3-Hydroxyisobutyric aciduria

Other Names: Disorder of valine metabolism

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).

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

Cases of 3-hydroxyisobutyric aciduria thought to be caused by changes (mutations) in the ALDH6A1 gene are inherited in an autosomal recessive manner. 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.

Signs and symptoms

The signs and symptoms of 3-hydroxyisobutyric aciduria vary but may include:

• 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Hypogonadotropic hypogonadism
• Lactic acidosis(Increased lactate in body)

30%-79% of people have these symptoms

• Long philtrum
• Microtia(Small ears)
• Triangular face(Face with broad temples and narrow chin)

5%-29% of people have these symptoms

• Aplasia/Hypoplasia of the cerebellum(Absent/small cerebellum)
• Aplasia/Hypoplasia of the corpus callosum
• Cerebral calcification(Abnormal deposits of calcium in the brain)
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Microcephaly(Abnormally small skull)
• Micrognathia(Little lower jaw)
• Seizure
• Sloping forehead(Inclined forehead)
• Ventriculomegaly

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.

NIH genetic and rare disease info

• NIH info on 3-Hydroxyisobutyric aciduria

3-Hydroxyisobutyric aciduria is a rare disease.

3-Hydroxyisobutyric aciduria Resources
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