The McArdle Disease Handbook A guide to the scientific and medical research into McArdle disease explained in plain English. Written by Kathryn Elizabeth Wright, Ph.D. Copyright ©Kathryn Wright 2010 Disclaimer Unless otherwise stated, this Handbook represents the views and opinions of the author, Kathryn Wright, and does not represent the views and opinions of AGSD (UK) or Vodafone World of Difference. The purpose of this Handbook is to explain scientific research and knowledge about McArdle disease in layman’s language so that it can be understood by people with McArdle disease or those interested in McArdle disease. It is not intended to replace medical advice from your family doctor or specialist. The information provided in this Handbook is correct to the best of the author’s knowledge. If you have any doubts about the accuracy of the information in this Handbook, it is recommended that you read the original source (full details in the reference list). Where no definitive information is available, the author has sought to suggest scientific rationale behind anecdotal observations reported by people with McArdle’s. It is stated where a theory or opinion of the author is given. Due to the nature of scientific research, current theories and understanding of the science behind McArdle’s may change over time and subsequently be proven or disproven. It is recommended that you check the AGSD (UK) website frequently to ensure you are reading the most up-to-date version of this Handbook. Funding for this project Kathryn Wright submitted a proposal and successfully obtained funding from the Vodafone World of Difference charitable foundation under the “World of Difference UK” scheme. This grant enabled AGSD (UK) to employ Kathryn Wright from January to March 2010 to write this Handbook. Further writing was carried out by Kathryn Wright on an unpaid voluntary basis. Kathryn Wright has no competing financial or academic interests. Acknowledgements I would like to acknowledge Vodafone World of Difference (UK) charitable foundation for providing two months funding for this project. I would also like to thank the AGSD (UK) for supporting my application for funding, and in particular I have to thank Andrew Wakelin for his encouragement and support. (This was originally going to be a pamphlet, but has become a book.) My Ph.D. project, funded by AGSD (UK) and The Institute of Orthopaedics, RJAH Orthopaedic Hospital, Oswestry, provided me with an opportunity to develop an interest in McArdle disease. I would like to thank Mum, Dad and Madelyn for their continued interest and encouragement and for proof-reading the Handbook. I am very grateful to Mr James Birch, for his endless patience and support. Definitions of terms used in this Handbook In this Handbook, “McArdle person” is used to mean a person who has received a definitive diagnosis of McArdle disease (who has no functional muscle glycogen phosphorylase enzyme in their 1 skeletal muscle cells). “Unaffected by McArdle’s” is used to describe a “normal” person who has no mutations in either copy of the PYGM gene. People unaffected by McArdle’s have two wildtype copies of the PYGM gene. (Wildtype means that it is a version of the gene with no mutations.) People unaffected by McArdle’s have a normal amount of active muscle glycogen phosphorylase enzyme in their muscle cells. “Carrier” is used to describe a person who has one copy of the PYGM gene without any mutations, and one copy of the PYGM gene which does carry a mutation. A carrier is likely to have approximately half the normal level of muscle glycogen phosphorylase enzyme. Carriers do not usually have symptoms of McArdle disease. Further definitions are given where appropriate throughout the Handbook. There is also a glossary at the end of the Handbook for scientific or medical words used frequently in the Handbook which would not be included in a standard English glossary. 2 Contents Disclaimer............................................................................................................................................ 1 Funding for this project ....................................................................................................................... 1 Acknowledgements ............................................................................................................................. 1 Definitions of terms used in this Handbook ....................................................................................... 1 1 Introduction to McArdle disease .................................................................................................. 12 1.1 A brief introduction to McArdle disease ............................................................................... 12 1.2 What is the cause of McArdle disease? ................................................................................ 13 1.3 McArdle disease is one of the family of glycogen storage diseases ..................................... 13 GAA ............................................................................................................................................... 14 1.4 Why is it called “McArdle disease”? ..................................................................................... 15 1.4.1 Other names for McArdle disease ................................................................................ 15 1.4.2 Other names and abbreviations for muscle glycogen phosphorylase enzyme ............ 15 1.5 How can I explain my McArdle disease to my friends and family who have never heard of it before? .............................................................................................................................................. 15 1.6 The future is promising for people with McArdle disease .................................................... 16 2 Symptoms and diagnosis of McArdle disease ............................................................................... 17 2.1 The personal history of symptoms described by a typical McArdle person ......................... 17 2.1.1 Activities which McArdle people have reported can cause pain/fatigue in muscles: .. 17 2.2 Symptoms of McArdle disease .............................................................................................. 18 2.3 Diagnosis of McArdle disease ............................................................................................... 19 2.3.1 Exercise test .................................................................................................................. 21 2.3.2 Muscle biopsy ............................................................................................................... 25 2.3.3 DNA testing ................................................................................................................... 27 2.3.4 Electromyogram (EMG)................................................................................................. 28 2.3.5 31P magnetic resonance spectroscopy (31P MRS) .......................................................... 29 2.4 Causes of similar symptoms to McArdle disease (in people who don’t have McArdle’s) .... 30 2.5 Other diseases which have similarities to McArdle disease ................................................. 30 2.5.1 Some of the diseases which McArdle people have been misdiagnosed with before getting a proper diagnosis of McArdle’s ....................................................................................... 30 2.5.2 Other muscle diseases with similar symptoms to McArdle disease ............................. 31 2.6 McArdle disease was considered a possible diagnosis for a patient with chronic pain in the television series “House” .................................................................................................................. 33 3 The genetics of McArdle disease .................................................................................................. 35 3 3.1 Genes, mRNA and protein .................................................................................................... 35 3.1.1 Genes are used to make mRNA, which is used to make protein .................................. 35 3.2 Mutations in the PYGM gene prevent production of active muscle glycogen phosphorylase enzyme and cause McArdle’s ........................................................................................................... 36 3.2.1 Stop codons ................................................................................................................... 37 3.2.2 Missense mutations ...................................................................................................... 38 3.2.3 Frameshift mutations .................................................................................................... 39 3.2.4 Splice site mutations ..................................................................................................... 39 3.2.5 Theoretical possible outcomes of various mutations ................................................... 39 3.2.6 How many of these mutations have been identified in the PYGM gene so far? .......... 40 3.2.7 What caused the first mutation in the PYGM gene? .................................................... 42 3.3 How is McArdle disease inherited?....................................................................................... 42 3.3.1 One copy of each gene is inherited from each parent ................................................. 42 3.3.2 What are the combinations