Disease Profile

3-Hydroxyisobutyric aciduria

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.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of Onset

Antenatal

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

no.svg

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

no.svg

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.

no.svg

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

no.svg

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.

no.svg

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.

no.svg

Not applicable

no.svg

Other Names (AKA)

Disorder of valine metabolism

Categories

Congenital and Genetic Diseases; Metabolic disorders

Summary

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]

Symptoms

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]

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:
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

Cause

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]

Treatment

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]

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

    • 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.

        References

        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.