
Lactic acidosis
Increased lactate in body
0003128
30%-79% of people have these symptoms
Long philtrum 0000343
Microtia
Small ears
Underdeveloped ears
[ more ] 		0008551
Triangular face
Face with broad temples and narrow chin
Triangular facial shape
[ more ] 		0000325
5%-29% of people have these symptoms
Aplasia/Hypoplasia of the cerebellum
Absent/small cerebellum
Absent/underdeveloped cerebellum
[ more ] 		0007360
Aplasia/Hypoplasia of the corpus callosum 0007370
Cerebral calcification
Abnormal deposits of calcium in the brain
0002514
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation
[ more ] 		0001511
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ] 		0000252
Micrognathia
Little lower jaw
Small jaw
Small lower jaw
[ more ] 		0000347
Seizure 0001250
Sloping forehead
Inclined forehead
Receding forehead
[ more ] 		0000340
Ventriculomegaly 0002119
Percent of people who have these symptoms is not available through HPO
Abnormal facial shape
Unusual facial appearance
0001999
Abnormality of neuronal migration 0002269
Aminoaciduria
High urine amino acid levels
Increased levels of animo acids in urine
[ more ] 		0003355
Autosomal recessive inheritance 0000007
Congenital intracerebral calcification 0006906
Episodic ketoacidosis 0005974
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Ketoacidosis 0001993
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Last updated: 7/1/2020
In many affected people, the exact underlying cause of 3-hydroxyisobutyric aciduria is poorly understood. Scientists believe that some cases are caused by changes (mutations) in the ALDH6A1 gene. This gene encodes an enzyme called methylmalonate semialdehyde dehydrogenase, which helps the body break down certain amino acids (the building blocks of protein) found in food. If this gene isn't working properly, the body is unable to break down the amino acids valine and thymine which leads to a build-up of toxic substances in the body and the many signs and symptoms of 3-hydroxyisobutyric aciduria.[4][1]
Last updated: 1/28/2015
Cases of 3-hydroxyisobutyric aciduria thought to be caused by changes (mutations) in the ALDH6A1 gene are inherited in an autosomal recessive manner.[1][4] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.
Last updated: 1/28/2015
There is no cure for 3-hydroxyisobutyric aciduria. Because it is so rare, there is limited evidence to support the effectiveness of treatment. However, affected people have been treated with a protein-restricted diet and carnitine supplementation with varying degrees of success.[1]
Last updated: 1/28/2015

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

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • The Centers for Mendelian Genomics program is working to discover the causes of rare genetic disorders. For more information about applying to the research study, please visit their website.

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

  • The Organic Acidemia Association has an information page on organic acidemias. Click on Organic Acidemia Association to view the information page.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • 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.
  • 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 3-Hydroxyisobutyric aciduria. Click on the link to view a sample search on this topic.

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.

  1. Sass JO, Walter M, Shield JP, Atherton AM, Garg U, Scott D, Woods CG, Smith LD. 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase. J Inherit Metab Dis. 2012 May;35(3):437-42. May 2012; 35(3):437-442.
  2. Song X, Anderson V, Guzman M, Rao C. Neuropathology of 3-hydroxyisobutyric aciduria, an autopsy case report. Can J Neurol Sci. July 2009; 36(4):483-486.
  3. Loupatty FJ, van der Steen A, Ijlst L, Ruiter JP, Ofman R, Baumgartner MR, Ballhausen D, Yamaguchi S, Duran M, Wanders RJ. Clinical, biochemical, and molecular findings in three patients with 3-hydroxyisobutyric aciduria. Mol Genet Metab. March 2006; 87(3):243-248.
  4. Marcadier JL, Smith AM, Pohl D, Schwartzentruber J, Al-Dirbashi OY; FORGE Canada Consortium, Majewski J, Ferdinandusse S, Wanders RJ, Bulman DE, Boycott KM, Chakraborty P, Geraghty MT. Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria. Orphanet J Rare Dis. July 2013; 8:98.