Adenosine Monophosphate Deaminase Deficiency type 1

The Myoadenylatdesaminase deficiency ( MAD deficiency, Myoadenylate deaminase deficiency, MADD ) is the most common inherited metabolic defect in the skeletal muscle, whose clinical significance is controversial since its first description in 1978.

Biochemistry of Myoadenylatdesaminase

The Myoadenylatdesaminase is an isoform of AMP deaminase, an enzyme that catalyzes Purinnukleotidzyklus of human skeletal muscle by means of so-called hydrolytic deamination of the formation of IMP from AMP to form ammonia and water. The exact meaning of the Purinnukleotidzyklus in energy metabolism, the purines subject is not yet fully understood.

Causes of MADD

It is customary to distinguish between three forms of MADD:

• A primary MADD is caused by mutations in the gene AMPD1,
• MADD is a secondary result of a serious muscle damage, such as in advanced muscular dystrophies, without evidence of changes in the genome,
• Koinzidentem at MADD are simultaneously before a caused by mutations MADD and another muscle disease without a recognizable correlation exists.

The MADD is not associated according to current knowledge with other muscle diseases. A suspected in the past associated with malignant hyperthermia could not be maintained in subsequent tests.

Genetics of MADD

1992 managed Morisaki et al. with the discovery of the most common mutation, the decryption of the genetics of primary MADD: the C34 - T transition in AMPD1 gene ( chromosome 1p, exon 2, codon 12), connected to a C143 - T transition (chromosome 1p, exon 3 codon 48 ) in place of 34 of exon 2 of the gene AMPD1 the base cytosine is replaced with thymine. This replacement of the purine bases, the formation of a stop codon for the sequence leading to the translation for forming a highly condensed and ineffective polypeptide: The result is a protein that consists of only 11 amino acids, compared to 747 amino acids of a normal, healthy enzyme. The C143 - T mutation has no meaning since it is no longer read out from the foregoing stop mutation at position 34. Chance of a MADD was at compound heterozygosity ( "compound heterozygosity " ) observed: the mutation C34 - T is here in front of only one allele, the second, different type of mutation is located on the allele that is not affected by this mutation: it is in this case also no effective enzyme synthesized. In individual cases could be observed inter alia as a cause of a MADD rare mutations such as G468 -T ( exon 5 ), G53 -A, 405delT, G1721 -A.

Clinic of MADD

The clinical symptoms in primary Myoadenylatdeaminase deficiency, as first described in 1978 by William N. Fishbein at the American AFIP, typically includes load-induced muscle weakness, muscle pain and cramps, preferably in close to the trunk muscle groups such as the upper arms and thighs. The symptoms, however, vary quite considerably affected: while suffering very considerably such complaints as the first discovery of MADD as a disease, some patients reported in scientific publications of numerous individuals that indicate no or only very slight symptoms. In many cases, the MADD remains completely asymptomatic, and the performance is not restricted. Accordingly, to date, the clinical significance of MADD is ambiguous, has been widely studied and sometimes controversial.

Diagnosis

Ischemic exercise test

The tentative diagnosis can by an ischemic stress test ( ischemic forearm exercise test, IFET or LAER test, lactate ammonia exercise ratio) to be corroborated. The implementation is done by the subject after ligation of the blood supply to the upper arm about a blood pressure cuff several times closes for a specified period of time against a resistance, such as a foam ball, fist, causing an anaerobic metabolism is provoked in the forearm muscles: with a positive diagnosis is recorded from an antecubital blood drawn only a slight increase in ammonia, due to the almost completely ligated AMP deamination. The increase in lactate concentration as an expression of the activity of glycogenolysis and lactic acid fermentation sizes normal. As a rule, can be assigned with very high specificity and sensitivity of a MADD, although the method is inferior in diagnostic safety of the combination of biochemical and human genetic investigation. The ammonia increase is in the healthy in any case, more than 0.4 %, typically 1-3 % of the rise in lactate, whereas in the present MADD, the value is always below this level.

Muscle biopsy

On a muscle biopsy the diagnosis can be confirmed by enzyme-histochemical determination of Myoadenylatdeaminase activity.

Genetic studies

Increasingly, the detection of known mutations by PCR and restriction analysis of DNA samples established, for example, of white blood cells (leukocytes) can be obtained.

Prognosis of the disease

The symptoms occur in those on with significant differences, both in terms of the age of manifestation as well as in the expression. In about 50 % of all cases, clinical symptoms developed only under extreme anaerobic muscle work or life never. The symptoms are usually non-progressive; only a small number of patients is significantly impaired. Severe cases do not occur, a limited life expectancy is not expected. Evidence of an effect of MADD on the course of pregnancy and birth are also missing. Nevertheless, although the disease is usually mild nature, the disease leads in a number of patients to significant impairments; in not a few cases caused the disease after initially slowly decreasing load a widening current decay. The problem in assessing the importance of the enzyme deficiency is since its first description, it is not clear to what extent symptoms that people perceive with proven MADD, are actually due to the lack of Myoadenylatdeaminasemangel. A statement of who and why of symptoms is affected or be reckoned with their development, can not be made until today.