Myoadenylate deaminase deficiency is a very common trait in the general population. Until now, this enzyme deficiency has been usually attributed to an erratic clinical entity characterized by rapid fatigue, myalgia and cramps after exercise, onset in late adolescence or early adulthood, equal distribution among males and females and, exept for the first period after onset, without features of progression to dystrophy or muscle tissue wasting. Some patients have also been reported to have experienced rhabdomyolysis and myoglobinuria (i.e. episodes of cell lysis followed by loss of muscle myoglobin in the urine). Nevertheless, the vast majority of patients appears to be asymptomatic, even if showing enzyme activity reduction at muscle biopsy and/or being carrier of what was considered to be the disease-mutation.
The myoadenylate deaminase enzyme is found in skeletal muscle, liver and red blood cells. The skeletal muscle isoform is called myoadenylate deaminase 1 and is encoded by the gene AMDP1. An AMDP1 “mutation” (C34T) was identified and demonstrated to prevent the synthesis of the enzyme. Indeed, C34T is estimated to be widespread, being homozygously represented in at least 1-3% of the general population. The estimated high frequency of homozygous individuals, who are mostly asymptomatic, has raised many doubts about the real pathogenicity of the C34T “mutation”(which should be more correctly referred to as a “polymorphism” rather than a mutaion) and other rarer mutation on the same gene. A recent study (2008) seems to indicate that the C34T variant (or other more rare mutations) is not differently distributed among healthy subjects and patients showing the characteristic picture of rapid fatigue, myalgia and cramps after exercise, whether or not these patients are also affected from neuromuscular diseases such as inherited, inflammatory, autoimmune or endocrine myopathies.
This study seems to indicate that a “primary” (i.e. genetically determined) myodenilate deaminase 1 deficiency is unlikely to be of clinical relevance and that the existence of a “secondary” myoadenylate deficiency (i.e. caused by neuromuscolar diseases) may also be excluded.
The causes of the clinical ensemble characterized by rapid fatigue, myalgia and cramps after exercise are therefore still to be investigated, as well as an etiologic therapy remains unavailable. In theory, the administration of creatine monohydrate could provide an alternative source of energy for the anaerobic muscle tissue, whereas administration of D-ribose has proved to be ineffective in the long run. However, aerobic exercise can be encouraged, even if attention should be paid to cases presenting with myoglobinuria.
References
van Adel BA, Tarnopolsky MA. Metabolic myopathies: update 2009. J Clin Neuromuscul Dis. 2009 Mar;10(3):97-121. Review. PMID: 19258857
Gross M. Adenosine monophosphate deaminase deficiency. Orphanet Encyclopedia, Feb 2007 URL: www.orpha.net. Consulted on 17th Sep 2009.
Hanisch F, Joshi P, Zierz S.AMP deaminase deficiency in skeletal muscle is unlikely to be of clinical relevance. J Neurol. 2008 Mar;255(3):318-22. PMID: 18338202
Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 102770 (last edited 7 Jan 2009). URL: http://www.ncbi.nlm.nih.gov/omim/102770. Consulted on 17 Sep 2010.
Safranow K, Czyzycka E, Binczak-Kuleta A, Rzeuski R, Skowronek J, Wojtarowicz A, Jakubowska K, Olszewska M, Loniewska B, Kaliszczak R, Kornacewicz-Jach Z, Ciechanowicz A, Chlubek D. Association of C34T AMPD1 gene polymorphism with features of metabolic syndrome in patients with coronary artery disease or heart failure.Scand J Clin Lab Invest. 2009;69(1):102-12. PMID: 18855224
The myoadenylate deaminase enzyme is found in skeletal muscle, liver and red blood cells. The skeletal muscle isoform is called myoadenylate deaminase 1 and is encoded by the gene AMDP1. An AMDP1 “mutation” (C34T) was identified and demonstrated to prevent the synthesis of the enzyme. Indeed, C34T is estimated to be widespread, being homozygously represented in at least 1-3% of the general population. The estimated high frequency of homozygous individuals, who are mostly asymptomatic, has raised many doubts about the real pathogenicity of the C34T “mutation”(which should be more correctly referred to as a “polymorphism” rather than a mutaion) and other rarer mutation on the same gene. A recent study (2008) seems to indicate that the C34T variant (or other more rare mutations) is not differently distributed among healthy subjects and patients showing the characteristic picture of rapid fatigue, myalgia and cramps after exercise, whether or not these patients are also affected from neuromuscular diseases such as inherited, inflammatory, autoimmune or endocrine myopathies.
This study seems to indicate that a “primary” (i.e. genetically determined) myodenilate deaminase 1 deficiency is unlikely to be of clinical relevance and that the existence of a “secondary” myoadenylate deficiency (i.e. caused by neuromuscolar diseases) may also be excluded.
The causes of the clinical ensemble characterized by rapid fatigue, myalgia and cramps after exercise are therefore still to be investigated, as well as an etiologic therapy remains unavailable. In theory, the administration of creatine monohydrate could provide an alternative source of energy for the anaerobic muscle tissue, whereas administration of D-ribose has proved to be ineffective in the long run. However, aerobic exercise can be encouraged, even if attention should be paid to cases presenting with myoglobinuria.
References
van Adel BA, Tarnopolsky MA. Metabolic myopathies: update 2009. J Clin Neuromuscul Dis. 2009 Mar;10(3):97-121. Review. PMID: 19258857
Gross M. Adenosine monophosphate deaminase deficiency. Orphanet Encyclopedia, Feb 2007 URL: www.orpha.net. Consulted on 17th Sep 2009.
Hanisch F, Joshi P, Zierz S.AMP deaminase deficiency in skeletal muscle is unlikely to be of clinical relevance. J Neurol. 2008 Mar;255(3):318-22. PMID: 18338202
Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 102770 (last edited 7 Jan 2009). URL: http://www.ncbi.nlm.nih.gov/omim/102770. Consulted on 17 Sep 2010.
Safranow K, Czyzycka E, Binczak-Kuleta A, Rzeuski R, Skowronek J, Wojtarowicz A, Jakubowska K, Olszewska M, Loniewska B, Kaliszczak R, Kornacewicz-Jach Z, Ciechanowicz A, Chlubek D. Association of C34T AMPD1 gene polymorphism with features of metabolic syndrome in patients with coronary artery disease or heart failure.Scand J Clin Lab Invest. 2009;69(1):102-12. PMID: 18855224
Taegtmeyer AB, Breen JB, Rogers P, Johnson PH, Smith J, Smolenski RT, Banner NR, Yacoub MH, Barton PJ. Effect of adenosine monophosphate deaminase-1 C34T allele on the requirement for donor inotropic support and on the incidence of early graft dysfunction after cardiac transplantation. Am J Cardiol. 2009 May 15;103(10):1457-62. PMID: 19427446
Teijeira S, San Millán B, Fernández JM, Rivas E, Viéitez I, Miranda S, González F, Navarro C.Myoadenylate deaminase deficiency: clinico-pathological and molecular study of a series of 27 Spanish cases.Clin Neuropathol. 2009 Mar-Apr;28(2):136-42. PMID: 19353846
