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 glucose breakdown, typically in muscles and/or liver cells.<ref>Template:Cite journal</ref>

GSD has two classes of cause: genetic and environmental. Genetic GSD is caused by any inborn error of carbohydrate metabolism (genetically defective enzymes or transport proteins) involved in these processes. In livestock, environmental GSD is caused by intoxication with the alkaloid castanospermine.<ref name="pmid7604496">Template:Cite journal</ref>

However, not every inborn error of carbohydrate metabolism has been assigned a GSD number, even if it is known to affect the muscles or liver. For example, phosphoglycerate kinase deficiency (gene PGK1) has a myopathic form.

Also, Fanconi-Bickel syndrome (gene SLC2A2) and Danon disease (gene LAMP2) were declassed as GSDs due to being defects of transport proteins rather than enzymes; however, GSD-1 subtypes b, c, and d are due to defects of transport proteins (genes SLC37A4, SLC17A3) yet are still considered GSDs.

Phosphoglucomutase deficiency (gene PGM1) was declassed as a GSD due to it also affecting the formation of N-glycans; however, as it affects both glycogenolysis and glycosylation, it has been suggested that it should re-designated as GSD-XIV.<ref name="nejm.org">Template:Cite journal</ref>

(See inborn errors of carbohydrate metabolism for a full list of inherited diseases that affect glycogen synthesis, glycogen breakdown, or glucose breakdown.)

Types

Type (Eponym)	Enzyme deficiency (Gene<ref name="medbiochem"/>)	Incidence (births)	Hypo- glycemia?	Hepato- megaly?	Hyper- lipidemia?	Muscle symptoms	Development/ prognosis	Other symptoms
GSD 0 (Lewis' disease)<ref>Template:Cite web</ref>	Glycogen synthase (Muscle GYS1 / Liver GYS2)	1 in 20,000–25,000<ref>Template:Cite journal</ref>	Liver 0a: Yes Muscle 0b: No	No	No	(Muscle 0b) Glycogen deficiency in muscle fibres. Type I muscle fibre predominance. Exercise-induced, muscle fatigue, myalgia, fainting.<ref name=":26">Template:Cite web</ref><ref name=":25">Template:Cite web</ref> Occasional muscle cramping Template:Citation needed	(Liver 0a) Growth failure in some cases.<ref name=":27" /> (Muscle 0b) Risk of sudden death in childhood due to cardiac arrest.<ref name=":26" />	(Liver 0a) Epilepsy<ref name=":27">Template:Cite web</ref> (Muscle 0b) Rarely epilepsy, tonic-clonic seizures.<ref name=":26" /> Arrhythmia, long QT syndrome.<ref name=":25" />
GSD I / GSD 1 (von Gierke's disease)	Glucose-6-phosphatase / Glucose-6-phosphate translocase (G6PC / SLC37A4 /SLC17A3)	Template:Ntsh1 in 50,000 – 100,000<ref name=Roth/><ref>Template:Cite web</ref><ref name="Glucose-6-Phosphate dehydrogenase d">Template:Cite journal</ref>	Yes	Yes	Yes	None	Growth failure	Lactic acidosis, hyperuricemia
GSD II / GSD 2 (Pompe disease, formerly GSD-IIa) Danon disease (formerly GSD-IIb)	Acid alpha-glucosidase (GAA) Lysosome-associated membrane protein 2 (LAMP2)	Template:NtshPompe disease is 1 in 13,000.<ref>Template:Cite journal</ref>	No	Yes	No	Muscle weakness, exercise intolerance, abnormal lysosomal glycogen accumulation in muscle biopsy. Late-onset Pompe may have a pseudoathletic appearance of hypertrophic calf muscles.<ref name=":18">Template:Cite journal</ref> The symptoms of both Pompe and Danon diseases are very similar due to a defect in lysosomes. However, in Danon disease, some show abnormal glycogen accumulation, but not all.<ref>Template:Cite web</ref>	Progressive proximal skeletal muscle weakness with varied timeline to threshold of functional limitation (early childhood to adulthood). Approximately 15% of the Pompe population is classified as infantile Pompe which is typically deadly within the first year if untreated.	Heart failure (infantile), respiratory difficulty (due to muscle weakness)
GSD III / GSD 3 (Cori's disease or Forbes' disease)	Glycogen debranching enzyme (AGL Template:Webarchive)	Template:Ntsh1 in 100,000	Yes	Yes	Yes	Myopathy. May have a pseudoathletic appearance of hypertrophic muscles.<ref name=":8" />	Failure to thrive<ref name="Tegay 2022 m937">Template:Cite journal</ref>	myogenic hyperuricemia<ref name=":0">Mineo I, Kono N, Hara N, Shimizu T, Yamada Y, Kawachi M, Kiyokawa H, Wang YL, Tarui S. Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med. 1987 Jul 9;317(2):75-80. doi: 10.1056/NEJM198707093170203. PMID 3473284.</ref>
GSD IV / GSD 4 (Andersen's disease)	Glycogen branching enzyme (GBE1)	Template:Ntsh1 in 500,000<ref name="ceaccp.oxfordjournals.org">Template:Cite journal</ref>	No	Yes, also cirrhosis	No	Myopathy and dilated cardiomyopathy	Failure to thrive, death at age ~5 years
GSD V / GSD 5 (McArdle's disease)	Muscle glycogen phosphorylase (PYGM)	Template:Ntsh1 in 100,000 – 500,000<ref>Template:Cite book</ref><ref name="ceaccp.oxfordjournals.org"/>	No	No	No	Exercise-induced muscle fatigue and cramps. Rhabdomyolysis possible. May have a pseudoathletic appearance of hypertrophic calf muscles.<ref name=":11">Template:Cite journal</ref>		Renal failure by myoglobinuria, second wind phenomenon, inappropriate rapid heart rate (sinus tachycardia) response to exercise, myogenic hyperuricemia<ref name=":0" />
GSD VI / GSD 6 (Hers' disease)	Liver glycogen phosphorylase (PYGL)	Template:Ntsh1 in 65,000 – 85,000<ref name="Ierardi-Curto">Template:Cite news</ref>	Yes	Yes	Yes<ref>Template:Cite book</ref>	None	initially benign, developmental delay follows.
GSD VII / GSD 7 (Tarui's disease)	Muscle phosphofructokinase (PFKM)	Template:Ntsh1 in 1,000,000<ref>Template:Cite web</ref>	No	No	No	Exercise-induced muscle cramps and weakness	developmental delay	In some haemolytic anaemia, myogenic hyperuricemia<ref name=":0" />
GSD IX / GSD 9	Phosphorylase kinase (PHKA2 / PHKB / PHKG2 / PHKA1)	?	Yes	Yes	Yes	IXd Exercise-induced muscle cramps, stiffness, weakness (fatigue), and pain.<ref>Template:Cite web</ref>	Liver type: Delayed motor development, Developmental delay
GSD X / GSD 10	Muscle Phosphoglycerate mutase(PGAM2)	?	?	?	?	Exercise-induced muscle cramps and weakness<ref name=":21" />		Myoglobinuria<ref>Template:Cite web</ref>
GSD XI / GSD 11	Muscle lactate dehydrogenase (LDHA)	?	?	?	?	Exercise-induced muscle cramps, stiffness, pain.<ref>Template:Cite web</ref>
Fanconi-Bickel syndrome formerly GSD XI / GSD 11, no longer considered a GSD	Glucose transporter (GLUT2)	?	Yes	Yes	No	None
GSD XII / GSD 12 Template:Nowrap	Aldolase A (ALDOA)	?	No	In some	No	Exercise intolerance, cramps. In some Rhabdomyolysis.		Hemolytic anemia and other symptoms
GSD XIII / GSD 13	β-enolase (ENO3)	?	No	?	No	Exercise intolerance, cramps	Increasing intensity of myalgias over decades<ref name="Httpneuromuscularwustledumsysglycogenhtmlenolase">Template:Cite web</ref>	Serum CK: Episodic elevations; Reduced with rest<ref name="Httpneuromuscularwustledumsysglycogenhtmlenolase"/>
CDG1T (formally GSD XIV / GSD 14)	Phosphoglucomutase-1(PGM1)	?	Episodic	?	No	Two forms: exclusively myopathic and multi-system (including muscles).<ref name=":9">Template:Cite journal</ref> Myopathy (including exercise-related fatigue, exercise intolerance, muscle weakness). Muscle biopsy shows glycogen accumulation.<ref name=":1">Template:Cite web</ref>	Short stature, some have developmental delay, and rarely delayed puberty.<ref name=":1" />	Highly variable phenotype and severity. Commonly elevated serum CK, abnormal serum transferrin (loss of complete N-glycans), short stature, cleft palate, bifid uvula, and hepatopathy.<ref name=":1" /> Second Wind phenomenon in some<ref name=":10">Template:Cite journal</ref> but not all<ref name="nejm.org"/>
GSD XV / GSD 15	Glycogenin-1 (GYG1)	Rare<ref name="Malfatti2014">Malfatti E, Nilsson J, Hedberg-Oldfors C, Hernandez-Lain A, Michel F, Dominguez-Gonzalez C, Viennet G, Akman HO, Kornblum C, Van den Bergh P, Romero NB, Engel AG, DiMauro S, Oldfors A (2014) A new muscle glycogen storage disease associated with glycogenin-1 deficiency. Ann Neurol 76(6):891-898 </ref>	No	No	No	Muscle atrophy, exercise intolerance, muscle biopsy shows abnormal glycogen depletion and marked proliferation of slow-twitch (type 1/oxidative) muscle fibres and mitochondrial proliferation.	Slowly progressive weakness over decades	Arrhythmia, biopsy of heart showed abnormal glycogen deposits (different from polyglucosan bodies) in cardiomyocytes.<ref>Template:Cite journal</ref>

• Some GSDs have different forms, e.g. infantile, juvenile, adult (late-onset).Template:Cn
• Some GSDs have different subtypes, e.g. GSD1a / GSD1b, GSD9A1 / GSD9A2 / GSD9B / GSD9C / GSD9D.<ref name="medbiochem"/>
• GSD type 0: Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is classified with the GSDs as type 0 because it is another defect of glycogen storage and can cause similar problems.Template:Cn
• GSD type VIII (GSD 8): In the past, liver phosphorylase-b kinase deficiency was considered a distinct condition,<ref name="pmid4508182">Template:Cite journal</ref> however it has been classified with GSD type VI<ref name="Ierardi-Curto"/> and GSD IXa1;<ref>GLYCOGEN STORAGE DISEASE IXa1; GSD9A1 OMIM — Online Mendelian Inheritance in Man</ref> it has been described as X-linked recessive inherited.<ref name="urlDefinition: glycogen storage disease type VIII from Online Medical Dictionary">Template:Cite web</ref> GSD IX has become the dominant classification for this disease, grouped with the other isoenzymes of phosphorylase-b kinase deficiency.<ref>Template:Citation</ref>
• GSD type XI (GSD 11): Fanconi-Bickel syndrome (GLUT2 deficiency), hepatorenal glycogenosis with renal Fanconi syndrome, no longer considered a glycogen storage disease, but a defect of glucose transport.<ref name="medbiochem"/> The designation of GSD type XI (GSD 11) has been repurposed for muscle lactate dehydrogenase deficiency (LDHA).Template:Cn
• GSD type XIV (GSD 14): No longer classed as a GSD, but as a congenital disorder of glycosylation type 1T (CDG1T), affects the phosphoglucomutase enzyme (gene PGM1).<ref name="medbiochem">Template:Cite web</ref> Phosphoglucomutase 1 deficiency is both a glycogenosis and a congenital disorder of glycosylation.<ref name=":2">Template:Cite journal</ref> Individuals with the disease have both a glycolytic block as muscle glycogen cannot be broken down, as well as abnormal serum transferrin (loss of complete N-glycans).<ref name=":2" /> As it affects glycogenolysis, it has been suggested that it should re-designated as GSD-XIV.<ref name="nejm.org" />
• Lafora disease is considered a complex neurodegenerative disease and also a glycogen metabolism disorder.<ref>Template:Cite journal</ref>
• Polyglucosan storage myopathies are associated with defective glycogen metabolism<ref>Template:Cite journal</ref>
• (Not McArdle disease, same gene but different symptoms) Myophosphorylase-a activity impaired: Autosomal dominant mutation on PYGM gene. AMP-independent myophosphorylase activity impaired, whereas the AMP-dependent activity was preserved. No exercise intolerance. Adult-onset muscle weakness. Accumulation of the intermediate filament desmin in the myofibers of the patients.<ref>Echaniz-Laguna A, Lornage X, Laforêt P, Orngreen MC, Edelweiss E, Brochier G, Bui MT, Silva-Rojas R, Birck C, Lannes B, Romero NB, Vissing J, Laporte J, Böhm J. A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation. Ann Neurol. 2020 Aug;88(2):274-282. doi: 10.1002/ana.25771. Epub 2020 Jun 3. PMID 32386344.</ref><ref>Template:Cite journal</ref> Myophosphorylase comes in two forms: form 'a' is phosphorylated by phosphorylase kinase, form 'b' is not phosphorylated. Both forms have two conformational states: active (R or relaxed) and inactive (T or tense). When either form 'a' or 'b' are in the active state, then the enzyme converts glycogen into glucose-1-phosphate. Myophosphorylase-b is allosterically activated by AMP being in larger concentration than ATP and/or glucose-6-phosphate. (See Glycogen phosphorylase§Regulation).
• Unknown glycogenosis related to dystrophy gene deletion: patient has a previously undescribed myopathy associated with both Becker muscular dystrophy and a glycogen storage disorder of unknown aetiology.<ref>Rose MR, Howard RS, Genet SA, McMahon CJ, Whitfield A, Morgan-Hughes JA. A case of myopathy associated with a dystrophin gene deletion and abnormal glycogen storage. Muscle Nerve. 1993 Jan;16(1):57-62. doi: 10.1002/mus.880160110. PMID 8423832.</ref>

Diagnosis

File:Glycogen storage disease in liver - high mag.jpg

Micrograph of glycogen storage disease with histologic features consistent with Cori disease. Liver biopsy. H&E stain.

Methods to diagnose glycogen storage diseases include history and physical examination for associated symptoms, blood tests for associated metabolic disturbances, and genetic testing for suspected mutations.<ref name=":8">Template:Cite journal</ref><ref name=":5" /> It may also include a non-ischemic forearm test, exercise stress test, or 12-minute walk test (12MWT).<ref name=":5">Template:Cite journal</ref> Advancements in genetic testing are slowly diminishing the need for biopsy; however, in the event of a VUS and inconclusive exercise tests, a biopsy would then be necessary to confirm diagnosis.<ref name=":5" />

Differential diagnosis

Muscle

Glycogen storage diseases that involve skeletal muscle typically have exercise-induced (dynamic) symptoms, such as premature muscle fatigue, rather than fixed weakness (static) symptoms.<ref name=":12">Template:Cite journal</ref> Differential diagnoses for glycogen storage diseases that involve fixed muscle weakness, particularly of the proximal muscles, would be an inflammatory myopathy or a limb-girdle muscular dystrophy.<ref name=":12" />

For those with exercise intolerance and/or proximal muscle weakness, the endocrinopathies should be considered.<ref>Template:Citation</ref><ref name=":13">Template:Cite journal</ref><ref name=":14">Template:Cite journal</ref> The timing of the symptoms of exercise intolerance, such as muscle fatigue and cramping, is important in order to help distinguish it from other metabolic myopathies such as fatty acid metabolism disorders.<ref>Template:Cite web</ref>

Problems originating within the circulatory system, rather than the muscle itself, can produce exercise-induced muscle fatigue, pain and cramping that alleviates with rest, resulting from inadequate blood flow (ischemia) to the muscles. Ischemia that often produces symptoms in the leg muscles includes intermittent claudication, popliteal artery entrapment syndrome, and chronic venous insufficiency.

Diseases disrupting the neuromuscular junction can cause abnormal muscle fatigue, such as myasthenia gravis, an autoimmune disease.<ref>Template:Cite journal</ref> Similar, are Lambert–Eaton myasthenic syndrome (autoimmune) and the congenital myasthenic syndromes (genetic).

Diseases can disrupt glycogen metabolism secondary to the primary disease. Abnormal thyroid function—hypo- and hyperthyroidism—can manifest as myopathy with symptoms of exercise-induced muscle fatigue, cramping, muscle pain and may include proximal weakness or muscle hypertrophy (particularly of the calves).<ref>Template:Cite web</ref><ref name=":13" /> Hypothyroidism up-regulates glycogen synthesis and down-regulates glycogenolysis and glycolysis; conversely, hyperthyroidism does the reverse, up-regulating glycogenolysis and glycolysis while down-regulating glycogen synthesis.<ref name=":15">Template:Cite journal</ref><ref name=":16">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=":13" /><ref name=":17">Template:Citation</ref>

Prolonged hypo- and hyperthyroid myopathy leads to atrophy of type II (fast-twitch/glycolytic) muscle fibres, and a predominance of type I (slow-twitch/oxidative) muscle fibres.<ref name=":16" /><ref name=":13" /><ref name=":14" /> Muscle biopsy shows abnormal muscle glycogen: high accumulation in hypothyroidism and low accumulation in hyperthyroidism.<ref name=":17" /><ref name=":15" /><ref name=":16" /> Hypothyroid myopathy includes Kocher-Debre-Semelaigne syndrome (childhood-onset), Hoffman syndrome (adult-onset), myasthenic syndrome, and atrophic form.<ref name=":17" />

In patients with increased growth hormone, muscle biopsy includes, among other features, excess glycogen deposition.<ref>Template:Citation</ref>

EPG5-related Vici syndrome is a multisystem disorder, a congenital disorder of autophagy, with muscle biopsy showing excess glycogen accumulation, among other myopathic features.<ref>Template:Cite journal</ref>

It is interesting to note, in comparison to hypothyroid myopathy, that McArdle disease (GSD-V), which is by far the most commonly diagnosed of the muscle GSDs and therefore the most studied,<ref name=":19" /><ref name=":5" /><ref name=":6" /> has as its second highest comorbidity endocrine disease (chiefly hypothyroidism)<ref>Template:Cite journal</ref><ref name=":5" /> and that some patients with McArdle disease also have hypertrophy of the calf muscles.<ref name=":11" /> Late-onset Pompe disease (GSD-II) also has calf hypertrophy and hypothyroidism as comorbidities.<ref name=":18" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Poor diet and malabsorption diseases (such as celiac disease) may lead to malnutrition of essential vitamins necessary for glycogen metabolism within the muscle cells. Malnutrition typically presents with systemic symptoms, but in rare instances can be limited to myopathy.<ref>Template:Cite journal</ref> Vitamin D deficiency myopathy (also known as osteomalic myopathy due to the interplay between vitamin D and calcium) results in muscle weakness, predominantly of the proximal muscles; with muscle biopsy showing abnormal glycogen accumulation, atrophy of type II (fast-twitch/glycolytic) muscle fibres, and diminished calcium uptake by the sarcoplasmic reticulum (needed for muscle contraction).<ref name=":20">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Although Vitamin D deficiency myopathy typically includes muscle atrophy,<ref name=":20" /> rarely calf muscle hypertrophy has been reported.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Exercise-induced, electrically silent, muscle cramping and stiffness (transient muscle contractures or "pseudomyotonia") are seen not only in GSD types V, VII, IXd, X, XI, XII, and XIII, but also in Brody disease, Rippling muscle disease types 1 and 2, and CAV3-related hyperCKemia (Elevated serum creatine phosphokinase).<ref name=":21">Template:Cite web</ref> Unlike the other myopathies, in Brody disease the muscle cramping is painless.<ref name=":22">Template:Cite web</ref><ref>Template:Cite journal</ref> Like GSD types II, III, and V, a pseudoathletic appearance of muscle hypertrophy is also seen in some with Brody disease and Rippling muscle disease.<ref name=":22" /><ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Erythrocyte lactate transporter defect (formerly Lactate transporter defect, myopathy due to) also includes exercise-induced, electrically silent, painful muscle cramping and transient contractures; as well as exercise-induced muscle fatigue.<ref name=":21" /><ref name=":23">Template:Cite web</ref> EMG and muscle biopsy is normal however, as the defect is not in the muscle but in the red blood cells that should clear lactate buildup from exercising muscles.<ref name=":23" />

Although most muscular dystrophies have fixed muscle weakness rather than exercise-induced muscle fatigue and/or cramping, there are a few exceptions. Limb–girdle muscular dystrophy autosomal recessive 23 (LGMD R23) has calf hypertrophy and exercise-induced cramping.<ref>Template:Cite web</ref> Myofibrillar myopathy 10 (MFM10) has exercise-induced muscle fatigue, cramping and stiffness, with hypertrophic neck and shoulder girdle muscles.<ref>Template:Cite web</ref> LGMD R28 has calf hypertrophy and exercise-induced muscle fatigue and pain.<ref>Template:Cite web</ref> LGMD R8 has calf pseudohypertrophy and exercise-induced weakness (fatigue) and pain.<ref>Template:Cite web</ref> LGMD R15 (a.k.a MDDGC3) has muscle hypertrophy, proximal muscle weakness, and muscle fatigue.<ref>Template:Cite web</ref>

DMD-related myopathies of Duchenne and Becker muscular dystrophy are known for fixed muscle weakness and pseudohypertrophic calf muscles, but they also have secondary muscular mitochondrial impairment causing low ATP production; as well as decreasing type II (fast-twitch/glycolytic) muscle fibres, producing a predominance of type I (slow-twitch/oxidative) muscle fibres.<ref>Template:Cite journal</ref> DMD-related childhood-onset milder phenotypes present with exercise-induced muscle cramping, stiffness, pain, fatigue, and elevated CK.<ref>Template:Cite journal</ref> Becker muscular dystrophy has adult-onset exercise-induced muscle cramping, pain, and elevated CK.<ref>Template:Cite web</ref>

Tubular aggregate myopathy (TAM) types 1 and 2 has exercise-induced muscle pain, fatigue, stiffness, with proximal muscle weakness and calf muscle pseudohypertrophy. TAM1 has cramping at rest, while TAM2 has cramping during exercise.<ref>Template:Cite web</ref><ref name=":24">Template:Cite journal</ref><ref>Template:Cite web</ref><ref>Template:Cite web</ref> Stormorken syndrome includes the symptoms of TAM, but is a more severe presentation including short stature and other abnormalities.<ref name=":24" /> Satoyoshi syndrome has exercise-induced painful muscle cramps, muscle hypertrophy, and short stature.<ref>Template:Cite web</ref> Dimethylglycine dehydrogenase deficiency has muscle fatigue, elevated CK, and fishy body odour.<ref>Template:Cite web</ref> Myopathy with myalgia, increased serum creatine kinase, with or without episodic rhabdomyolysis (MMCKR) has exercise-induced muscle cramps, pain, and fatigue; with some exhibiting proximal muscle weakness.<ref>Template:Cite web</ref>

Liver

(help wikipedia by contributing to this subsection)

Glycogenosis-like phenotype of congenital hyperinsulinism due to HNF4A mutation or MODY1 (maturity-onset diabetes of the young, type 1). This phenotype of MODY1 has macrosomia and infantile-onset hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in liver and erythrocytes, increased liver transaminases, transient hepatomegaly, renal Fanconi syndrome, and later develop liver cirrhosis, decreased succinate-dependent respiration (mitochondrial dysfunction), rickets, nephrocalcinosis, chronic kidney disease, and diabetes.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite web</ref>

Treatment

Treatment is dependent on the type of glycogen storage disease. Von Gierke disease (GSD-I) is typically treated with frequent small meals of carbohydrates and cornstarch, called modified cornstarch therapy, to prevent low blood sugar, while other treatments may include allopurinol and human granulocyte colony stimulating factor.<ref name="Rare2017">Template:Cite web</ref>

Cori/Forbes disease (GSD-III) treatment may use modified cornstarch therapy, a high protein diet with a preference to complex carbohydrates. However, unlike GSD-I, gluconeogenesis is functional, so simple sugars (sucrose, fructose, and lactose) are not prohibited.<ref name=":8" />

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

For phosphoglucomutase deficiency (formerly GSD-XIV), D-galactose supplements and exercise training has shown favourable improvement of signs and symptoms.<ref name=":9" /> In terms of exercise training, some patients with phosphoglucomutase deficiency also experience "second wind."<ref name=":9" /><ref name=":10" />

For McArdle disease (GSD-V), regular aerobic exercise utilizing "second wind" to enable the muscles to become aerobically conditioned, as well as anaerobic exercise (strength training) that follows the activity adaptations so as not to cause muscle injury, helps to improve exercise intolerance symptoms and maintain overall health.<ref name=":5" /><ref name=":6">Template:Cite book</ref><ref name=":3">Template:Cite journal</ref><ref name=":4">Template:Cite journal</ref> Studies have shown that regular low-moderate aerobic exercise increases peak power output, increases peak oxygen uptake (V̇O_2peak), lowers heart rate, and lowers serum CK in individuals with McArdle disease.<ref name=":3" /><ref name=":4" />

Regardless of whether the patient experiences symptoms of muscle pain, muscle fatigue, or cramping, the phenomenon of second wind having been achieved is demonstrable by the sign of an increased heart rate dropping while maintaining the same speed on the treadmill.<ref name=":4" /> Inactive patients experienced second wind, demonstrated through relief of typical symptoms and the sign of an increased heart rate dropping, while performing low-moderate aerobic exercise (walking or brisk walking).<ref name=":4" />

Conversely, patients that were regularly active did not experience the typical symptoms during low-moderate aerobic exercise (walking or brisk walking), but still demonstrated second wind by the sign of an increased heart rate dropping.<ref name=":4" /><ref name=":7">Template:Cite journal</ref> For the regularly active patients, it took more strenuous exercise (very brisk walking/jogging or bicycling) for them to experience both the typical symptoms and relief thereof, along with the sign of an increased heart rate dropping, demonstrating second wind.<ref name=":4" /><ref name=":7" /><ref>Template:Cite book</ref>

In young children (<10 years old) with McArdle disease (GSD-V), it may be more difficult to detect the second wind phenomenon. They may show a normal heart rate, with normal or above normal peak cardio-respiratory capacity (V̇O_2max).<ref name=":5" /><ref>Template:Cite journal</ref> That said, patients with McArdle disease typically experience symptoms of exercise intolerance before the age of 10 years,<ref name=":5" /> with the median symptomatic age of 3 years.<ref name=":19">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Tarui disease (GSD-VII) patients do not experience the "second wind" phenomenon; instead are said to be "out-of-wind."<ref name=":5" /><ref name=":6" /><ref>Template:Citation</ref> However, they can achieve sub-maximal benefit from lipid metabolism of free fatty acids during aerobic activity following a warm-up.<ref name=":5" />

Epidemiology

File:Relative incidences of glycogen storage diseases.png

Relative incidences of the main types of glycogen storage disease

Overall, according to a study in British Columbia, approximately 2.3 children per 100,000 births (1 in 43,000) have some form of glycogen storage disease.<ref name="BC">Template:Cite journal</ref> In the United States, they are estimated to occur in 1 per 20,000–25,000 births.<ref name="Roth">eMedicine Specialties > Glycogen-Storage Disease Type I Author: Karl S Roth. Updated: Aug 31, 2009</ref> Dutch incidence rate is estimated to be 1 per 40,000 births. While a Mexican incidence showed 6.78:1000 male newborns.<ref name="Glucose-6-Phosphate dehydrogenase d" /><ref>Template:Cite journal</ref>

Within the category of muscle glycogenoses (muscle GSDs), McArdle disease (GSD-V) is by far the most commonly diagnosed.<ref name=":19" />

See also

• Metabolic myopathies
• Inborn errors of carbohydrate metabolism

External links

• AGSD. - Association for Glycogen Storage Disease. A US-based non-profit, parent and patient oriented support group dedicated to promoting the best interest of all the different types of glycogen storage disease.
• AGSD-UK - Association for Glycogen Storage Disease (UK). A UK-based charity which helps individuals and families affected by Glycogen Storage Disease by putting people in contact, providing information and support, publishing a magazine and holding conferences, workshops, courses and family events.
• IamGSD - International Association for Muscle Glycogen Storage Disease. A non-profit, patient-led international group encouraging efforts by research and medical professionals, national support groups and individual patients worldwide.
• IPA - International Pompe Association. (Pompe Disease is also known as GSD-II). A non-profit, federation of Pompe disease patient's groups world-wide. It seeks to coordinate activities and share experience and knowledge between different groups.
• EUROMAC - EUROMAC is a European registry of patients affected by McArdle Disease and other rare neuromuscular glycogenoses.
• CoRDS - Coordination of Rare Diseases at Sanford (CoRDS) is a centralized international patient registry for all rare diseases. They work with patient advocacy groups, including IamGSD, individuals and researchers.
• CORD - Canadian Organization for Rare Disorders (CORD) is a Canadian national network for organizations representing all those with rare disorders. CORD provides a strong common voice to advocate for health policy and a healthcare system that works for those with rare disorders.
• NORD - National Organization for Rare Disorders (NORD) is an American national non-profit patient advocacy organization that is dedicated to individuals with rare diseases and the organizations that serve them.
• EURODIS - Rare Diseases Europe (EURODIS) is a unique, non-profit alliance of over 700 rare disease patient organizations across Europe that work together to improve the lives of the 30 million people living with a rare disease in Europe.