HIBCH deficiency

Alternate names

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

Definition

HIBCH deficiency is a rare metabolic disease. Early symptoms include poor muscle tone, poor feeding, seizures, and a gradual loss of skills.

Cause

• 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.
• Valine is an essential amino acid, which means that it cannot be made by the body, but instead must be obtained from diet.
• 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.
• 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.
• 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

pattern of inheritance is called "autosomal recessive."

Signs and symptoms

Signs and symptoms of HIBCH deficiency are very similar to Leigh syndrome, and may include:

• 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

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. Physical stress, infectious illness (such as viral infections), and fasting can trigger a sudden worsening of symptoms in all people with HIBCH deficiency.

Diagnosis

• 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.
• 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).

Treatment

• Treatment of HIBCH deficiency involves frequent carbohydrate-rich meals, along with coenzyme Q10, vitamin C, and vitamin E supplementation.
• People with HIBCH deficiency may also benefit from a low-valine diet with carnitine and N-acetyl-cysteine supplementation.
• 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.

NIH genetic and rare disease info

• NIH info on HIBCH deficiency

HIBCH deficiency is a rare disease.

HIBCH deficiency Resources
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