Myoadenylate deaminase deficiency
The Myoadenylatdesaminase deficiency (MAD deficiency, Myoadenylate deaminase deficiency, MADD) is an autosomal recessive concerns hereditary disease that approximately 1-2% of the European population. It is therefore the most common known metabolic disease of the skeletal muscles . This muscular form of adenosine monophosphate deaminase deficiency is caused by homozygous null alleles in the AMPD1 gene , which codes for AMP deaminase type 1 and the most common known null mutation is c.34C> T, p.Q12 *. However, these and similar biallelic genotypes in AMPD1 are not fully penetrative , so that a high proportion of patients who carry biallelic null allele mutations show no clinical symptoms. Because of the incomplete penetrance of the homozygous null alleles, the clinical meaning is still not exactly known since the first description in 1978 and is scientifically controversial.
Myoadenylate deaminase biochemistry
Myoadenylate deaminase (AMP deaminase 1, AMPD1 ) is a genomic isoform of AMP deaminases , i. H. one of the three paralog AMP deaminases in the human genome. These are enzymes that catalyze the formation of IMP from AMP with the formation of ammonia and water through so-called hydrolytic deamination in the purine nucleotide cycle of human skeletal muscles . The exact meaning of the purine nucleotide cycle in the energy metabolism to which purines are subject has not yet been fully clarified.
Causes of the MADD
It is common to distinguish between three forms of MADD:
- A primary MADD is caused by biallelic (i.e. homozygous or compound heterozygous) mutations in the AMPD1 gene (two null alleles with loss of function of the protein, LOF),
- A secondary MADD is the result of severe muscle damage, for example in advanced muscular dystrophies , without evidence of changes in the genome,
- In the case of coincident MADD , a mutational MADD and another muscle disease are present at the same time, without any recognizable connection.
As far as we know today, MADD is not associated with other muscle diseases. A connection with malignant hyperthermia that was suspected in the past could not be maintained in later investigations.
Genetics of the MADD
In 1992 Morisaki et al. the discovery of homozygous mutations with loss of function in the AMPD1 gene on chromosome 1p as the cause of primary MADD . The most common mutation found was the transition c.34C> T in exon 2, codon 12 of the AMPD1 gene, which leads to the introduction of the premature stop codon p.Q12 * into the MAD protein. If the current canonical transcript ENST00000520113.2 of the AMPD1 gene is taken into account , this mutation is nowadays referred to as c.133C> T, p.Q45 *. This premature stop codon results in the formation of a greatly shortened and ineffective MAD protein during translation , which consists of only 11 amino acids , compared to 747 amino acids of a normal, healthy enzyme .
A MADD in was Chance compound heterozygosity ( "compound heterozygosity") observed: the mutation c.34C> T is in this case only one allele before, on the second allele, is a different mutation, which also results in a null allele: it is in In this case, too, no effective enzyme was synthesized from either of the two alleles. Other loss-of-function mutations besides c.133C> T were rare mutations such as c.468G> T (exon 5), c.53G> A, c.405delT, c.1721G> A and the like. a. to be established.
Clinic of the MADD
The clinical symptoms of primary myoadenylate deaminase deficiency, as described for the first time in 1978 by William N. Fishbein at the American AFIP, typically include exercise-related muscle weakness, muscle pain and cramps, preferably in muscle groups near the trunk such as the upper arms and thighs. The symptoms, however, vary considerably among those affected: while, as with the first discovery of MADD as a disease, some patients suffer quite considerably from such complaints, numerous people report in scientific publications who report no or only very few symptoms. In many cases the MADD remains completely asymptomatic, and performance is not restricted. Accordingly, the clinical significance of MADD is still ambiguous, has been studied many times and sometimes discussed controversially.
Diagnosis
Ischemic exercise test
The diagnosis can by means of an ischemic stress test ( ischemic forearm exercise test , IFET or LAER test, lactate ammonia exercise ratio ) will hardens. The test is carried out by closing the fist several times for a fixed period of time against a resistance, such as a foam ball, after the blood supply to the upper arm has been cut off, for example with a blood pressure cuff, which provokes an anaerobic metabolism in the forearm muscles : if the diagnosis is positive, in Blood taken from an elbow vein shows only a slight increase in ammonia, a consequence of the almost completely suppressed AMP deamination . The increase in lactate concentration as an expression of the activity of glycogenolysis and lactic acid fermentation is normal. As a rule, MADD can be proven with very high specificity and sensitivity , although the diagnostic reliability of the method is inferior to the combination of biochemical and human genetic testing. The increase in ammonia in healthy individuals is in any case more than 0.4%, normally 1–3% of the increase in lactate, while in the presence of MADD the value is always below this level.
Muscle biopsy
The suspected diagnosis can be confirmed on a muscle biopsy by enzyme-histochemical determination of the myoadenylate desaminase activity.
Genetic Studies
The detection of the known mutations by means of DNA extraction from white blood cells ( leukocytes ) followed by PCR and DNA sequencing of the corresponding region of AMPD1 is becoming increasingly established .
Prognosis of the disease
The symptoms appear in those affected with considerable differences, both in terms of age and severity. In about 50% of all cases, clinical symptoms develop only with extreme anaerobic muscle work or never in a lifetime. The symptoms are usually not progressive; only a small number of patients are significantly affected. There are no severe courses, and a limited life expectancy is not to be expected. There is also no evidence of an effect of MADD on the course of pregnancy and childbirth.
Nevertheless: although the course of the disease is usually mild, the disease leads to considerable impairment in a number of patients; in quite a few cases the disease causes an increasing decline in performance after initially slowly decreasing resilience.
The problem with assessing the significance of the enzyme deficiency since it was first described has been that it is not clear to what extent symptoms that people with proven MADD perceive are actually due to the deficiency in myoadenylate deaminase. A statement as to who and for what reasons is affected by symptoms or has to expect their development cannot be made to this day.
treatment
Administration of ribose (a simple sugar) before physical exercise can improve performance. However, the effects are short-lived and it is difficult to find the optimal dose to avoid diarrhea but still get an effect.
literature
- M. Gross: The MAD deficiency . I. Holzapfel, Munich 1994
- S. Fischer: Studies on the clinical significance of the primary myoadenylate deaminase deficiency (MADD) . 2005. katalog.ub.uni-leipzig.de
- JCW Drenckhan: The myoadenylate desaminase deficiency (MADD): molecular genetic studies of the AMPD1 gene and myopathological correlation . 2010. katalog.ub.uni-leipzig.de
- S Fischer, C Drenckhahn, C Wolf et al .: Clinical significance and neuropathology of primary MADD in C34-T and G468-T mutations of the AMPD1 gene . In: Clin Neuropathol. , 2005 Mar-Apr, 24 (2), pp. 77-85, PMID 15803807
Web links
References and comments
- ↑ Adenosine monophosphate deaminase deficiency . In: Genetics Home Reference . United States National Library of Medicine . July 2008.
- ↑ a b Adenosine monophosphate deaminase deficiency, Doctor Manfred Gross, Orphanet
- ↑ AMPD1 c.133C> T p.Q45 * in the Varsome Database, Saphetor
- ^ Armed Forces Institute of Pathology in the English language Wikipedia.
- ↑ Fishbein et al., 1990.