Glutaric aciduria

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A group of metabolic diseases is called glutaric aciduria or glutaric acid disease , a distinction is made between types 1 and 2. Glutaric aciduria is a rare disease .

Type 1 glutaric aciduria

Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency - or GA1 for short) is a congenital metabolic disease that affects the breakdown of the amino acids lysine , hydroxylysine and tryptophan . The cause is inherited mutations in the gene that codes for the enzyme glutaryl-CoA dehydrogenase.

causes

By the enzyme defect, the amino acids may lysine and tryptophan not be broken down properly and so stow itself. In various intermediate steps, the body converts lysine into the metabolic products glutaric acid (GA) and 3-hydroxyglutaric acid (3OH-GA). These metabolic products accumulate in tissues and body fluids and are also excreted in the urine , for example (hence the name of the disease glutaric acid uria = 'glutaric acid in the urine'). 3OH-GA is mainly held responsible for the development of symptoms.

In the context of so-called catabolic crises, i.e. states with an insufficient supply of energy, symptoms then break out. These crises occur mainly in the case of febrile infections, infections or diarrheal illnesses. Due to the lack of energy, the body switches to catabolism , i.e. the breakdown of the body's own proteins. When the body's own protein mass is broken down, lysine is also produced. This cannot be broken down properly in GA1 patients, and the accumulation of GA and 3OH-GA increases. These metabolic products are particularly concentrated in the brain . One brain region that is particularly sensitive to this is the corpus striatum , which belongs to the basal ganglia. This region is responsible for the coordination of movement sequences in the context of voluntary motor skills . The accumulation of 3OH-GA in particular leads to irreversible damage to the nerve cells in the striatum and ultimately to the destruction of this brain region.

Symptoms

GA1 patients are usually symptom-free prior to the onset of a catabolic crisis. The consequence of a catabolic "encephalopathic" crisis is a movement disorder of varying degrees, which can range from slight motor deficits to severe motor disabilities. Since the nerve cells of the cerebral cortex are not affected, the patient usually retains normal intelligence; in individual cases, learning or partial performance weaknesses (so-called minor cognitive deficits) are described. Furthermore, there are individual case descriptions of adult patients who had no symptoms in childhood, but who had abnormalities in the white matter of the brain in advanced adulthood without these abnormalities causing any apparent problems.

therapy

The most important thing in therapy is to recognize the disease and start treatment before the onset of symptoms. The main therapy consists in avoiding these catabolic crises. The frequency of such crises decreases with increasing age, beyond the 4th – 5th As a rule, such crises no longer occur after the year of life. If the therapy succeeds in preventing the outbreak of a crisis up to the age of 5, according to the current state of knowledge, the patient will most likely be spared a motor disability. It is particularly important for therapy to identify the disease before a crisis occurs, that is, before symptoms appear. Essential for this is the comprehensive newborn screening carried out in Germany since 2003 ("extended" means with measurement of the acylcarnitine profile). If the disease can be diagnosed in this way, the patients must be treated permanently in a center for pediatric metabolic medicine. The treatment consists in restricting the lysine supply through a special diet that is low in lysine, as well as giving a drug called carnitine. Carnitine has the function that GA and 3OH-GA can couple to carnitine and are thus more easily excreted in the urine. Furthermore, a special emergency management is of particular importance in therapy. Catabolic conditions such as febrile infections, diarrhea or the like must, if they cannot be avoided, be treated with increased energy intake. If this cannot be done by drinking high-energy solutions, it is necessary to see the nearest children's clinic as quickly as possible, so that high-percentage glucose solution and carnitine can be infused via the vein.

literature

  • Kölker S et al. (2011) Diagnosis and management of glutaric aciduria type I - revised recommendations . In: J Inherit Metab Dis 34: 677-694
  • Mühlhausen C, Hoffmann GF, Strauss KA, Kölker S, Okun JG, Greenberg CR, Naughten ER, and Ullrich K (2004) Maintenance treatment of glutaryl-CoA dehydrogenase deficiency . In: J Inherit Metab Dis 27: 885-892
  • Kölker S, Garbade SF, Greenberg CR, et al. (2006) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency . In: Pediatr Res 59: 840-846
  • S3 guideline : Diagnostics, therapy and management of glutaric aciduria type I , AWMF register number 027/018 (online: [1] ; PDF; 313 kB), status 03/2011

Web links

Type 2 glutaric aciduria

Type 2 glutaric aciduria is based on an inherited defect of the “electrotransfer flavoprotein” or “ETF cytochrome Q oxidoreductase”, which biochemically leads to a multiple acyl-CoA dehydrogenase deficiency.

causes

At the biochemical level, the genetic defect affects not only fatty acid oxidation but also the breakdown of various amino acids (e.g. valine, leucine, isoleucine, tryptophan and lysine).

Symptoms

In addition to facial and brain malformations, kidney cysts, epilepsy and cardiomyopathy or myopathy occur. Crisis can lead to the development of a so-called Reye's syndrome , as well as metabolic acidosis, hypoglycaemia. The main clinical feature of the disease is a progressive encephalopathy.

therapy

In addition to avoiding catabolic conditions, a low-fat diet and administration of riboflavin and D3-hydroxybutyrate have been tried. However, these are experimental therapeutic approaches. There are currently no reliable, controlled studies on the treatment of this disease.

As far as we know, the disease is fatal if it starts early, usually within the first few weeks of life.

See also