Glutaric acidemia type I - GCDH gene.
Glutaric acidemia type I, also known as glutaric aciduria type I, is a rare disease of genetic origin, in which the body cannot process certain proteins correctly due to a metabolic alteration that causes a deficiency of the glutaryl-CoA enzyme -dehydrogensase (GCDH). This enzyme is involved in the metabolism of three amino acids: lysine, hydrolysin and tryptophan. Excessive concentrations of these amino acids and their intermediate degradation products can accumulate and cause damage to the brain, particularly in the basal ganglia, which help control movement, as well as intellectual disability.
The severity of the disease is very variable. The disease usually begins to manifest between the first 3 to 24 months of life, through an acute encephalopathy crisis that causes necrosis in the basal ganglia, whose main consequence is an important neurological dysfunction that usually involves alterations of dystonia and/or movement type dyskinesia. Macrocephaly is also a common feature. Affected people may have difficulty moving, spasms, shaking, stiffness or decreased muscle tone. In addition, some people with glutaric acidemia have developed hemorrhages in the brain or eyes that could be confused with the effects of child abuse. Early detection, prior to the onset of encephalopathy, and the beginning of adequate treatment allow a substantial improvement in the evolution of the disease and, in some cases, the absence of symptoms is achieved, without choreoathetosis or dystonia and with ratios of development within normal limits. On the contrary, in those patients in whom diagnosis and intervention are late, after encephalopathic crises, they are more likely to suffer from persistent neurological involvement.
This process is due to mutations in the GCDH (glutaryl-CoA dehydrogenase) gene, located on the long arm of chromosome 19 (19p13.3), which encodes the enzyme glutaryl-CoA-dehydrogensase (GCDH), involved in the processing of amino acids lysine, hydrolysin and tryptophan, basic elements of proteins.
More than 150 GCDH gene mutations responsible for glutaric acidemia type I have been described. Most of these mutations result in the substitution of one amino acid for another in the enzyme. In the Amish community, all known cases of glutaric acidemia type I derive from the substitution of the amino acid alanine for the amino acid valine at position 421 (Ala421Val or A421V). Some specific mutations have been found in certain Native American populations. In individuals with glutaric acidemia type I that belong to the Lumbee community of North Carolina, it has been found that they have a mutation in which the amino acid glutamic acid is replaced by lysine at position 414 (Glu414Lys or E414K). Likewise, a mutation that replaces the guanine nucleotide with cytosine (IVS1, G-T, 5) is common in the Ojibwa population of Canada.
Mutations in the GCDH gene inhibit the synthesis of the glutaryl-CoA-dehydrogensase enzyme (GCDH) or lead to the synthesis of a non-functional defective enzyme. This enzyme deficiency allows lysine, hydrolysin and tryptophan and its intermediate metabolites to accumulate in abnormal concentrations, especially at times when the body is under stress. Intermediate metabolites resulting from the incomplete transformation of lysine, hydrolysin and tryptophan can damage the brain, particularly the basal ganglia, which causes the signs and symptoms of glutaric acidemia type I.
This disease is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI we detect mutations associated with glutaric acidemia type I, by means of complete PCR amplification of the exons of the GCDH gene, and their subsequent sequencing.
Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).