3-Methylglutaconic aciduria (MGA) is used to describe at least five different disorders that impair the body's ability to make energy in the mitochondria. As a result of this impairment, 3-methylglutaconic acid

3-Methylglutaconic acid

3-Methylglutaconic acid is a glutarate which builds up in the urine in 3-Methylglutaconic aciduria or 3-Hydroxy-3-methylglutaric aciduria.-External links:*...

 and 3-methylglutaric acid build up and can be detected in the urine.

3-Methylglutaconic acid is classified as an organic acid. The double carboxylic acid functions are the principal cause of the strength of this acid. 3-methylglutaconic acid can be detected by the presence of the acid function and the double connection that involves reactivity with some specific substances.

Classification

There are currently 5 known subgroups of MGA; MGA type I,II,III,IV & V.

Type	OMIM	Gene	Locus Locus (genetics) In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...	Also known as/Description	Genetics >- | Type I		AUH	Chr.9	3-Methylglutaconic aciduria type I, 3-Methylglutaconic acidemia or 3-Methylglutaconyl-CoA Hydratase Deficiency	AUH gene cause 3-methylglutaconic aciduria type I. This gene provides instructions for producing 3-methylglutaconyl-CoA hydratase, an enzyme that is involved in processing the amino acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...  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, which is eliminated in the urine. Researchers believe that other genes or environmental factors also contribute to the development of this disorder. >- | Type II		TAZ Tafazzin Tafazzin is a protein that in humans is encoded by the TAZ gene. Tafazzin is highly expressed in cardiac and skeletal muscle. It is involved in the metabolism of cardiolipin....	Xq28	Barth syndrome Barth syndrome Barth syndrome , also known as 3-Methylglutaconic aciduria type II, is a X-linked genetic disorder.-Presentation:Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy , neutropenia Barth syndrome (BTHS), also known as 3-Methylglutaconic... (BTHS), 3-Methylglutaconic aciduria type II or Cardiomyopathy-neutropenia syndrome	TAZ gene cause 3-methylglutaconic aciduria type II (Barth syndrome). This gene provides instructions for making a protein called tafazzin Tafazzin Tafazzin is a protein that in humans is encoded by the TAZ gene. Tafazzin is highly expressed in cardiac and skeletal muscle. It is involved in the metabolism of cardiolipin.... . This protein plays a critical role in maintaining the levels of a particular lipid, called 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 heart defects and other problems seen in this disorder. >- | Type III		OPA3 OPA3 Optic atrophy 3 protein is a protein that in humans is encoded by the OPA3 gene.-External Links:* *...	19q13.2-q13.3	3-Methylglutaconic aciduria type III or Costeff syndrome	OPA3 gene cause 3-methylglutaconic aciduria type III. This gene carries 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 more susceptible to a process that eliminates damaged or unneeded cells (programmed cell death called apoptosis Apoptosis Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation... ). >- | Type IV		?	?	3-Methylglutaconic aciduria type IV >- | Type V		DNAJC19 DNAJC19 Mitochondrial import inner membrane translocase subunit TIM14 is an enzyme that in humans is encoded by the DNAJC19 gene.-Further reading:...	3q26.3	3-Methylglutaconic aciduria type V >-

The characteristic features of 3-methylglutaconic aciduria type I include speech delay

Speech delay

Speech delay, also known as alalia, refers to a delay in the development or use of the mechanisms that produce speech. Speech, as distinct from language, refers to the actual process of making sounds, using such organs and structures as the lungs, vocal cords, mouth, tongue, teeth, etc...

, delayed development of both 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 affecting the arms and legs (spastic quadriparesis). Fewer than 20 cases of 3-methylglutaconic aciduria type I have been reported.

Barth syndrome

Barth syndrome

Barth syndrome , also known as 3-Methylglutaconic aciduria type II, is a X-linked genetic disorder.-Presentation:Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy , neutropenia Barth syndrome (BTHS), also known as 3-Methylglutaconic...

 is a common name for 3-methylglutaconic aciduria type II. The main features of Barth syndrome include a weakened and enlarged heart (dilated cardiomyopathy), recurrent infections due to low numbers of white blood cells (neutropenia), skeletal problems, and delayed growth. The incidence of 3-methylglutaconic aciduria type II is approximately 1 in 200,000 male infants.

Costeff optic atrophy syndrome is another name for 3-methylglutaconic aciduria type III. This disorder is characterized mainly by the degeneration of the optic nerves, which carry information from the eyes to the brain. Sometimes other nervous system problems occur, such as an inability to maintain posture, poor muscle tone, the development of certain involuntary movements (extrapyramidal dysfunction), and a general decrease in brain function (cognitive deficit). 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 signs and symptoms of 3-methylglutaconic aciduria type IV are variable and overlap with types I-III. The incidence of 3-methylglutaconic aciduria type IV is unknown.

Epidemiology

3-Methylglutaconic aciduria, seems to be most prevalent amongst the Jewish population of Iraq

Iraq

Iraq ; officially the Republic of Iraq is a country in Western Asia spanning most of the northwestern end of the Zagros mountain range, the eastern part of the Syrian Desert and the northern part of the Arabian Desert....

. However, a high concentration of one type is found in the Saguenay-Lac-Saint-Jean

Saguenay-Lac-Saint-Jean

Saguenay–Lac-Saint-Jean is a region in Quebec, Canada. It contains the Saguenay Fjord, the estuary of the Saguenay River, stretching through much of the region...

 region of Canada

Canada

Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

. This tends to show that the disease is more frequent in insular areas where there is more chance that both parents be carriers, a higher birth rate, and higher number of congenital marriages. As all types of 3-Methylglutaconic aciduria are known to be genetic diseases and show a recessive pattern it is likely that congenital marriages where both partners are carriers increase the chance to have a baby with the condition.

Inheritance patterns

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

• Types I and III are inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

• Type II is inherited in an X-linked recessive
  Recessive
  In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
  
   pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome
  Chromosome
  A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
  
  , 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.

External links

• GeneReviews/NCBI/NIH/UW entry on 3-Methylglutaconic Aciduria Type 3
• OMIM entries on 3-Methylglutaconic Aciduria Type 3