3-methylglutaconic aciduria

The name 3-methylglutaconic aciduria is used to describe five different disorders that impair the functioning of energy-producing centers within cells (mitochondria). As a result of this impairment, pathways that aid in mitochondrial function are disrupted and large amounts of particular acids (3-methylglutaconic acid and 3-methylglutaric acid) build up and are excreted in the urine.

There are five types of 3-methylglutaconic aciduria numbered I, II, III, IV, and V. Types I-III and V are caused by mutations in four different genes and have distinct signs and symptoms. The genetic cause of 3-methylglutaconic aciduria type IV has not been established. The common link among all types of 3-methylglutaconic aciduria is the excretion of large amounts of 3-methylglutaconic acid and 3-methylglutaric acid in the urine.

The features of 3-methylglutaconic aciduria type I include speech delay, delay in the development of mental and motor skills (psychomotor delay), elevated levels of acid in the blood and tissues (metabolic acidosis), abnormal muscle tone (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis).

Barth syndrome is the common name for 3-methylglutaconic aciduria type II. The features of Barth syndrome include an enlarged and weakened heart (dilated cardiomyopathy), recurrent infections due to small numbers of white blood cells (neutropenia), weakness in muscles used for movement (skeletal myopathy), and delayed growth.

Costeff optic atrophy syndrome is the common name for 3-methylglutaconic aciduria type III. This disorder is characterized by degeneration (atrophy) of the optic nerves, which carry information from the eyes to the brain. Other nervous system problems might occur, such as an inability to maintain posture, poor muscle tone, a gradual increase of involuntary jerking movements (choreiform movements), and a general decrease in brain function (cognitive deficit).

The signs and symptoms of 3-methylglutaconic aciduria type IV are variable and overlap with types I-III.

Dilated cardiomyopathy with ataxia (DCMA) is the common name for 3-methylglutaconic aciduria type V. An enlarged and weakened heart (dilated cardiomyopathy) and an inability to coordinate voluntary muscular movements (ataxia) are the hallmark signs of DCMA. The dilated cardiomyopathy usually develops by the age of 3. Some people with DCMA can also have growth failure; mild intellectual disability; optic atrophy; and in males, undescended testes (cryptorchidism) and the opening of the urethra on the underside of the penis (hypospadias).

The five types of 3-methylglutaconic aciduria appear to be rare disorders. Fewer than 20 cases of 3-methylglutaconic aciduria type I have been reported.

The incidence of 3-methylglutaconic aciduria type II is approximately 1 in 200,000 male infants.

The incidence of 3-methylglutaconic aciduria type III is about 1 in 10,000 newborns in the Iraqi Jewish population. This disorder is extremely rare in all other populations.

The incidence of 3-methylglutaconic aciduria type IV is unknown.

The incidence of 3-methylglutaconic aciduria type V is also unknown. It has been reported only in the genetically isolated Hutterite population of Canada and the Northern United States.

Mutations in the AUH, DNAJC19, OPA3, and TAZ genes cause 3-methylglutaconic aciduria.

Mutations in the AUH gene cause 3-methylglutaconic aciduria type I. This gene provides instructions for producing 3-methylglutaconyl-CoA hydratase, an enzyme that is involved in breaking down a building block of proteins (amino acid) called leucine. This amino acid is broken down in the mitochondria during the process of energy production. A deficiency of this enzyme leads to a buildup of 3-methylglutaconic acid, a byproduct of leucine breakdown. Researchers believe that other genes or environmental factors also contribute to the development of this disorder.

Mutations in the TAZ gene cause 3-methylglutaconic aciduria type II (Barth syndrome). This gene provides instructions for making a protein called tafazzin. This protein plays a critical role in maintaining the levels of a particular lipid, cardiolipin, located in the inner membrane of the mitochondria. A lack of tafazzin results in abnormalities in the structure and function of mitochondria, leading to the signs and symptoms of Barth syndrome.

Mutations in the OPA3 gene cause 3-methylglutaconic aciduria type III. This gene provides instructions for making a protein that is also found in mitochondria, but whose function is unknown. Researchers have suggested that cells with a defective OPA3 protein are prematurely vulnerable to self-destruction (apoptosis).

The genetic factors involved in causing 3-methylglutaconic aciduria type IV are unknown.

Mutations in the DNAJC19 gene cause 3-methylglutaconic aciduria type V. Researchers believe that this gene provides instructions for making a protein that has a role in transporting other proteins into the mitochondria. It is also thought that the DNAJC19 protein aids in the assembly and disassembly of other proteins.

Read more about the AUH, DNAJC19, OPA3, and TAZ genes.

The inheritance patterns of 3-methylglutaconic aciduria differ depending on the gene involved.

Types I, III, and V are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Type II is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

The inheritance pattern of 3-methylglutaconic aciduria type IV is unknown.