McArdle's Disease
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Glycogen storage disease type V (GSD5, GSD-V), also known as McArdle's disease, is a
metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
, one of the metabolic myopathies, more specifically a muscle
glycogen storage disease A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glycolysis, glucose breakdown, typically in m ...
, caused by a deficiency of myophosphorylase. Its incidence is reported as one in 100,000, roughly the same as
glycogen storage disease type I Glycogen storage disease type I (GSD I) is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD ...
. The disease was first reported in 1951 by British physician Brian McArdle of
Guy's Hospital Guy's Hospital is an NHS hospital founded by philanthropist Thomas Guy in 1721, located in the borough of Southwark in central London. It is part of Guy's and St Thomas' NHS Foundation Trust and one of the institutions that comprise the Kin ...
, London.


Signs and symptoms


Onset of symptoms and diagnostic delay

In the classic
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
, the onset of this disease is usually noticed in childhood, but often not diagnosed until the third or fourth decade of life, frequently due to misdiagnosis and dismissal of symptoms. The median age of symptom onset is 3 years, with the median diagnostic delay being 29 years. Misdiagnosis is overwhelmingly common, with approximately 90% of patients being misdiagnosed, and approximately 62% receiving multiple misdiagnoses before a correct diagnosis. The prolonged diagnostic delay, misdiagnosis or multiple misdiagnoses, or being given inappropriate exercise advice (such as ignore pain or avoid exercise) severely impacts the quality of life (QoL), physically and mentally.


Ultra-rare phenotypes


Late adult-onset, limb–girdle phenotype

There is an ultra-rare adult-onset, limb–girdle phenotype that presents very late in life (70+ years of age) due to a recessive
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
PYGM mutation (p. Lys42Profs*48) resulting in severe upper and lower limb atrophy, with the possibility of ptosis (drooping eyelids) and camptocormia (stooped posture). As of 2017, there have been two reported cases of this specific homozygous mutation and phenotype. In 1980, a woman also had a limb–girdle phenotype with onset at age 60, histochemical staining showed myophosphorylase deficiency; however the genetic mutation was unknown.


Fatal infantile-onset phenotype

There is an ultra-rare, fatal infantile-onset phenotype that results in profound muscle weakness (" floppy baby") and respiratory failure within weeks of birth (perinatal asphyxia). Post-mortem biopsy showed a deficiency of myophosphorylase and abnormal glycogen accumulation in skeletal muscle tissue. This phenotype may also include premature birth and joint contractures. Two reported cases, in 1978 and 1989.


Mild phenotype

There is an ultra-rare mild phenotype caused by recessive
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
alleles in the PYGM gene, where one allele is a common
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
mutation and the other allele is an ultra-rare
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...
ic mutation. It can also be caused by recessive homozygous intronic mutations. These intronic mutations result in a milder phenotype compared to the classic phenotype of McArdle disease. There is residual myophosphorylase activity, between 1-2% residual activity compared to unaffected individuals. This results in greater exercise capacity compared to classic phenotype McArdle individuals, particularly for sustained aerobic activity, but the capacity was still below that of unaffected individuals. In this mild phenotype, since their early teens, they did experience cramping and premature muscle fatigue during sudden vigorous exercise and prolonged isometric exercise; however, due to their less diminished capacity for aerobic activity, they were able to keep up with their peers in sports and everyday activities. As of 2009, there have been 3 reported cases of non-related individuals, a reported
Druze The Druze ( ; , ' or ', , '), who Endonym and exonym, call themselves al-Muwaḥḥidūn (), are an Arabs, Arab Eastern esotericism, esoteric Religious denomination, religious group from West Asia who adhere to the Druze faith, an Abrahamic ...
family of
consanguineous Consanguinity (from Latin '' consanguinitas'' 'blood relationship') is the characteristic of having a kinship with a relative who is descended from a common ancestor. Many jurisdictions have laws prohibiting people who are closely related by blo ...
(related) individuals and 9 reported cases in two Finnish families.


Common signs and symptoms

The most prominent symptom is that of
exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe pos ...
which includes: * premature
muscle fatigue Muscle fatigue is when muscles that were initially generating a normal amount of force, then experience a declining ability to generate force. It can be a result of vigorous exercise, but abnormal fatigue may be caused by barriers to or interfer ...
(particularly for anaerobic activity and high-intensity aerobic activity, which may be described as inability to keep up with peers or reduced stamina); * exercise-induced painful cramps; * inappropriate rapid heart rate response to exercise; * exaggerated cardiorespiratory response to exercise (
heavy Heavy may refer to: Measures * Heavy, a characterization of objects with substantial weight * Heavy, a wake turbulence category used by pilots and air traffic controllers to refer to aircraft with a maximum takeoff mass of 136,000 kgs or mo ...
or rapid breathing with inappropriately rapid heart rate); *
second wind Second wind is a phenomenon in endurance sports, such as marathons or road running (as well as other sports), whereby an athlete who is out of breath and too tired to continue (known as " hitting the wall"), finds the strength to press on at top p ...
phenomenon (muscle fatigue and heart rate improve for aerobic activity after approximately 6–10 minutes). Heart rate during exercise is a key indicator as, unlike the symptoms of muscle fatigue and cramping, it is a medical sign (meaning that it is observable and measurable by a third party rather than felt subjectively by the patient). In regularly active individuals with McArdle disease, they may not feel the usual symptoms of muscle fatigue and cramping until they increase their speed to very brisk walking, jogging, or cycling; however, they will still show an inappropriately rapid heart rate response to exercise, with a declining heart rate once second wind has been achieved.
"In McArdle's, our heart rate tends to increase in what is called an 'inappropriate' response. That is, after the start of exercise it increases much more quickly than would be expected in someone unaffected by McArdle's."


Other symptoms and comorbidities

Myoglobinuria Myoglobinuria is the presence of myoglobin in the urine, which usually results from rhabdomyolysis or muscle injury. Myoglobin is present in muscle cells as a reserve of oxygen. Signs and symptoms Signs and symptoms of myoglobinuria are usua ...
(reddish-brown urine) may be seen due to the breakdown of
skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
known as
rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...
(a condition in which muscle cells breakdown, sending their contents into the bloodstream). In 2020, the largest study to-date of 269 GSD-V patients, 39.4% reported no previous episodes of myoglobinuria and 6.8% had normal CK (including those with fixed muscle weakness); so an absence of myoglobinuria and normal CK should not rule out the possibility of the disease. Between 33-51.4% develop fixed
muscle weakness Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includ ...
, typically of the trunk and upper body, with the onset of muscle weakness usually occurring later in life (40+ years of age). Younger people may display unusual symptoms, such as difficulty chewing, swallowing, or utilizing normal oral motor functions. Idiopathic leg pains were common in children, usually occurring at night, often presumed to be "growing pains" and not investigated further. Several comorbidities were found in GSD-V individuals at a higher rate than in the general population, including (but not limited to): hypertension (17%), endocrine diseases (15.7%), musculoskeletal/rheumatic disease (12.9%), hyperuricemia/gout (11.6%), gastrointestinal diseases (11.2%), neurological disease (10%), respiratory disease (9.5%), and coronary artery disease (8.3%). They may have a
pseudoathletic appearance Pseudoathletic appearance is a medical sign meaning to have the false appearance of a well-trained athlete due to pathologic causes (disease or injury) instead of true athleticism. It is also referred to as a Herculean or bodybuilder-like ap ...
of muscle hypertrophy (24%), particularly of the legs, and may have lower bone mineral content and density in the legs. Besides exercise-induced premature muscle fatigue, GSD-V individuals may also have comorbidities of mental fatigue, general fatigue, reduced motivation, sleep disturbances, anxiety, and depression. As skeletal muscle relies predominantly on
glycogenolysis Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase. Mechanis ...
for the first few minutes as it transitions from rest to activity, as well as throughout high-intensity aerobic activity and all anaerobic activity, individuals with GSD-V experience during exercise:
sinus tachycardia Sinus tachycardia is a sinus rhythm of the heart, with an increased rate of electrical discharge from the sinoatrial node, resulting in a tachycardia, a heart rate that is higher than the upper limit of normal (90–100 beats per minute for adu ...
,
tachypnea Tachypnea, also spelt tachypnoea, is a respiratory rate greater than normal, resulting in abnormally rapid and shallow breathing. In adult humans at rest, any respiratory rate of 1220 per minute is considered clinically normal, with tachypnea b ...
, muscle fatigue and pain, during the aforementioned activities and time frames. They may exhibit a "second wind" phenomenon, which is characterized by the individual's better tolerance for aerobic exercise such as walking and cycling after approximately 10 minutes. This is attributed to the combination of increased blood flow and the ability of the body to find alternative sources of energy, like fatty acids, proteins, and increased blood glucose uptake. AMP is primarily produced from the myokinase (adenylate kinase) reaction, which runs when the ATP reservoir is low. The myokinase reaction is one of three reactions in the phosphagen system (ATP-PCr), with the myokinase reaction occurring after phosphocreatine (creatine phosphate) has been depleted. In McArdle disease individuals, their muscle cells produce far more AMP than non-affected individuals as the reduced glycolytic flux from impaired glycogenolysis results in a chronically low ATP reservoir during exercise. The muscle cells need ATP (adenosine triphosphate) as it provides energy for
muscle contraction Muscle contraction is the activation of Tension (physics), tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in musc ...
by actively transporting calcium ions into the sarcoplasmic reticulum before muscle contraction, and it is used during muscle contraction for the release of myosin heads in the sliding filament model during the cross-bridge cycle. Along with the myokinase reaction, AMP is also produced by the
purine nucleotide cycle The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP conv ...
, which also runs when the ATP reservoir in muscle cells is low, and is a part of
protein metabolism Protein metabolism denotes the various biochemical processes responsible for the synthesis of proteins and amino acids (anabolism), and the breakdown of proteins by catabolism. The steps of protein synthesis include transcription, translation, an ...
. In the purine nucleotide cycle, three nucleotides:
AMP Amp or AMP may refer to: * Ampere, a unit of electric current, often shortened to amp * Amplifier, a device that increases the amplitude of a signal Arts and entertainment Music * After Midnight Project, Los Angeles alternative rock band * A ...
(adenosine monophosphate),
IMP IMP or imp may refer to: * Imp, a fantasy creature Arts and entertainment Music * IMP (band) a Japanese boy band Fictional characters * Imp (She-Ra), a character in ''She-Ra: Princess of Power'' * Imp a character in '' Artemis Fowl: The L ...
(inosine monophosphate), and S-AMP (adenylosuccinate) are converted in a circular fashion; the byproducts are fumarate (which goes on to produce ATP via oxidative phosphorylation), ammonia (from the conversion of AMP into IMP), and uric acid (from excess AMP). GSD-V patients may experience myogenic
hyperuricemia Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 ...
(exercise-induced accelerated breakdown of purine nucleotides in skeletal muscle). To avoid health complications, GSD-V patients need to get their ATP primarily from free fatty acids (
lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...
) rather than
protein metabolism Protein metabolism denotes the various biochemical processes responsible for the synthesis of proteins and amino acids (anabolism), and the breakdown of proteins by catabolism. The steps of protein synthesis include transcription, translation, an ...
. Over-reliance on protein metabolism can be best avoided by not depleting their ATP reservoir, such as by not pushing through the pain and by not going too fast, or too soon.
"Be wary of pushing on when you feel pain start. This pain is a result of damaging muscles, and repeated damage will cause problems in the long term. But also this is counterproductive–it will stop you from getting into second wind. By pressing on despite the pain, you start your protein metabolism which then effectively blocks your glucose and fat metabolism. If you ever get into this situation, you need to stop completely for 30 minutes or more and then start the whole process again."
Patients may present at emergency rooms with a transient
contracture In pathology, a contracture is a shortening of muscles, tendons, skin, and nearby soft tissues that causes the joints to shorten and become very stiff, preventing normal movement. A contracture is usually permanent, but less commonly can be temp ...
of the muscles and often severe pain (e.g. "clawed hand"). These require urgent assessment for
rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...
as in about 30% of cases this leads to
acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in renal function, kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both. ...
, which left untreated can be life-threatening. In a small number of cases
compartment syndrome Compartment syndrome is a serious medical condition in which increased pressure within a Fascial compartment, body compartment compromises blood flow and tissue function, potentially leading to permanent damage if not promptly treated. There are ...
has developed, requiring prompt surgical referral.


Genetics

McArdle disease (GSD-V) is inherited in an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
manner. If both parents are carriers (not having the disease, but each parent having one copy of the mutated allele), then each child of the couple will have a 25% chance of being affected (having McArdle disease), a 50% chance of being a carrier, and a 25% chance of being unaffected (neither a carrier nor diseased). Two autosomal recessive forms of this disease occur, childhood-onset and adult-onset. The gene for myophosphorylase, ''PYGM'' (the muscle-type of the glycogen phosphorylase gene), is located on chromosome 11q13. According to the most recent publications, 95 different mutations have been reported. The forms of the mutations may vary between ethnic groups. For example, the ''R50X'' (Arg50Stop) mutation (previously referred to as ''R49X'') is most common in North America and Western Europe, and the ''Y84X'' mutation is most common among central Europeans. The exact method of protein disruption has been elucidated in certain mutations. For example, ''R138W'' is known to disrupt to pyridoxal phosphate binding site. In 2006, another mutation (c.13_14delCT) was discovered which may contribute to increased symptoms in addition to the common Arg50Stop mutation.


Myophosphorylase


Structure

The myophosphorylase structure consists of 842 amino acids. The molecular weight of the unprocessed precursor is 97 kDa. The three-dimensional structure has been determined for this protein. The interactions of several amino acids in myophosphorylase's structure are known. Ser-14 is modified by phosphorylase kinase during activation of the enzyme. Lys-680 is involved in binding the pyridoxal phosphate, which is the active form of vitamin B6, a cofactor required by myophosphorylase. By similarity, other sites have been estimated: Tyr-76 binds AMP, Cys-109 and Cys-143 are involved in subunit association, and Tyr-156 may be involved in allosteric control.


Function

Myophosphorylase is the form of the glycogen phosphorylase found in muscle that catalyses the following reaction: ((1→4)-alpha-D-glucosyl) (n) +
phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...
= ((1→4)-alpha-D-glucosyl) (n-1) + alpha-D-glucose 1-phosphate During exercise, a deficiency of this enzyme ultimately leads to rapid depletion of phosphocreatine, a decrease in available ATP, and an exaggerated rise of ADP and AMP. McArdle disease individuals also have increased maximum fat oxidation compared to unaffected individuals. During exercise, in affected individuals, there is no significant rise in lactic acid production compared to resting levels (it may even fall below resting levels), and plasma pH levels rise (become more alkaline) rather than fall (become more acidic).


Pathophysiology

Myophosphorylase is involved in the breakdown of glycogen to glucose-1-phosphate for use in muscle. The enzyme removes 1,4 glycosyl residues from the outer branches of glycogen and adds inorganic phosphate to form
glucose-1-phosphate Glucose 1-phosphate (also called Cori ester) is a glucose molecule with a phosphate group on the 1'-carbon. It can exist in either the α- or β-anomeric form. Reactions of α-glucose 1-phosphate Catabolic In glycogenolysis, it is the direct pro ...
. Ordinarily, the removal of 1,4 glycosyl residues by myophosphorylase leads to the formation of glucose-1-phosphate during glycogen breakdown and the polar, phosphorylated glucose cannot leave the cell membrane and so is marked for intracellular catabolism. In McArdle's disease, deficiency of myophosphorylase leads to the accumulation of intramuscular glycogen and a lack of glucose-1-phosphate for cellular fuel. Myophosphorylase comes in two forms: form 'a' is phosphorylated by
phosphorylase kinase Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformati ...
, form 'b' is not phosphorylated. Form 'a' is de-phosphorylated into form 'b' by the enzyme
phosphoprotein phosphatase A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modifi ...
, which is activated by elevated insulin. Both forms have two conformational states: active (R or relaxed) and inactive (T or tense). When either form 'a' or 'b' is in the active state, then the enzyme converts glycogen into glucose-1-phosphate. Myophosphorylase-b is
allosterically In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...
activated by elevated AMP within the cell, and allosterically inactivated by elevated ATP and/or glucose-6-phosphate. Myophosphorylase-a is active unless allosterically inactivated by elevated glucose within the cell. In this way, myophosphorylase-a is the more active of the two forms as it will continue to convert glycogen into glucose-1-phosphate even with high levels of glycogen-6-phosphate and ATP.


Diagnosis

There are some
laboratory tests A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratories are found in a variety of settings such as schools, u ...
that may aid in the diagnosis of GSD-V. A
muscle biopsy In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. A muscle biopsy can lead to the discovery of problems with the nervous system, connective tissue, vascular s ...
will note the absence of myophosphorylase in muscle fibers. In some cases, abnormal glycogen accumulation stained by
periodic acid-Schiff Periodicity or periodic may refer to: Mathematics * Bott periodicity theorem, addresses Bott periodicity: a modulo-8 recurrence relation in the homotopy groups of classical groups * Periodic function, a function whose output contains values tha ...
can be seen with microscopy. Genetic sequencing of the PYGM gene (which codes for the muscle isoform of
glycogen phosphorylase Glycogen phosphorylase is one of the phosphorylase enzymes (). Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphor ...
) may be done to determine the presence of gene mutations, determining if McArdle's is present. This type of testing is considerably less invasive than a muscle biopsy. The
physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...
can also perform an ischemic forearm exercise test as described below (see ''
History History is the systematic study of the past, focusing primarily on the Human history, human past. As an academic discipline, it analyses and interprets evidence to construct narratives about what happened and explain why it happened. Some t ...
''). Some findings suggest a nonischemic test could be performed with similar results. The nonischemic version of this test would involve not cutting off the blood flow to the exercising arm. Findings consistent with McArdle's disease would include a failure of lactate to rise in
venous blood Venous blood is deoxygenated blood which travels from the peripheral blood vessels, through the venous system into the right atrium of the heart. Deoxygenated blood is then pumped by the right ventricle to the lungs via the pulmonary artery whi ...
and exaggerated
ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...
levels. These findings would indicate a severe muscle glycolytic block. Serum lactate may fail to rise in part because of increased uptake via the monocarboxylate transporter (MCT1), which is upregulated in
skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
in McArdle disease. Lactate may be used as a fuel source once converted to
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic ...
. Ammonia levels may rise given ammonia is a by-product of
AMP deaminase AMP deaminase 1 is an enzyme that in humans is encoded by the ''AMPD1'' gene. Adenosine monophosphate deaminase is an enzyme that converts adenosine monophosphate (AMP) to inosine monophosphate (IMP), freeing an ammonia molecule in the process. ...
which follows after the production of AMP by
adenylate kinase Adenylate kinase ( ECbr>2.7.4.3 (also known as ADK or myokinase) is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates (ATP, ADP, and AMP). By constantly monitoring phosphate nucleotide levels insid ...
, an alternative pathway for ATP production. In this pathway, adenylate kinase combines two ADP molecules to make ATP and AMP; AMP is then deaminated, producing inosine monophosphate (IMP) and ammonia (NH3) as part of
purine nucleotide cycle The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP conv ...
. Physicians may also check resting levels of
creatine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phos ...
, which are moderately increased in 90% of patients. In some, the level is increased by multitudes - a person without GSD-V will have a CK between 60 and 400IU/L, while a person with the syndrome may have a level of 5,000 IU/L at rest, and may increase to 35,000 IU/L or more with muscle exertion. This can help distinguish McArdle's syndrome from
carnitine palmitoyltransferase II deficiency Carnitine palmitoyltransferase II deficiency, sometimes shortened to CPT-II or CPT2, is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported ...
(CPT-II), a lipid-based metabolic disorder that prevents fatty acids from being transported into
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
for use as an energy source. Also, serum electrolytes and endocrine studies (such as thyroid function, parathyroid function, and growth hormone levels) will also be completed. Urine studies are required only if rhabdomyolysis is suspected. Urine volume, urine sediment, and myoglobin levels would be ascertained. If rhabdomyolysis is suspected, serum myoglobin, creatine kinase, lactate dehydrogenase, electrolytes, and renal function will be checked. Physicians may also conduct an
exercise stress test A cardiac stress test is a cardiological examination that evaluates the cardiovascular system's response to external stress within a controlled clinical setting. This stress response can be induced through physical exercise (usually a treadmill) o ...
to test for an inappropriately rapid heart rate (
sinus tachycardia Sinus tachycardia is a sinus rhythm of the heart, with an increased rate of electrical discharge from the sinoatrial node, resulting in a tachycardia, a heart rate that is higher than the upper limit of normal (90–100 beats per minute for adu ...
) in response to exercise. Due to the rare nature of the disease, the inappropriate rapid heart rate in response to exercise may be misdiagnosed as inappropriate sinus tachycardia (which is a
diagnosis of exclusion A diagnosis of exclusion or by exclusion (''per exclusionem'') is a diagnosis of a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from history, examination o ...
). The 12 Minute Walk Test (12MWT) can be used to determine "
second wind Second wind is a phenomenon in endurance sports, such as marathons or road running (as well as other sports), whereby an athlete who is out of breath and too tired to continue (known as " hitting the wall"), finds the strength to press on at top p ...
," which requires a treadmill (no incline), heart rate monitor, stopwatch, pain scale, and that the patient has rested for 30 minutes before the test to ensure that "second wind" has stopped (that is, that increased ATP production primarily from free fatty acids has returned to resting levels).
Electromyography Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyo ...
(EMG) may show normal or myopathic results (short duration, polyphasic, small amplitude MUAPs). Before exercise, a minority of GSD-V patients show myopathic results (5/25 patients); whereas after 5 minutes of high-intensity isometric exercise, the majority showed myopathic results (22/25 patients). The myopathic results were a decrease in CMAP amplitude, which was evident immediately after exercise and, after a plateau phase of a few minutes, reached its maximum after 30 minutes.


Differential diagnosis

Dynamic symptoms of exercise intolerance (e.g. muscle fatigue and cramping) with or without fixed proximal muscle weakness: * Another
glycogen storage disease A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glycolysis, glucose breakdown, typically in m ...
that affects muscle (muscle GSD); *
Metabolic myopathy Metabolic myopathies are myopathies that result from defects in biochemical metabolism that primarily affect muscle. They are generally genetic defects (inborn errors of metabolism) that interfere with the ability to create energy, causing a low A ...
other than glycogen storage disease; * Endocrine myopathy that affects carbohydrate metabolism secondary to the primary disease; * Inadequate blood flow (
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
), particularly of the calves **
Intermittent claudication Intermittent claudication, also known as vascular claudication, is a symptom that describes muscle pain on mild exertion (ache, cramp, numbness or sense of fatigue), classically in the calf muscle, which occurs during exercise, such as walking, ...
; **
Popliteal artery entrapment syndrome The popliteal artery entrapment syndrome (PAES) is an uncommon pathology that occurs when the popliteal artery is compressed by the surrounding popliteal fossa myofascial structures. This results in claudication and chronic leg ischemia. This con ...
; **
Chronic venous insufficiency Chronic venous insufficiency (CVI) is a medical condition characterized by blood pooling in the veins, leading to increased pressure and strain on the vein walls. The most common cause of CVI is superficial venous reflux, which often results in ...
. * Poor diet or
malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a varie ...
disease resulting in malnutrition of micronutrients essential for muscle glycogen metabolism; * Other rare myopathies, such as Brody disease, Rippling muscle disease, Erythrocyte lactate transporter defect, a small number of muscular dystrophies, Tubular aggregate myopathy (TAM), etc. Exercise-induced muscle fatigue without cramping: *
Myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...
; *
Lambert–Eaton myasthenic syndrome Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs. It is also known as myasthenic syndrome, Eaton–Lambert syndrome, and when related to cancer, carcinomatous myopathy. ...
; *
Congenital myasthenic syndrome Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference ...
s. Fixed symptoms of muscle weakness, predominantly of the proximal muscles: * Limb-girdle muscular dystrophy; *
Inflammatory myopathy Inflammatory myopathy, also known as idiopathic inflammatory myopathy (IIM), is disease featuring muscle weakness, inflammation of muscles (myositis), and in some types, muscle pain (myalgia). The cause of much inflammatory myopathy is unknown (i ...
. Allelic to McArdle disease (GSD-V) is a recently discovered disease that has a pathogenic autosomal dominant mutation in exon 16 of the PYGM gene c.1915G>C (p.Asp639His). Discovered in 2020, it affected 13 members of a family over four generations and has yet to be assigned a GSD number. Unlike McArdle disease (GSD-V), this disease does not have an overall deficiency of myophosphorylase, only a deficiency of functioning myophosphorylase-a with plenty of functioning myophosphorylase-b (similar to GSD-IXd). Myophosphorylase-b can be
allosterically In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...
activated to break down glycogen (glycogenolysis) by high levels of AMP, and as the AMP-dependent activity was preserved, the individuals of this family had normal muscle glycogen concentrations as well as lacked exercise intolerance (which are prominent distinguishing features from McArdle disease). The only symptom was adult-onset (40+ years of age) fixed muscle weakness, initially of the proximal muscles of the legs, followed by proximal arms, then distal leg muscles. Muscle biopsy also showed accumulation of the intermediate filament desmin in the myofibres.


Treatment

Supervised exercise programs have been shown in small studies to improve exercise capacity by several measures: lowering heart rate, lowering serum creatine kinase (CK), increasing the exercise intensity threshold before symptoms of muscle fatigue and cramping are experienced, and the skeletal muscles becoming aerobically conditioned. Oral sucrose treatment (for example a sports drink with 75 grams of sucrose in 660 ml.) taken 30 minutes before exercise has been shown to help improve exercise tolerance, including a lower heart rate and lower perceived level of exertion compared with placebo. This is because the ingestion of a high-carbohydrate meal or drink causes transient hyperglycaemia, with the exercising muscle cells utilizing the high glucose in the blood for the glycolytic pathway. However, the ingestion of a high-carbohydrate meal or drink is problematic as a frequent form of treatment since it will increase the release of
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
, which inhibits the release of fatty acids and subsequently will delay the ability to get into
second wind Second wind is a phenomenon in endurance sports, such as marathons or road running (as well as other sports), whereby an athlete who is out of breath and too tired to continue (known as " hitting the wall"), finds the strength to press on at top p ...
. The frequent ingestion of sucrose (e.g. sugary drinks), to avoid premature muscle fatigue and cramping, is also problematic in that it can lead to obesity as insulin will also stimulate triglyceride synthesis (develop body fat), and obesity-related ill health (e.g. type II diabetes and heart disease). A low dosage treatment with
creatine Creatine ( or ) is an organic compound with the nominal formula . It exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). Creatine is found in vertebrates, where it facilitates recycling of ...
showed a significant improvement of muscle problems compared to placebo in a small clinical study, while other studies have shown minimal subjective benefit. High-dosage treatment of creatine has been shown to worsen symptoms of myalgia (muscle pain). A ketogenic diet has demonstrated beneficial for McArdle disease (GSD-V) as ketones readily convert to acetyl CoA for oxidative phosphorylation, whereas free fatty acids take a few minutes to convert into acetyl CoA. Ketones are a part of fat metabolism, the ketones can act as the main fuel before fatty acid catabolism takes over (second wind), during which the ketones would act as a supplementary fuel alongside the fatty acids to produce adenosine triphosphate (ATP) by oxidative phosphorylation.


History

The deficiency was the first
metabolic myopathy Metabolic myopathies are myopathies that result from defects in biochemical metabolism that primarily affect muscle. They are generally genetic defects (inborn errors of metabolism) that interfere with the ability to create energy, causing a low A ...
to be recognized when the physician Brian McArdle described the first case in a 30-year-old man who always experienced pain and weakness after exercise. McArdle noticed this patient's cramps were electrically silent and his venous lactate levels failed to increase upon ischemic exercise. (The ischemic exercise consists of the patient squeezing a hand dynamometer at maximal strength for a specific period, usually a minute, with a blood pressure cuff, which is placed on the upper arm and set at 250 mmHg, blocking blood flow to the exercising arm.) Notably, this is the same phenomenon that occurs when muscle is poisoned in vitro by iodoacetate, which inhibits the breakdown of glycogen into glucose and prevents the formation of lactate; as well as produces an electronically silent muscle contracture. Knowing what occurs to muscle poisoned by iodoacetate, helped McArdle speculate that a glycogenolytic block might be occurring when he first described the disease. McArdle accurately concluded that the patient had a disorder of glycogen breakdown that specifically affected skeletal muscle. The associated enzyme deficiency was discovered in 1959 by W. F. H. M. Mommaerts et al.


In animals

Naturally occurring myophosphorylase deficiency (GSD-V; McArdle disease) has been found in
Charolais cattle The Charolais () or Charolaise () is a French breed of taurine beef cattle. It originates in, and is named for, the Charolais area surrounding Charolles, in the Saône-et-Loire department, in the Bourgogne-Franche-Comté region of eastern Fr ...
and
Merino sheep The Merino is a list of sheep breeds, breed or group of breeds of domestic sheep, characterised by very fine soft wool. It was established in Spain near the end of the Middle Ages, and was for several centuries kept as a strict Spanish monop ...
. The cattle were asymptomatic at rest, but when forced to exercise, would become noticeably fatigued and recumbent (having to lie down) for approximately 10 minutes before being able to resume exercise (the second wind phenomenon). Artificially-induced myophosphorylase deficiency was created in mice, by altering their embryonic DNA, for use in laboratory experiments.


See also

*
Glycogen storage disease A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glycolysis, glucose breakdown, typically in m ...
*
Hitting the wall In endurance sports such as road cycling and long-distance running, hitting the wall or the bonk is a condition of sudden fatigue and loss of energy which is caused by the depletion of glycogen stores in the liver and muscles. Milder instances ...
(muscle fatigue due to glycogen depletion) *
Inborn errors of carbohydrate metabolism Inborn errors of carbohydrate metabolism are inborn errors of metabolism that affect the catabolism and anabolism of carbohydrates. An example is lactose intolerance. Carbohydrates account for a major portion of the human diet. These carbohydr ...
* Purine nucleotide cycle§Glycogenoses (GSDs) *
Second wind Second wind is a phenomenon in endurance sports, such as marathons or road running (as well as other sports), whereby an athlete who is out of breath and too tired to continue (known as " hitting the wall"), finds the strength to press on at top p ...
(increased ATP production primarily by fatty acids after glycogen depletion)


References


External links


Euromac
an EU-funded consortium of medical and research institutes across Europe which is building a patient registry and raising standards of care for people with McArdle Disease.
International Association for Muscle Glycogen Storage Disease (IamGSD).

Walking With McArdle's
- IamGSD videos
EUROMAC Introduction
- Video about McArdle disease and the EUROMAC Registry of McArdle disease and other rare glycogenoses patients {{Inborn errors of carbohydrate metabolism Autosomal recessive disorders Inborn errors of carbohydrate metabolism Muscular disorders