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3-methylglutaconyl-CoA hydratase deficiency (AUH defect)

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Alternate names

MGA type I; 3 alpha methylglutaconic aciduria type I; 3 methylglutaconyl CoA hydratase deficiency; 3MG CoA hydratase deficiency; 3-MGCA type I (3-MGCA-1); 3 methylglutaconic aciduria type 1


3-methylglutaconic aciduria (3-MGA) type I is an inborn error of leucine metabolism with a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia.


3-methylglutaconyl-CoA hydratase deficiency is a rare disorder; at least 20 cases have been reported in the scientific literature.


  • Mutations in the AUH gene cause 3-methylglutaconyl-CoA hydratase deficiency.
  • This gene provides instructions for producing 3-methylglutaconyl-CoA hydratase, an enzyme that is involved in breaking down a protein building block (amino acid) called leucine to provide energy for cells.
  • This amino acid is broken down in cell structures called mitochondria, which convert energy from food into a form that cells can use.

Gene mutations

  • AUH gene mutations lead to an absence of enzyme activity. Without any functional 3-methylglutaconyl-CoA hydratase, leucine is not properly broken down, which leads to a buildup of related compounds, including multiple acids: 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid.
  • Researchers speculate that an accumulation of these acids in the fluid that surrounds and protects the brain and spinal cord (the cerebrospinal fluid or CSF) can damage these structures and contribute to the neurological features of 3-methylglutaconyl-CoA hydratase deficiency.
  • Because the age at which the condition begins varies widely and because the signs and symptoms improve in some affected children, researchers speculate that other genes or environmental factors may play a role in the features of 3-methylglutaconyl-CoA hydratase deficiency.


Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

  • Beginning in infancy to early childhood, children with this condition often have delayed development of mental and motor skills (psychomotor delay), speech delay, involuntary muscle cramping (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis).
  • Affected individuals can also have optic atrophy, which is the degeneration (atrophy) of nerve cells that carry visual information from the eyes to the brain.
  • In some cases, signs and symptoms of 3-methylglutaconyl-CoA hydratase deficiency begin in adulthood, often in a person's twenties or thirties.
  • These individuals have damage to a type of brain tissue called white matter (leukoencephalopathy), which likely contributes to progressive problems with speech (dysarthria), difficulty coordinating movements (ataxia), stiffness (spasticity), optic atrophy, and a decline in intellectual function (dementia).
  • Affected individuals who show symptoms of 3-methylglutaconyl-CoA hydratase deficiency in childhood often go on to develop leukoencephalopathy and other neurological problems in adulthood.
  • All people with 3-methylglutaconyl-CoA hydratase deficiency accumulate large amounts of a substance called 3-methylglutaconic acid in their body fluids.

As a result, they have elevated levels of acid in their blood (metabolic acidosis) and excrete large amounts of acid in their urine (aciduria).

  • 3-methylglutaconyl-CoA hydratase deficiency is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels 3-methylglutaconic acid in urine (3-methylglutaconic aciduria).
  • People with 3-methylglutaconyl-CoA hydratase deficiency also have high urine levels of another acid called 3-methylglutaric acid.

Clinical presentation

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

  • 3-Methylglutaconic aciduria
  • Failure to thrive(Faltering weight)

30%-79% of people have these symptoms

5%-29% of people have these symptoms

1%-4% of people have these symptoms

  • Abnormality of the cerebral white matter
  • Adult onset(Symptoms begin in adulthood)
  • Ataxia
  • Athetosis(Involuntary writhing movements in fingers, hands, toes, and feet)
  • Dementia(Dementia, progressive)
  • Infantile onset(Onset in first year of life)
  • Optic atrophy
  • Psychomotor retardation
  • Self-mutilation(Deliberate self-harm)
  • Spasticity(Involuntary muscle stiffness, contraction, or spasm)


Patients with 3-MGA type I can be distinguished from those with other forms of 3-MGA (types II, III and IV; see these terms) by the distinctive pattern of metabolite excretion: 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA) whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA).

Antenatal diagnosis Prenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes.


Treatment is largely symptomatic but dietary management with a modest leucine restriction and supplementation with L-carnitine may be beneficial in some cases.

NIH genetic and rare disease info

3-methylglutaconyl-CoA hydratase deficiency (AUH defect) is a rare disease.

Latest research - 3-methylglutaconyl-CoA hydratase deficiency (AUH defect)

Clinical trials


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