Nonlysosomal muscle glycogenoses …

Ezequiel A Piccione MD

Neuromuscular Disorders

Updated 04.05.2024
Released 02.25.2013
Expires For CME 04.05.2027

Nonlysosomal muscle glycogenoses

Author: Ezequiel A Piccione MD

See Contributor Disclosures

Editor: Aravindhan Veerapandiyan MD

Nonlysosomal muscle glycogenoses

In This Article

Quick Link

Introduction

Overview

Glycogen storage disorders or glycogenoses are a heterogenous group of inborn errors affecting carbohydrate metabolism. In this review of the muscle glycogenoses (excepting acid maltase deficiency and Danon disease, the only lysosomal glycogen storage diseases), the authors provide brief descriptions of the still increasing list of specific enzyme defects as well as a more general rational diagnostic framework. As a clinical approach, they divide the glycogenoses into two distinct groups: (1) those that cause exercise intolerance, cramps, and recurrent episodes of muscle breakdown (rhabdomyolysis) with myoglobinuria and (2) those clinically characterized by fixed progressive weakness. Finally, they present symptomatic therapeutic strategies that have been found to be helpful in these conditions.

Key points

	• Disorders of glycogen metabolism can be due to defects in glycogen synthesis or glycogen breakdown.
	• These defects may result in deposits of normal glycogen, abnormal glycogen (phosphorylase-limit-dextrin, PLD), or polyglucosan. They may also result in the absence of glycogen (glycogenoses type 0).
	• The most frequent muscle glycogenoses are McArdle disease (GSDV), Pompe disease (GSDII, not reviewed here), and debranching enzyme deficiency (GSDIII).
	• GSD II, III, IV, and IX are known to be associated with hypertrophic cardiomyopathy.
	• GSD III and GSD IV (branching enzyme deficiency) cause congenital or later-onset weakness, sometimes accompanied by liver disease or cardiomyopathy. A late-onset form of GSD IV causes adult polyglucosan body disease (APBD), a motor neuron disease that can mimic amyotrophic lateral sclerosis. Lafora disease, better known as a progressive myoclonus epilepsy, is also a polyglucosan storage disease.
	• PFK deficiency and McArdle disease can be differentiated by simple laboratory tests, such as increased bilirubin concentration and reticulocyte count without anemia (reflecting compensated hemolytic anemia) in PFK deficiency.
	• The differential diagnosis of glycogenoses with exercise intolerance, cramps, and myoglobinuria includes other metabolic myopathies, especially defects of fatty acid oxidation and defects of the mitochondrial respiratory chain, and, more generally, all genetic causes of recurrent myoglobinuria.
	• The differential diagnosis of glycogenoses with fixed weakness includes the muscular dystrophies, congenital myopathies, and other metabolic myopathies.
	• Depending on the tissue specificity of the isozyme or enzyme subunit involved, glycogenoses can be confined to muscle or involve other tissues, such as erythrocytes, cardiac muscle, or the central nervous system.
	• All muscle glycogenoses are inherited as autosomal recessive traits, excepting two variants of phosphorylase b kinase (PHK) deficiency and phosphoglycerate kinase (PGK) deficiency, which are X-linked disorders.

Historical note and nomenclature

In 1951, Brian McArdle gave a remarkably precise description of the metabolic problem of muscle phosphorylase deficiency (GSD V) on the basis of clinical observations and a few critical laboratory tests in one patient (88). He noted that ischemic exercise resulted in painful cramps of forearm muscles and that no electrical activity was recorded from the shortened muscles, indicating that they were in a state of contracture. He also noted that oxygen consumption and ventilation were normal at rest but increased more than normal with exercise. The astute observation that venous lactate and pyruvate did not increase after exercise led McArdle to conclude that his patient's disorder was "characterized by a gross failure of the breakdown of glycogen to lactic acid." Nor was the specific involvement of muscle lost to McArdle, who noted that epinephrine elicited a normal rise of blood glucose and "shed blood" in vitro accumulated lactate normally, leading him to conclude that "the disorder of carbohydrate metabolism affected chiefly, if not entirely, the skeletal muscles."

In its typical presentation, muscle phosphofructokinase deficiency (GSD VII), first described by Tarui and colleagues in a Japanese family (140) and soon thereafter by Layzer and colleagues in an Ashkenazi Jewish-American patient (73), can closely resemble McArdle disease. Certain clinical and laboratory findings can help separate these conditions.

Several less common glycolytic defects similarly involve symptoms similar to those of McArdle disease and Tarui disease.

Muscle nonlysosomal glycogenoses with fixed weakness have been associated early with debrancher deficiency (GSD III) and brancher deficiency (GSD IV), but new interest has been generated by polyglucosan myopathy in juvenile patients with cardiomyopathy and in late-onset patients without cardiac involvement.

Glycogenoses causing exercise intolerance and myoglobinuria

Phosphorylase kinase (PhK) deficiency (GSD IX). PhK is a key regulatory enzyme in glycogen metabolism because it activates glycogen phosphorylase in response to neuronal or hormonal stimuli. PhK deficiency can cause four distinct clinical presentations, which are distinguished by tissue involvement (liver, muscle, heart, or liver and muscle) and mode of inheritance (autosomal or X-linked). This clinical and genetic heterogeneity is explained by the complexity of the enzyme, a protein composed of four sets of subunits (αβγδ)4. In addition, there are two isoforms for the α subunit (muscle and liver, A1 and A2), both encoded by genes on the X-chromosome, and two isoforms for the γ subunit (muscle and testis, G1; liver, G2). Both G isozymes and the B subunit are encoded by autosomal genes (56).

The cardiac variant demonstrates frequent thickening of myocardium by echocardiography (126). The purely myopathic variant of PhK deficiency (GSDIXd) has an estimated prevalence of 1 in 100,000 (116). It has a variable age of onset and usually manifests as a milder form of myophosphorylase deficiency (GSDV, McArdle disease). Predominant symptoms include exercise intolerance with stiffness, cramps, and occasional myoglobinuria. Cognitive impairment accompanying myopathy and exercise intolerance has also been reported (18). One distinguishing laboratory feature of this condition is the lactate response to the forearm exercise test, which is usually flat in patients with McArdle disease, whereas it is normal or blunted in patients with PhK deficiency. Most cases reported of myopathic PhK deficiency have been men consistent with X-linked inheritance (Xq13.1). In agreement with this concept, all molecular defects identified so far are in PHKA1 (109).

The liver and muscle variant of PhK (GSD IXb) is an autosomal recessive disorder dominated by short stature, hepatomegaly, and fasting hypoglycemia with minimal muscle involvement (weakness and hypotonia): in one female and four male patients, five distinct nonsense mutations were identified in the PHKB gene on chromosome 16q (23). No specific treatment is available, but prevention of hypoglycemia with uncooked starch, high protein, and complex carbohydrate diet has been suggested (116).

Myophosphorylase deficiency (glycogenosis type V, McArdle disease)

Clinical presentation. The clinical picture of McArdle disease is dominated by exercise intolerance manifested by myalgia, premature fatigue, and stiffness or weakness of exercising muscles, which is relieved by rest (79). The type and amount of exercise needed to precipitate these symptoms varies considerably from patient to patient, possibly in relation to training and diet, but two types of exertion are likely to cause problems: brief intense isometric exercise, such as lifting heavy weights, or less intense but sustained dynamic exercise, such as walking uphill. Moderate exercise, such as walking on level ground, is usually well tolerated. On the other hand, strenuous exercise often results in painful cramps and muscle swelling, which can last for hours. Myoglobinuria is seen in about half of the patients. In fact, McArdle disease is the second most common metabolic cause of recurrent myoglobinuria after CPT II deficiency (144). An unusual presentation worth mentioning is recurrent atraumatic acute compartment syndrome (42). An interesting clinical clue, described by patients with McArdle disease and useful for diagnosis (151), is the "second wind" phenomenon: if at the first appearance of exercise-induced myalgia they slow down or rest briefly (5 to 15 minutes), tolerance is improved when resuming activity. This is due to increased blood flow to muscles and metabolic switch to free fatty acids as source of energy.

The severity of symptoms varies markedly in different patients: some have neither cramps nor myoglobinuria, but some degree of exercise intolerance is almost universal. Symptoms start before age 15 years in most cases. About 20% to 47% of patients have progressive weakness, usually starting after age 40 years (111; 63). Severe axial myopathy and prominent proximal and paraspinal muscle involvement have been reported (163; 07; 77). Masticatory weakness is present in 5% of cases (63).

A distinct clinical variant reported in four children is characterized by severe generalized weakness at or soon after birth, respiratory insufficiency, and death in infancy (33; 89).

Etiology and pathogenesis. Myophosphorylase deficiency is an autosomal recessive disease due to mutations of the muscle isoform of glycogen phosphorylase (PYGM) on chromosome 11q (79; 102). Prevalence has been estimated to be 1 in 100,000 to 140,000 patients (121). Family history is positive in approximately a quarter of cases (63). The apparently autosomal dominant transmission in a few families may be explained by at least two mechanisms: (1) the presence in subsequent generations of homozygous and manifesting heterozygous individuals (124; 105; 87); or (2) the presence of one homozygous and one heterozygous parent (148).

The molecular heterogeneity of myophosphorylase deficiency is striking: from the description of the first molecular defects (16; 148), more than 150 different mutations have been reported (79; 150; 134). The most common mutation in North America and Northern Europe (approximately 50% of cases in Caucasian population) appears to be a cytosine-to-thymine substitution in codon 50 of exon 1, converting an arginine to a stop codon (R50X). This has allowed the use of molecular genetic analysis in leukocytes for diagnostic purposes, thus, avoiding the need of a muscle biopsy (40). However, as more and more mutations in the PYGM gene are described and blood DNA is increasingly used for diagnosis (46), it becomes important to establish the relative frequency of the different mutations in ethnic groups (150). For example, the R50X mutation has never been observed in Japan, where the most common mutation appears to be a 3-bp deletion, TTC at codon 708/709 (136).

The genotype/phenotype relationship in McArdle disease remains unclear: the most common genetic defect in typical McArdle patients, R50X, was also found in an infant who had the fatal myopathic variant (148) and in a child who died of sudden infant death syndrome (SIDS) (39). Of course, one cannot exclude that these unusual presentations may be due to additional gene defects.

Phosphorylase activity is virtually absent in muscle biopsies when determined either histochemically or biochemically. Biochemical studies show that the enzyme is lacking in most patients, which is consistent with the most common genetic error, a nonsense mutation (R50X). As a consequence, glycogen of normal structure accumulates in muscle, reaching concentrations two or three times higher than normal. Morphologically, the stored glycogen collects mostly at the periphery of muscle fibers, where it forms subsarcolemmal "blebs." Vacuolar myopathy and increase glycogen by periodic acid Schiff staining are the classic pathological findings.

Phosphorylase catalyzes the first step in glycogenolysis by removing 1,4-glucosyl residues phosphorolytically with liberation of glucose-1-phosphate. Hence, lack of phosphorylase impedes glycolysis, as shown by the flat venous lactate response to the ischemic forearm exercise test. Similarly, 31P-nuclear magnetic resonance spectroscopy shows lack of acidification during aerobic or ischemic exercise and a greater than normal drop of the phosphocreatine/inorganic phosphate ratio (50). In addition to blunting of lactate, there is typically an abnormal increase in ammonia following exercise. This is due to an increased reliance on adenosine monophosphate (AMP)-deaminase pathway as an alternative way to provide the necessary ATP.

The nonischemic forearm exercise test (grip test) has a sensitivity of 100%: a normal lactate/ammonia response after proper exercise eliminates the possibility of McArdle disease (59). A provocative test (long exercise test) can be used as a complement in the neurophysiological evaluation. A postexercise decrease in compound muscle action potential was present in 23 of 25 patients with McArdle disease (125).

Three main pathophysiological mechanisms underlie the exercise intolerance of myophosphorylase deficiency and, in fact, of all glycogenoses with exertional premature fatigue (152): (1) decreased or absent muscle acidosis, which, by decreasing chloride permeability, maintains membrane excitability; (2) loss of the osmotic effect of lactate accumulation, leading to increased extracellular potassium concentration; and (3) excessive accumulation of ADP, likely leading to inhibition of Na+/K+ and Ca++ ATPases. In agreement with the concept that oxidative phosphorylation is curtailed by decreased substrate availability, oxygen extraction and maximal oxygen uptake are decreased in myophosphorylase deficiency but may be at least partially restored by intravenous glucose infusion (53). The pathogenesis of contracture and myoglobinuria remains unknown: depletion of high-energy phosphate compounds, especially ATP, has long been postulated to occur, but experimental evidence is lacking.

Resting serum creatine kinase (CK) is consistently elevated (5- to 13-fold) in patients with McArdle disease (63), indicating that individual fiber necrosis probably occurs even with daily activities, a concept supported by morphological observations. The cumulative effect of this focal muscle damage along the years may explain the appearance of fixed weakness in older individuals. Muscle imaging with whole body MRI shows fatty replacement of paravertebral and proximal muscles in middle-aged patients (07; 77).

Treatment and management. Many patients adapt their lifestyles to their limited exercise tolerance and, within these limitations, can lead nearly normal lives. Late in the course of the disease, fixed weakness, although usually moderate, may become a problem.

Acute renal insufficiency occurs in about 50% of patients with myoglobinuria. In these cases, abundant fluid intake to induce diuresis may suffice, but renal dialysis is often necessary. Uncomplicated episodes of myoglobinuria are followed by complete functional recovery.

There is no specific therapy for McArdle disease. Naturally, patients should be warned about the risks of strenuous exercise and advised to seek medical attention at the first appearance of pigmenturia, especially if accompanied by oliguria.

Oral sucrose loading 30 to 40 minutes prior to exercise helps with initial lack of glucose release from deficient glycogenolysis (153) and can improve exercise capacity in a dose-dependent manner (149). However, carbohydrates must be used sparingly to avoid weight gain (08). Regular moderate aerobic training (resulting in a heart rate of no more than 60% to 70% of maximal) to develop mitochondrial oxidation is recommended (49). Vitamin B6 bounds to phosphorylase enzyme and, therefore, was a promising agent in cases with residual phosphorylase activity (107; 61; 122). A metanalysis found no difference of B6 compared to placebo (112). Low-dose creatine has been shown to enhance power output (159).

Ketone bodies constitute an alternative energy source that is independent of glycogenolysis. However, a placebo-controlled study failed to demonstrate improved exercise capacity when patients with McArdle disease were administered exogenous ketone bodies (78). The ketogenic diet improved exercise tolerance in an anecdotal report and in one open-label study (24; 76). A complex carbohydrate-rich diet resulted in better exercise performance compared to a protein-rich diet (112). Animal models have demonstrated that sodium valproate can increase muscle expression of brain glycogen phosphorylase isoenzyme. However, an open-label study of 16 patients failed to show improvement in any of the biochemical or functional outcomes at 6 months (123).

Phosphofructokinase (PFK) deficiency (glycogenosis type VII, Tarui disease)

Clinical presentation. Typically, there is intolerance to intense exercise, often accompanied by cramps of exercising muscles, which is relieved by rest (35). The onset of disease is typically between 3 and 25 years of age (97). Symptoms are more likely to occur with isometric exercise (such as pushing a stalled car) or intense dynamic exercise (such as walking uphill). The exercise intolerance appears to worsen with high carbohydrate intake (52). In contrast to patients with McArdle disease, patients with PFK deficiency do not experience a "second wind" (54).

A few patients may be jaundiced as a consequence of the hemolytic trait that accompanies PFK-M deficiency, and a few may suffer from gouty arthritis due to hyperuricemia. Increased bilirubin without anemia is reflective of compensated hemolytic anemia.

Fixed weakness of late onset has been described in a few patients who suffered from exercise intolerance earlier in life (127; 55; 29; 14; 84; 157).

A strikingly different clinical presentation consists of severe myopathy in infancy or early childhood, with respiratory failure and death before 2 years of age. This variant has been reported in several children (35).

Studies of 31P-nuclear MRS show the accumulation, even with mild exercise, of glycolytic intermediates in the form of phosphorylated monoesters, which occurs also in other defects of glycolysis, but not in myophosphorylase deficiency (13).

Etiology and pathogenesis. PFK is a tetrameric enzyme under the control of three autosomal loci: a locus on chromosome 1 encodes the muscle (M) subunit; a locus on chromosome 21 encodes the liver (L) subunit, and a locus on chromosome 10 encodes the platelet (P) subunit (35). The three subunits are variably expressed in different tissues. Mature human muscle expresses only the M subunit and contains only the homotetramer M4, whereas erythrocytes express both the M and L subunits and contain five isozymes: the two homotetramers, M4 and L4, and three hybrid isoforms. In patients with typical PFK deficiency, genetic defects of the M subunit cause total lack of activity in muscle, but only partial PFK deficiency in red blood cells, where the residual activity (approximately 50% of normal) is accounted for by the L4 isozyme.

This disease is inherited as an autosomal recessive trait. The first molecular defect in PFK deficiency (a splice junction mutation resulting in a large deletion) was identified in the Japanese family originally described by Tarui and coworkers (99). Soon thereafter, Raben and coworkers described two mutations, a splicing defect and a nucleotide deletion, which are common among Ashkenazi Jewish patients (115; 128). About 20 distinct mutations have been identified in patients of different ethnic origins (97), although in the United States, the disease predominantly affects individuals of Ashkenazi Jewish origin.

Genetic defects of PFK-M cause virtual absence of PFK in muscle biopsies when the activity is determined either histochemically (20) or biochemically. Tissues such as liver and platelets express predominantly or exclusively in the non-M PFK subunits and are not affected. The lack of frequent involvement of the heart is puzzling because the PFK-M is abundantly represented in cardiac tissue (38).

As a consequence of PFK deficiency, glycogen accumulates in muscle, reaching concentrations two to three times greater than normal. Morphologically, the stored glycogen is mostly seen at the periphery of the fibers, where it is revealed by the periodic acid-Schiff (PAS) histochemical reaction and is normally digested by preincubation with diastase. However, a peculiarity of PFK deficiency is the additional finding of an abnormal polysaccharide, which stains intensely with PAS, but is not digested by diastase (polyglucosan). Ultrastructurally, polyglucosan affects about 10% of type 1 fibers (55) and is composed of finely granular and filamentous material, similar to the amylopectin-like polysaccharide that accumulates in branching enzyme deficiency. The presence of this material is likely due to the accumulation in muscle of glucose-6-phosphate, an activator of the enzyme glycogen synthetase, which alters the delicate ratio between the two main glycogenosynthetic enzymes, synthetase and branching enzyme (01; 114).

PFK is the rate-limiting enzyme of glycolysis, and PFK deficiency blocks glycolysis, thus, explaining the flat venous lactate response to forearm ischemic exercise. The accumulation in muscle of phosphorylated monoesters, observed by 31P-nuclear MRS in PFK but not in myophosphorylase deficiency, is explained by the sites of the two metabolic blocks: midway in the glycolytic pathway for PFK deficiency and upstream of glycolysis for myophosphorylase deficiency.

Glycogen and glucose metabolism associated enzyme deficiencies

Roman numbers indicate nomenclature for muscle glycogenoses: numerals in color orange for glycogenoses causing rhabdomyolysis, in green color for those causing fixed weakness. Glycogenoses types: 0, glycogen synthase; II, acid mal...

As in myophosphorylase deficiency, PFK deficiency also impairs both anaerobic and aerobic glycogen metabolism and blocks the fall in muscle pH that normally accompanies heavy exercise. It also results in high levels of adenosine diphosphate (ADP) and increased adenine nucleotide degradation with exaggerated production of ammonia and myogenic hyperuricemia during exercise (91). It causes substrate-limited oxidative metabolism with fluctuations in exercise and oxidative capacity related to the availability of blood-borne fuels (52). Finally, PFK deficiency causes exaggerated sympathetic neural responses to exercise associated with enhanced mobilization of extramuscular fuels (156) and exaggerated heart rate, cardiac output, and blood flow relative to the muscle capacity to use oxygen (75).

The negative effect of high-carbohydrate meals on exercise tolerance is attributed to the fact that glucose lowers the blood concentration of free fatty acids and ketones, which are alternative fuels in PFK-deficient patients. Thus, not only is glucose ineffective in alleviating exercise intolerance (in contrast to myophosphorylase deficiency), but it is actually harmful, a situation dubbed "out-of-wind" phenomenon (52).

Evaluation and diagnosis. This entity should be differentiated from myophosphorylase deficiency. The latter is the prototype of glycogenolytic disorder and Tarui disease, a typical glycolytic disorder.

Table 1. Clinical Differences Between McArdle Disease (GSD V) and Tarui Disease (GSD VII)

Clinical feature	GSD V	GSD VII
2^nd wind phenomenon	Yes	No
Simple carbs prior to exercise	Beneficial	Detrimental
Hemolytic anemia	No	yes (reticulocytosis, high bilirubin, uric acid)
Rhabdomyolysis	Frequent	Rare
Forearm exercise test	Abnormal: No lactate increase, high ammonia	Abnormal: mild lactate increase, high ammonia
Muscle biopsy	Glycogen	Glycogen+polyglucosan

Clinical differences include lack of a typical "second wind" phenomenon, more common nausea and vomiting accompanying exercise-induced myalgia, detrimental effect of glucose administration, and lower frequency of myoglobinuria attacks in Tarui disease. More useful in distinguishing PFK deficiency from McArdle disease are a few simple laboratory tests, such as increased uric acid, bilirubin concentration, and reticulocyte count in the former.

Needle electromyography may be normal or show "myopathic" abnormalities (small and short-duration motor unit action potentials with early recruitment). Furthermore, no electrical activity is recorded from maximally shortened muscles during contractures induced by ischemic exercise.

The forearm exercise test is a valuable, but not specific, diagnostic test. In patients with an abnormal forearm exercise test, laboratory evidence of hemolytic anemia suggests PFK deficiency. Of note, an increase in lactate to two to three times the basal level but still lower than control can be seen in Tarui disease (108). CK is typically elevated greater than 1000 U/L (97). Until recently, definitive diagnosis required biochemical documentation of the enzyme defect in muscle (keeping in mind that PFK is notoriously labile and PFK deficiency is often a spurious finding if muscle is not flash-frozen at the time of biopsy). Present knowledge of multiple molecular defects in the PFK-M gene allows identification of many suspected patients using genomic DNA isolated from white blood cells.

Treatment and management. Most patients adapt their lifestyles to their limited exercise tolerance and may lead nearly normal lives. In the fifth or sixth decade, some patients develop proximal limb weakness, which can limit their functional independence, but is rarely disabling.

Although myoglobinuria is rare in this condition, acute renal insufficiency may occur in patients with myoglobinuria, requiring forced diuresis or renal dialysis. Uncomplicated episodes of myoglobinuria are followed by complete functional recovery.

There is no specific therapy. Glucose administration prior to exercise is detrimental (52). Supplementation with aneplerotic substrate (triheptanoin) did not improve exercise performance in a placebo-controlled study (113).

A 2-year-old boy with the infantile form of PFK deficiency benefited remarkably – as had a patient with McArdle disease (24) – from a ketogenic diet, which was instituted to provide muscle and brain with ketone bodies as alternative fuels (138). Improvement of exercise performance and ammonia peak reduction was seen in an adult treated long-term with a ketogenic diet (129). Overall, ketogenic diet should be tried in infants or children with severe deficiency and could be considered in the milder form.

Aldolase (ALD) deficiency (glycogenosis type XII)

Two children with muscle and erythrocyte aldolase deficiency have been reported (71; 164). Both had transfusion-requiring nonspherocytic hemolytic anemia, muscle weakness, exercise-induced myalgia, and increased serum CK, especially during febrile illnesses (2620 U/L in one patient and 13,800 U/L in the other). One patient was alive at 4.5 years (71); the other died at 4 years during an episode of myoglobinuria and hyperkalemia (164). Both children were compound heterozygous for mutations in ALDOA, the gene that encodes aldolase A, the only aldolase isozyme present in muscle and erythrocytes. The increased thermolability of the mutant enzyme probably explains the vulnerability of patients to febrile illnesses (86).

Phosphoglycerate kinase (PGK) deficiency

Primary myopathy is not a common presentation of PGK deficiency, an X-linked recessive disorder most commonly presenting as nonspherocytic hemolytic anemia and central nervous system (CNS) dysfunction. However, purely myopathic presentation is the second most frequent presentation, whereas isolated hemolytic anemia was reported in six patients and the association of myopathy and CNS dysfunction in four patients (132). All myopathic patients complained of exercise intolerance, with cramps and myoglobinuria. Molecular defects have been documented in several patients and one, T378P (PGK Afula), caused the peculiar association of myopathy and severe juvenile parkinsonism (130; 37).

The wide spectrum of clinical phenotypes in PGK deficiency is difficult to explain because PGK is a monomeric enzyme encoded by a single gene on Xq13 and expressed in all tissues except the testis (a testicular isozyme, PGK2, is encoded by a gene on chromosome 19). Different amounts of residual activities in different tissues do not explain the clinical heterogeneity (132). Although lack of myoglobinuria in patients with severe hemolytic anemia and brain dysfunction may be attributed to their inability to exercise, it is more difficult to explain the converse situation, lack of blood or brain involvement, in patients with myopathy. The highly perturbed catalytic properties of a mutation (I371K) may account for the PGK deficiency found in an Italian patient with hemolytic anemia, intellectual disability, and severe myopathy (44). A further unusual clinical manifestation of PGK deficiency is retinal dystrophy in a 6-year-old boy with deteriorated vision, but no hemolytic anemia associated with a known mutation (D164V) (94).

Phosphoglycerate mutase (PGAM) deficiency (glycogenosis type X)

In contrast to PGK deficiency, PGAM deficiency affects only muscle, causing exercise intolerance, cramps, and recurrent myoglobinuria with onset on childhood or adolescence (36). This is because PGAM is a dimeric enzyme composed of a muscle-specific (M) and a brain-specific (B) subunit, and normal muscle contains predominantly the MM homodimer, which accounts for 95% of the total activity. Most cases have been reported in the United States (98). All patients in the U.S. have been black, and they harbor one common mutation (W78X) in the PGAM-M gene (encoded by a gene on chromosome 7), suggesting a founder effect (98). Different mutations were found in two Italian families (145; 143), in a Japanese family (47), and in a Pakistani patient (155; 98).

Despite the abundance of PGAM in muscle, exercise intolerance often occurs in heterozygous PGAM-deficient patients (47; 98; 120). A second unusual feature of PGAM deficiency is the frequent occurrence of tubular aggregates in muscle pathology (33% of patients), which has never been associated with other, more common glycogen storage diseases.

Cycle exercise responses in two patients were markedly different from those of patients with clinically similar McArdle disease: the PGAM-deficient patients had virtually normal cycle exercise and oxidative capacity, no second wind, and no improvement of their exercise capacity with lipid or lactate supplements (154).

Beta-enolase deficiency (glycogenosis type XIII)

Beta-enolase deficiency presents with adult-onset myalgias post-exertion, mildly elevated CK levels to recurrent rhabdomyolysis (96). The first case reported was a compound heterozygous with flat lactate response to forearm ischemic exercise (27). Muscle ultrastructure showed subsarcolemmal accumulations of glycogen, and muscle biochemistry revealed an isolated severe deficiency of enolase activity (5% of the normal mean). Over 90% of this muscle enzyme in the distal glycolytic pathway is accounted for by the beta-enolase form, which is encoded by the ENO3 gene on chromosome 17.

Phosphoglucomutase-1 deficiency (glycogenosis type XIV)

This enzyme is involved in glycogen metabolism and in protein glycosylation. There are two main phenotypes: one with predominant muscle involvement and one with multisystem disease. The first pathogenic mutation reported was present in a patient with episodes of exercise-induced rhabdomyolysis (135). Interestingly, this patient had a normal lactate response to forearm exercise but with increased ammonia levels. Muscle biopsy did not reveal vacuoles or increased glycogen content. Treatment with oral D-galactose should be considered in this disease (158).

Lactate dehydrogenase (LDH) deficiency (glycogenosis type XI)

The discovery of this glycogenosis was due to the astute observation that a patient with myoglobinuria had predictably sky-high values of serum CK, but extremely low values of LDH (65). This enzyme converts pyruvate to lactate in skeletal muscle and is composed of a muscle-specific subunit (LDH-A) and a cardiac subunit (LDH-B). LDH-A is encoded by a gene on chromosome 11, and three different mutations have been identified in Japanese patients (81; 83; 82), whereas the only two described white patients had two distinct mutations (146). In addition to muscle symptoms, three affected Japanese women suffered from dystocia necessitating cesarian sections, and a few patients had dermatologic problems (64). Generalized pustular psoriasis is attributed to abnormal activity of LDH (60).

Muscle glycogen synthetase (GS) deficiency (glycogenosis type 0)

Although glycogen synthetase (GS) deficiency of the liver was described several years ago and dubbed glycogenosis type 0 (104; 162), the first cases of muscle glycogenosis type 0 were reported in 2007 in a Swedish family (69). Of three siblings, a boy died of sudden cardiac arrest at 10 years of age, his brother suffered from exercise intolerance and hypertrophic cardiomyopathy, and his sister was asymptomatic. Muscle biopsies from the younger siblings showed conspicuous lack of glycogen by periodic acid Schiff (PAS) histochemistry and by electron microscopy, as well as increased numbers of mitochondria. All three children harbored a homozygous nonsense mutation in the gene (GYS1) encoding the muscle and heart isoform of the glycogen synthetase.

Two other reported of sudden cardiac death had preceding history of exertional syncope (25; 137). The diagnosis of glycogenosis type 0 is complicated by the mild muscle symptoms (exercise intolerance), the scarce attention paid by morphologists to lack of glycogen (as opposed to glycogen storage), and the misleading clue of the reactive mitochondrial proliferation.

Differential diagnosis

Exercise intolerance and recurrent rhabdomyolysis can be caused by other metabolic myopathies, especially disorders of lipid metabolism.

On purely clinical grounds, myophosphorylase deficiency is difficult to differentiate from other defects of glycolytic enzymes described above. Laboratory data may offer useful clues. Patients with PFK deficiency have a compensated hemolytic trait, with hyperuricemia, hyperbilirubinemia, and increased reticulocyte count, whereas patients with PGK deficiency often have overt nonspherocytic hemolytic anemia.

The forearm exercise test (grip test) is a common investigation performed in the workup of patients presenting with exercise intolerance and rhabdomyolysis. It consists of the measurement of lactate and ammonia from the antecubital vein before and after exercise. The exercise test with nonischemic conditions (grip with 70% of maximal contraction for 30 seconds) has been shown to be as useful as the ischemic one (with inflated blood pressure cuff) and avoids the risk of pain, compartment syndrome, or rhabdomyolysis (58). Normally, a nearly 4-fold increase in lactate and 2- to 3-fold increase in ammonia is present after exercise. Patients with McArdle disease typically demonstrate a null lactate response (less than 2-fold) with excessive Ammonia peak (more than 3-fold). In Tarui disease a low lactate response with increased ammonia is present (see Table 1). Patients with defects of terminal glycolysis (PGK, PGAM, and LDH deficiencies) have a blunted, but not absent, venous lactate response, and patients with LDH deficiency show low lactate, but excessive pyruvate, response.

The most common metabolic cause of recurrent myoglobinuria in adults is CPT II deficiency. In patients with myophosphorylase deficiency, myoglobinuria is invariably triggered by exercise, usually of high intensity. Patients with CPT II deficiency, however, have episodes of myoglobinuria not only after exercise (which can be of moderate intensity, but is usually prolonged), but also after prolonged fasting without exertion, or after the combination of exercise and fasting. The forearm exercise test is normal in patients with CPT II deficiency. CK level is typically normal between attacks in CPTII deficiency, unlike McArdle disease. The other two disorders of lipid metabolism that mimic CPT II deficiency and ought to be considered in the differential diagnosis of recurrent myoglobinuria are very long-chain acyl-CoA dehydrogenase (VLCAD) and trifunctional protein (TFP) deficiencies. Blood acylcarnitine profile can be helpful in distinguishing these disorders (low free carnitine with increased intermediates) specially if drawn at the time of rhabdomyolysis.

Exercise intolerance is one of the most common signs of mitochondrial encephalomyopathies and especially of mitochondrial myopathies (32). In these cases, there are no cramps, but rather shortness of breath and premature fatigue even with moderate exertion and, sometimes, recurrent myoglobinuria related to fasting or prolonged exercise. Recognition of the underlying mitochondrial etiology, especially in cases harboring mtDNA mutations, is obscured by the lack of the typical stigmata of mtDNA-related diseases: (i) most cases are sporadic without evidence of maternal inheritance; (ii) instead of being multisystemic disorders, these are isolated myopathies. Between episodes of myoglobinuria, serum CK is normal, but lactate is usually elevated (with high lactate/pyruvate ratio) and provides a good clue to the correct diagnosis. Plasma and urinary organic acids may also show abnormalities. Growth differentiating factor 15 (GDF-15) has been found to be elevated in mitochondrial disorders of respiratory chain (165), but several conditions that cause chronic ischemia (cancer, diabetes, cardiovascular disease) may give false positives.

Most cases of mitochondrial myopathies with recurrent myoglobinuria have been attributed to mutations in genes encoding subunits of complex I (12) and complex IV (66), but especially cytochrome b (MTCYB) of complex III (10; 09; 11).

Muscle biopsies show a mosaic pattern of succinate dehydrogenase (SDH)-hyperintense (“ragged blue”), Gomori trichrome (“ragged red”), and COX-positive fibers (except, of course, if the mutation affects a complex IV subunit, in which case the ragged-blue fibers are COX-negative). Electron-microscopic analysis often shows increased number of mitochondria that may contain paracrystalline inclusions. Genetic analysis for definitive diagnosis of mitochondrial myopathies is best done on muscle-derived material as mtDNA deletions are not commonly seen in white blood cell derived DNA.

The reason these disorders escape the rules of mitochondrial genetics is that they are due to de novo mutations that arise in myoblasts or myoblast precursors after germ-layer differentiation. One notable nucleus-related mitochondrial myopathy characterized by exercise-induced myoglobinuria was described in Swedish individuals and was associated with muscle deficiency of SDH and aconitase (51; 48). The peculiar pattern of biochemical abnormalities suggested a defect of non-heme iron-sulfur (FeS) clusters in the respiratory chain. This was confirmed by the documentation of homozygous mutations in the gene encoding the FeS scaffold protein, ISCU (92).

Exercise-related myoglobinuria may occur in some muscular dystrophies and in malignant hyperthermia. In patients with dystrophinopathies, serum CK levels between attacks are usually much higher than in patients with myophosphorylase deficiency, and transmission is X-linked recessive. Dysferlinopathy can also cause rhabdomyolysis; its baseline CK is high (more than 10-fold), and inheritance is autosomal recessive. In patients with malignant hyperthermia, there is usually a family history of characteristic attacks related to the administration of volatile anesthetics, and inheritance is autosomal dominant (RYR1 gene).

Intolerance to exercise without myoglobinuria rarely can be due to adenylate deaminase deficiency. In patients with adenylate deaminase deficiency, the ischemic forearm exercise test causes a normal rise of venous lactate, in contrast with a lack in the rise of ammonia. Because of the high frequency of the adenylate deaminase deficiency trait, an association with myophosphorylase deficiency (147; 117) or phosphofructokinase deficiency (21) may occur, and this "double trouble" may aggravate the clinical phenotype.

Exercise intolerance without myoglobinuria is a common complaint of malingering and functional disorders and is the cardinal symptom of "chronic fatigue syndrome."

Muscle phosphorylase and PFK deficiencies should be included in the differential diagnosis of late-onset proximal limb weakness. These patients usually have a history of lifelong exercise intolerance and cramps. Laboratory signs of a hemolytic trait, an abnormal forearm exercise test, and abundant polyglucosan in the muscle biopsy are clues to the diagnosis of PFK deficiency.

Glycogenoses causing fixed weakness

Debrancher deficiency (glycogenosis type III, Cori or Forbes disease). This is usually a benign disease of childhood characterized by hepatomegaly, growth retardation, and fasting hypoglycemia, which tend to resolve around puberty (68). Thickened myocardium, a risk factor for cardiomyopathy, has been observed (126). A few patients develop a myopathy later in life (third or fourth decade), which is often more distal, but a proximal predominant phenotype has also been reported (118). Weakness and hepatomegaly are the most common and bothersome manifestations in adults as reported on a large patient survey (41). Wasting of leg muscles and intrinsic hand muscles often suggests the diagnosis of motor neuron disease or peripheral neuropathy. This clinical picture, the "mixed" myopathic and neurogenic EMG pattern, and the slowed nerve conduction velocity reinforce the impression that the weakness in these patients may have a neurogenic component (34; 161). A subacute presentation of respiratory weakness in a 47-year-old woman was reported (67). This patient had undergone strict fasting prior to the onset of weakness and weaning-off respirator was only possible after high-protein diet. The latter may be beneficial as gluconeogenesis is intact in this condition.

It is surprising that an enzyme that acts "hand-in-hand" with muscle phosphorylase in the degradation of glycogen should not cause exercise intolerance and myoglobinuria, at least in those patients that are not severely weak. This conundrum has been partially resolved by the demonstration that patients without overt weakness gave results similar to those obtained in McArdle disease: decreased skeletal muscle carbohydrate oxidation, increased fatty acid oxidation, and exercise intolerance improved by fructose administration (110).

The debranching enzyme is a single protein that catalyzes two enzymatic reactions, an oligo-1,4-1,4-glucantransferase and an amylo-1,6-glucosidase, and is encoded by a gene on chromosome 1p21. There are three biochemical variants: a rare deficiency of the transferase activity alone (type IIId), a common deficiency of both enzyme activities in both muscle and liver (type IIIa), and a less frequent deficiency of both enzyme activities in liver but not in muscle (type IIIb) (35). In the myopathic form, pathology reveals extensive nonrimmed glycogen vacuoles of subsarcolemmal location (118).

Glycogen branching enzyme (GBE) deficiency (glycogenosis IV, Andersen disease). This glycogenosis has a wide spectrum of clinical phenotypes, considering that GBE is a single polypeptide (encoded by a gene on chromosome 3). The enzyme defect can be silent, or predominantly affect the liver, the heart, skeletal muscle, or the brain (35). GBE deficiency results in the deposition of an amylopectin-like polysaccharide that has fewer branching points and longer outer chains than normal glycogen and is known as polyglucosan. Polyglucosan is PAS-positive and only partially digested by diastase, which makes it easily recognizable in various tissues and offers an important clue to the correct diagnosis.

The presentation described in most textbooks as "typical" is in infancy with hepatosplenomegaly, progressive cirrhosis, and chronic hepatic failure.

As recognized in a seminal paper (22), there are two main infantile presentations. The first is a perinatal disorder called “fetal akinesia-deformation sequence” (FADS), characterized by multiple congenital contractures (arthrogryposis multiplex congenita), hydrops fetalis, pulmonary hypoplasia, craniofacial abnormalities, intrauterine growth retardation, abnormal amniotic fluid volume, and perinatal death. The second form, labeled “congenital” should probably be called “fatal infantile” because it presents at or soon after birth with hypotonia, muscle wasting, neuronal involvement, inconsistent cardiomyopathy, and early death.

It is becoming increasingly clear that patients with congenital GBE deficiency present a clinical continuum from FADS to a rapidly fatal congenital multisystem disorder dominated by profound hypotonia, respiratory failure, and inconsistent cardiomyopathy (06; 22; 62; 141; 04; 70; 15; 139). Detailed neuropathology in a few infants showed polyglucosan inclusions in neurons of the basal ganglia and thalamus, oculomotor and pontine nuclei, and periaqueductal neurons (139). In the medulla, polyglucosan deposits were found in the hypoglossal nucleus, the dorsal motor nucleus of the vagus, and the nucleus ambiguous (141; 70). The motor neurons of the spinal cord are also severely affected (57), thus, explaining how one of the patients we studied was initially diagnosed as spinal muscular atrophy type I until mutations in the SMN1 gene were ruled out (141).

Brain involvement also dominates the clinical picture in a characteristic late-onset form of GBE deficiency known as "adult polyglucosan body disease" (APBD) manifesting as a leukoencephalopathy with a clinical triad of spastic paraparesis, neurogenic bladder, and peripheral neuropathy. Median age of onset in a large registry was 51 years, and around one third reported positive family history (131). There is also frequent cognitive involvement, which is characterized by frontal executive impairment and disinhibition (31). The polyglucosan bodies accumulate in the axons of brain neurons and of peripheral nerves, thus, impairing axonal flow. Presentation with asymmetric motor syndrome can mimic amyotrophic lateral sclerosis (160) or spinal stenosis (131). Differential diagnosis also includes CMT neuropathy, but sural nerve or muscle biopsy can point toward the diagnosis (polyglucosan bodies). Although adult polyglucosan body disease is seen in various ethnic groups, it predominates among Ashkenazi Jews, in whom one common mutation (Y329S) probably reflects a founder effect (93). An interesting conundrum was that several patients with adult polyglucosan body disease carried a single Y329S mutation: these “manifesting heterozygotes” were found to harbor a second deep intronic GBE1 mutation (03).

An “intermediate” variant of adult polyglucosan body disease has been recognized in patients who have earlier adult onset and a subacute relapsing-remitting clinical course, often simulating multiple sclerosis. They are not Ashkenazi Jews, and harbor GBE1 mutations that are different from the Y329S that is the signature of typical adult polyglucosan body disease (17; 106; 119).

Measurement of leucocyte GBE activity can be helpful for diagnostic purposes, especially when a variant of unknown significance is found on genetic testing (31). There is no specific therapy for GBE deficiency, but the creation of transgenic mice models that faithfully recapitulate both the fatal infantile form (05) and the late-onset adult polyglucosan body disease (Orhan 03) will facilitate the development of therapeutic modalities.

Lafora disease. Lafora disease is an autosomal recessive progressive myoclonus epilepsy (PME) with onset in adolescence and severe course, characterized by myoclonic, absence, and generalized tonic-clonic seizures, followed by difficulties with speech and gait, and dementia. Death, often in status epilepticus, occurs about 10 years after the first appearance of symptoms (72; 90).

Lafora bodies, the hallmark of the disease, are polyglucosan bodies structurally identical to those found in the APBD variant of branching enzyme deficiency. They are seen in many tissues, including skeletal muscle, heart, liver, and brain. In brain neurons, Lafora bodies, at difference from APBDs (that are in axons), are localized in dendrites and in close proximity of synaptic vesicles. Skin biopsy can be used for diagnostic purposes by demonstration of Lafora bodies in apocrine sweat glands.

Two genes can be mutated in Lafora disease, EPM2A, encoding laforin, or NHLRC1, encoding malin. The precise pathogenic roles of mutated laforin and malin in causing polyglucosan accumulation are not known. In the absence of laforin, glycogen is hyperphosphorylated and becomes polyglucosan (28). The role of malin, a ubiquitin ligase, may be that of removing laforin: in its absence, laforin remains abnormally attached to glycogen and also leads to polyglucosan formation (142). Clearly, Lafora disease is both a neurodegenerative disease and a glycogen storage disease (30).

Differential diagnosis

As mentioned above, debrancher deficiency should be considered in the differential diagnosis of distal atrophies, including amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease, which may be complicated by the mixed myopathic and neurogenic pattern of the EMG. Clues to the diagnosis of debrancher deficiency are a history of transient hepatomegaly in infancy or childhood, markedly increased serum CK levels, and abnormal electrocardiography even in the absence of overt cardiopathy. The muscle biopsy showing pools of extralysosomal glycogen bolsters the diagnosis, which has to be confirmed by biochemical and molecular analyses. However, debrancher deficiency should be considered more often as a benign form of myophosphorylase deficiency (ie, McArdle disease light), as described by Preisler and colleagues (110).

Branching enzyme deficiency should be considered in all infants with arthrogryposis multiplex congenita, congenital myopathy with or without cardiomyopathy, or spinal muscular atrophy without mutations in the SMN1 gene. Muscle biopsy showing storage of PAS-positive but amylase-resistant polysaccharide (polyglucosan) establishes the diagnosis, which will have to be confirmed by biochemical analysis (in white blood cells if muscle is not available) and by sequencing of the GBE1 gene. The APBD variant of branching enzyme deficiency should be part of the differential diagnosis in older patients with motor neuron disease, especially when they complain of urinary incontinence (it is often said that these patients see a urologist before seeing a neurologist), have cognitive problems, and are mostly (but not exclusively) of Ashkenazi Jewish origin. Lafora disease does not pose a differential diagnostic problem because of its characteristic clinical presentation, adolescent onset, and rapid downhill course with intractable epilepsy and dementia.

Polyglucosan myopathy and cardiomyopathy due to mutations in RBCK1 encoding a ubiquitin ligase. Ten patients from eight families had juvenile-onset myopathy, accompanied in eight patients by rapidly progressive cardiomyopathy, which required cardiac transplantation in four of them (100). There was extensive accumulation of polyglucosan in skeletal and cardiac muscle in patients with cardiomyopathy (now classified as Polyglucosan body myopathy type 1). All patients were homozygous or compound heterozygous for missense or truncating mutations in the gene RBCK1, which encodes a ubiquitin ligase (note that malin is also a ubiquitin ligase). Cognitive impairment with mild subcortical white matter disease accompanying hip girdle predominant muscle weakness has been reported in a teenager (26). Some patients with mutations in the same gene have a different phenotype characterized by failure to thrive, chronic autoinflammation, and recurrent episodes of sepsis. They also accumulate polyglucosan in muscle, heart, and liver (19). Careful genotype-phenotype correlation analysis will be needed to clarify the different tissue involvement in these allelic disorders. Prognosis of this relatively new disorder is poor.

Glycogenin deficiency (glycogenosis type XV). The primer of glycogen synthesis is a glycosyl-transferase that uses uridine diphosphate glucose (UDPG) as a substrate in an autoglycosylation reaction to generate a short (about 10 glucosyl units) glucose polymer, the kernel of the new glycogen molecule. There are two isoforms of glycogenin, the muscle isozyme glycogenin-1 and the liver isozyme glycogenin-2, which is also partially expressed in the heart.

The first pathogenic mutation in the gene encoding glycogenin-1 (GYG1) was described in 2010 in a young man who was slower than his peers as a child, suffered from exertional dyspnea, and, at 27 years of age, had a life-threatening episode of ventricular fibrillation and was equipped with a permanent defibrillator (95). Skeletal muscle was devoid of glycogen, whereas the heart showed large accumulation of a poorly structured PAS-positive material, presumably a novel form of abnormal polysaccharide due to the presence of some glycogenin in the heart.

More interestingly, seven patients with mutations in GYG1 (chromosome 3q) resulting in residual glycogenin-1, had no lack of glycogen in muscle but presence of abundant polyglucosan (30% to 40% of fibers) and no cardiomyopathy or respiratory involvement. Polyglucosan body myopathy type 2 has late-onset weakness affecting predominantly limb girdle muscles (43; 80; 02). The decreased amount of glycogenin-1 or its impaired interaction with glycogen synthase may explain the accumulation of polyglucosan (85). Proximal involvement can mimic limb-girdle muscular dystrophy (74), but muscle biopsy aids in the differential diagnosis. Polyglucosan bodies are round or oval subsarcolemmal or cytoplasmatic inclusions that appear pinkish matt.

There is no specific treatment for this disorder. Improved exercise tolerance with glucose infusion was seen in four patients (133), but the practical implications of this finding are not clear.

References

01: Agamanolis DP, Askari AD, Di Mauro S, et al. Muscle phosphofructokinase deficiency: two cases with unusual polysaccharide accumulation and immunologically active enzyme protein. Muscle Nerve 1980;3(6):456-67. PMID 6450324
02: Akman HO, Aykit Y, Amuk OC, et al. Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1. Neuromusc Disord 2016;26(1):16-20. PMID 26652229
03: Akman HO, Kakhlon O, Coku Y, et al. Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease. JAMA Neurol 2015;72(4):441-5. PMID 25665141
04: Akman HO, Karadimas CL, Gyftodimou Y, et al. Prenatal diagnosis of glycogen storage disease type IV. Prenatal Diagnosis 2006;26(10):951-5. PMID 16874838
05: Akman HO, Sheiko T, Tay SK, Finegold MJ, DiMauro S, Craigen WJ. Generation of a novel mouse model that recapitulates early and adult onset glycogenosis type IV. Hum Mol Genet 2011;20(22):4430-9. PMID 21856731
06: Alegria A, Martins E, Dias M, Cunha A, Cardoso ML, Maire I. Glycogen storage disease type IV presenting as hydrops fetalis. J Inherit Metab Dis 1999;22(3):330-2. PMID 10384399
07: Alvarez-Velasco R, Nuñez-Peralta CA, Alonso-Pérez J, et al. High prevalence of paraspinal muscle involvement in adults with McArdle disease. Muscle Nerve 2022;65(5):568-73. PMID 35174518
08: Andersen ST, Haller RG, Vissing J. Effect of oral sucrose shortly before exercise on work capacity in McArdle disease. Arch Neurol 2008;65(6):786-9. PMID 18541798
09: Andreu AL, Bruno C, Dunne TC, et al. A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria. Ann Neurol 1999a;45(1):127-30. PMID 9894887
10: Andreu AL, Bruno C, Shanske S, et al. Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy. Neurology 1998;51(5):1444-7. PMID 9818877
11: Andreu AL, Hanna MG, Reichmann H, et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. New Engl J Med 1999b;341(14):1037-44. PMID 10502593
12: Andreu AL, Tanji K, Bruno C, et al. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 1999c;45(6):820-3. PMID 10360780
13: Argov Z, Bank WJ. Phosphorus magnetic resonance spectroscopy (31P MRS) in neuromuscular disorders. Ann Neurol 1991;30(1):90-7. PMID 1834009
14: Argov Z, Barash V, Soffer D, Sherman J, Raben N. Late-onset muscular weakness in phosphofructokinase deficiency due to exon5/intron5 junction point mutation: a unique disorder or the natural course of this glycolytic disorder. Neurology 1994;44(6):1097-100. PMID 8208408
15: Assereto S, van Diggelen OP, Diogo L, et al. Null mutations and lethal congenital form of glycogen storage disease type IV. Biochem Biophys Res Comm 2007;361(2):445-50. PMID 17662246
16: Bartram C, Edwards RH, Clague J, Beynon RJ. McArdle's disease: a nonsense mutation in exon 1 of the muscle glycogen phosphorylase gene explains some but not all cases. Hum Mol Genet 1993;2(8):1291-3. PMID 8401511
17: Billot S, Herve D, Akman HO, et al. Acute but transient neurological deterioration revealing adult polyglucosan body disease. J Neurol Sci 2013;324(1-2):179-82. PMID 23146612
18: Bisciglia M, Froissart R, Bedat-Millet AL, et al. A novel PHKA1 mutation associating myopathy and cognitive impairment: expanding the spectrum of phosphorylase kinase b (PhK) deficiency. J Neurol Sci 2021;424:117391. PMID 33799212
19: Boisson B, Laplantine E, Prando C, et al. Immunodeficiency, autoinflammation, and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 2012;13:1178-86. PMID 23104095
20: Bonilla E, Schotland DL. Histochemical diagnosis of muscle phosphofructokinase deficiency. Arch Neurol 1970;22(1):8-12. PMID 4243256
21: Bruno C, Minetti C, Shanske S, et al. Combined defects of muscle phosphofructokinase and AMP deaminase in a child with myoglobinuria. Neurology 1998;50(1):296-8. PMID 9443500
22: Bruno C, van Diggelen OP, Cassandrini D, et al. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 2004;63(6):1053-8. PMID 15452297
23: Burwinkel B, Maichele AJ, Aagenaes O, et al. Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB). Hum Mol Genet 1997;6(7):1109-15. PMID 9215682
24: Busch V, Gempel K, Hack A, et al. Treatment of glycogenosis type V with ketogenic diet. Ann Neurol 2005;58(2):341. PMID 16049943
25: Cameron JM, Levandovskiy V, MacKay N, et al. Identification of a novel mutation in GSY1 (muscle-specific glycogen synthase) resulting in sudden cardiac death, that is diagnosable from skin fibroblasts. Mol Genet Metab 2009;98(4):378-82. PMID 19699667
26: Chen L, Wang N, Hu W, et al. Polyglucosan body myopathy 1 may cause cognitive impairment: a case report from China. BMC Musculoskelet Disord 2021;22(1):35. PMID 33413275
27: Comi GP, Fortunato F, Lucchiari S, et al. B-enolase deficiency, a new metabolic myopathy of distal glycolysis. Ann Neurol 2001;50(2):202-7. PMID 11506403
28: Contreras CJ, Segvich DM, Mahalingan K, et al. Incorporation of phosphate into glycogen by glycogen synthase. Arch Biochem Biophys 2016;597:21-20. PMID 27036853
29: Danon MJ, Servidei S, DiMauro S, Vora S. Late-onset muscle phosphofructokinase deficiency. Neurology 1988;38(6):956-60. PMID 2966901
30: Delgado-Escueta AV. Lafora progressive myoclonus epilepsy. Glycogen storage disease vs neurodegenerative disease. Neurology 2012;79(1):21-2. PMID 22622859
31: De Winter J, Cypers G, Jacobs E, et al. Distinct features in adult polyglucosan body disease: a case series. Neuromuscul Disord 2023;33(2):148-52. PMID 36628840
32: DiMauro S, Nishino I, Hirano M. Mitochondrial myopathies. In: Katjiri B, Kamisnski HJ, Ruff RL, editors. Neuromuscular disorders in clinical practice, 2nd edition. New York: Springer, 2014:1335-53.
33: DiMauro S, Hartlage P. Fatal infantile form of muscle phosphorylase deficiency. Neurology 1978;28(11):1124-9. PMID 101896
34: DiMauro S, Hartwig GB, Hays A, et al. Debrancher deficiency: neuromuscular disorder in 5 adults. Ann Neurol 1979;5(5):422-36. PMID 288318
35: DiMauro S, Hays AP, Tsujino S. Nonlysosomal glycogenoses. In: Engel AG, Franzini-Armstrong C, editors. Myology. Vol II. New York: McGraw-Hill, 2004:1535-58.
36: DiMauro S, Miranda AF, Khan S, Gitlin K, Friedman R. Human muscle phosphoglycerate mutase deficiency: newly discovered metabolic myopathy. Science 1981;212(4500):1277-9. PMID 6262916
37: DiMauro S, Spiegel R. Progress and problems in muscle glycogenoses. Acta Myol 2011;30(2):96-102. PMID 22106711
38: Dunaway GA, Kasten TP, Sebo T, Trapp R. Analysis of the phosphofructokinase subunits and isoenzymes in human tissues. Biochem J 1988;251(3):677-83. PMID 2970843
39: El-Schahawi M, Bruno C, Tsujino S, et al. Sudden infant death syndrome (SIDS) in a family with myophosphorylase deficiency. Neuromusc Disord 1997;7(2):81-3. PMID 9131647
40: El-Schahawi M, Tsujino S, Shanske S, DiMauro S. Diagnosis of McArdle's disease by molecular genetic analysis of blood. Neurology 1996;47(2):579-80. PMID 8757044
41: Evins A, Mayhew J, Cimms T, et al. Glycogen storage disease type III: a mixed-methods study to assess the burden of disease. Ther Adv Endocrinol Metab 2024;15:20420188231224233. PMID 38196773
42: Famili DT, Fernandez-Garcia MA, Vanegas M, et al. Recurrent atraumatic compartment syndrome as a manifestation of genetic neuromuscular disease. Neuromuscul Disord 2023;33(11):866-72. PMID 37919205
43: Fanin M, Torella A, Savarese M, Nigro V, Angelini C. GYG1 gene mutation in a family with polyglucosan body myopathy. Neurol Genet 2015;1(3):e21. PMID 27066558
44: Fermo E, Bianchi P, Chiarelli LR, et al. A new variant of phosphoglycerate kinase deficiency (p.I371K) with multiple tissue involvement: molecular and functional characterization. Mol Genet Metab 2012;106(4):455-61. PMID 22705348
45: Ganesh S, Delgado-Escueta AV, Sakamoto T, et al. Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet 2002;11(11):1251-62. PMID 12019206
46: Garcia-Consuegra I, Blazquez A, Rubio JC, et al. Taking advantage of an old concept, “illegitimate transcription”, for a proposed novel method of genetic diagnosis of McArdle disease. Genet Med 2016;18(11):1128-35. PMID 26913921
47: Hadjigeorgiou GM, Kawashima N, Bruno C, et al. Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene. Neuromusc Disord 1999;9(6-7):399-402. PMID 10545043
48: Hall RE, Henriksson KG, Lewis SF, Haller RG, Kennaway NG. Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins. J Clin Invest 1993;92(6):2660-6. PMID 8254022
49: Haller RG. Treatment of McArdle disease. Arch Neurol 2000;57(7):923-24. PMID 10891971
50: Haller RG, Bertocci LA. Exercise evaluation of metabolic myopathies. In: Engel AG, Franzini-Armstrong C, editors. Myology. Vol 1. New York, NY: McGraw-Hill, 1994:807-21.
51: Haller RG, Henriksson KG, Jorfeldt L, et al. Deficiency of skeletal muscle succinate dehydrogenase and aconitase. J Clin Invest 1991;88(4):1197-206. PMID 1918374
52: Haller RG, Lewis SF. Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency. New Engl J Med 1991;324(6):364-9. PMID 1824792
53: Haller RG, Lewis SF, Cook JD, Blomqvist CG. Myophosphorylase deficiency impairs muscle oxidative metabolism. Ann Neurol 1985;17(2):196-19. PMID 3856415
54: Haller RG, Vissing J. No spontaneous second wind in muscle phosphofructokinase deficiency. Neurology 2004;62(1):82-6. PMID 14718702
55: Hays AP, Hallett M, Delfs J, et al. Muscle phosphofructokinase deficiency: abnormal polysaccharide in a case of late-onset myopathy. Neurology 1981;31(9):1077-86. PMID 6943439
56: Hendrickx J, Lee P, Keating JP, et al. Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II. Am J Hum Genet 1999;64(6):1541-9. PMID 10330341
57: Herrick MK, Twiss JL, Vladutiu GD, Glasscock GF, Horoupian DS. Concomitant branching enzyme and phosphorylase deficiencies. An unusual glycogenosis with extensive neuronal polyglucosan storage. J. Neuropath Exp Neurol 1994;53(3):239-46. PMID 8176407
58: Hogrel JY, Laforêt P, Ben Yaou R, Chevrot M, Eymard B, Lombès A. A non-ischemic forearm exercise test for the screening of patients with exercise intolerance. Neurology 2001;56(12):1733-8. PMID 11425942
59: Hogrel JY, van den Bogaart F, Ledoux I, et al. Diagnostic power of the non-ischaemic forearm exercise test in detecting glycogenosis type V. Eur J Neurol 2015;22(6):933-40. PMID 25740218
60: Ito T, Aoshima M, Sugiura K, et al. Pustular psoriasis-like lesions associated with lactate dehydrogenase M subunit deficiency without interleukin-36 receptor antagonist mutation: long-term follow-up of two cases. Brit J Dermatol 2015;172(6):1674-6. PMID 25640002
61: Izumi R, Suzuki N, Kato K, et al. A case of McArdle disease: efficacy of vitamin B6 on fatigability and impaired glycogenolysis. Inter Med 2010;49(15):1623-5. PMID 20686302
62: Janecke AR, Dertinger S, Ketelsen UP, et al. Neonatal type IV glycogen storage disease associated with "null" mutations in glycogen branching enzyme 1. J Pediatr 2004;145(5):705-9. PMID 15520786
63: Joshi PR, Deschauer M, Zierz S. McArdle disease: clinical, biochemical, histological and molecular genetic analysis of 60 patients. Biomedicines 2020;8(2):33. PMID 32075227
64: Kanno T, Maekawa M. Lactate dehydrogenase M-subunit deficiencies: clinical features, metabolic background, and genetic heterogeneities. Muscle Nerve 1995;3:S54-60. PMID 7603529
65: Kanno T, Sudo K, Takeuchi I, et al. Hereditary deficiency of lactate dehydrogenase M-subunit. Clin Chim Acta 1980;108(2):267-76. PMID 7449146
66: Karadimas CL, Greenstein P, Sue CM, et al. Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA. Neurology 2000;55(5):644-9. PMID 10980727
67: Kiechl S, Willeit J, Vogel W, Kohlendorfer U, Poewe W. Reversible severe myopathy of respiratory muscles due to adult-onset type III glycogenosis. Neuromuscul Disord 1999;9(6-7):408-10. PMID 10545045
68: Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010;12(7):446-63. PMID 20631546
69: Kollberg G, Tulinius M, Gilljam T, et al. Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0. New Engl J Med 2007;357(15):1507-14. PMID 17928598
70: Konstantinidou AE, Anninos H, Gyftodimou Y, et al. Neonatal neuromuscular variant of glycogen storage disease type IV: histopathological findings leading to the diagnosis. Histopathology 2006;48(7):878-80. PMID 16722943
71: Kreuder J, Borkhardt A, Repp R, et al. Brief report: Inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. New Engl J Med 1996;334(17):1100-4. PMID 8598869
72: Lafora GR. Uber das Vorkommen amyloider Korperchen in Innern der Ganglienzellen. Virchows Arch Pathol Anat 1911;205:295-303.
73: Layzer RB, Rowland LP, Ranney HM. Muscle phosphofructokinase deficiency. Arch Neurol 1967;17(5):512-23. PMID 4228297
74: Lefeuvre C, Schaeffer S, Carlier RY, et al. Glycogenin-1 deficiency mimicking limb-girdle muscular dystrophy. Mol Genet Metab Rep 2020;24:100597. PMID 32477874
75: Lewis SF, Vora S, Haller RG. Abnormal oxidative metabolism and O2 transport in muscle phosphofructokinase deficiency. J Appl Physiol 1991;70(1):391-8. PMID 1826293
76: Lokken N, Hansen KK, Storgaard JH, Ørngreen MC, Quinlivan R, Vissing J. Titrating a modified ketogenic diet for patients with McArdle disease: a pilot study. J Inherit Metab Dis 2020;43(4):778-86. PMID 32060930
77: Lokken N, Revsbech KL, Jacobsen LN, et al. Muscle MRI in McArdle disease: a European multicenter observational study. Neurology 2022a;99(15):e1664-75. PMID 35853747
78: Lokken N, Storgaard JH, Revsbech KL, et al. No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease and healthy controls: a randomized placebo-controlled cross-over study. J Inherit Metab Dis 2022b;45(3):502-16. PMID 35150142
79: Lucia A, Nogales-Gadea G, Perez M, Martin MA, Andreu AL, Arenas J. McArdle disease: what do neurologists need to know. Nature Clin Pract Neurol 2008;4(10):568-77. PMID 18833216
80: Luo S, Zhu W, Yue D, et al. Muscle pathology and whole-body MRI in a polyglucosan myopathy associated with a novel glycogenin-1 mutation. Neuromusc Disord 2015;25(10):780-5. PMID 26255073
81: Maekawa M, Sudo K, Kanno T, Li SS. Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency. Biochem Biophys Res Comm 1990;168(2):677-82. PMID 2334430
82: Maekawa M, Sudo K, Kanno T, et al. A novel mutation of lactate dehydrogenase A (M) gene in the fifth family with the enzyme deficiency. Hum Mol Genet 1994;3(5):825-6. PMID 8081370
83: Maekawa M, Sudo K, Li S, Kanno T. Analysis of genetic mutations in human lactate dehydrogenase-A(M) deficiency using DNA conformation polymorphism in combination with polyacrilamide gradient gel and silver staining. Biochem Biophys Res Comm 1991;180(2):1083-90. PMID 1953713
84: Malfatti E, Birouk N, Romero NB, et al. Juvenile-onset permanent weakness in muscle phosphofructokinase deficiency. J Neurol Sci 2012;316(1-2):173-7. PMID 22364848
85: Malfatti E, Nilsson J, Hedberg-Oldfors C, et al. A new muscle glycogen storage disease associated with glycogenin-1 deficiency. Ann Neurol 2014;76:891-8. PMID 25272951
86: Mamoune A. Bahau M, Hamel Y, et al. A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia. PLoS Genet 2014;10(11):e1004711. PMID 25392908
87: Manfredi G, Silvestri G, Servidei S, et al. Manifesting heterozygotes in McArdle's disease: clinical, morphological, and biochemical studies in a family. J Neurol Sci 1993;115(1):91-4. PMID 8468596
88: McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 1951;10:13-33. PMID 24540673
89: Milstein JM, Herron TM, Haas JE. Fatal infantile muscle phosphorylase deficiency. J Child Neurol 1989;4(3):186-8. PMID 2768781
90: Minassian BA. Progressive myoclonus epilepsy with polyglucosan bodies: Lafora disease. In: Fahn S, Frucht SJ, Hallett M, Truong DD, editors. Myoclonus and Paroxysmal Dyskinesias. Philadelphia: Lippincott Williams & Wilkins, 2002:199-210.
91: Mineo I, Kono N, Hara N, et al. Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med 1987;317(2):75-80. PMID 3473284
92: Mochel F, Knight MA, Tong WH, et al. Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am J Hum Genet 2008;82(3):652-60. PMID 18304497
93: Mochel F, Schiffmann R, Steenweg M, et al. Adult polyglucosan body disease: Natural history and key magnetic resonance imaging findings. Ann Neurol 2012;72(3):433-41. PMID 23034915
94: Mohd Khialdin S, Grigg J, Rowe N, Crofts S, Wilson M, Troedson C. A negative waveform in the scotopic response in a patient with phosphoglycerate kinase deficiency: a visual electrophysiology report. Doc Ophthalmol 2015;131(3):215-20. PMID 26396085
95: Moslemi AR, Lindberg C, Nilsson J, Tajsharghi H, Andersson B, Oldfors A. Glycogenin-1 deficiency and inactivated priming of glycogen synthesis. New Engl J Med 2010;362(13):1203-10. PMID 20357282
96: Musumeci O, Brady S, Rodolico C, et al. Recurrent rhabdomyolysis due to muscle β-enolase deficiency: very rare or underestimated? J Neurol 2014;261(12):2424-8. PMID 25267339
97: Musumeci O, Bruno C, Mongini T, et al. Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII). Neuromusc Dis 2012;22:325-30. PMID 22133655
98: Naini A, Toscano A, Musumeci O, Vissing J, Akman HO, DiMauro S. Muscle phosphoglycerate mutase deficiency revisited. Arch Neurol 2009;66(3):394-8. PMID 19273759
99: Nakajima H, Kono N, Yamasaki T, et al. Genetic defect in muscle phosphofructokinase deficiency. Abnormal splicing of the muscle phosphofructokinase gene due to a point mutation at the 5'-splice site. J Biol Chem 1990;265(16):9392-5. PMID 2140573
100: Nilsson J, Schoser B Laforet P, et al. Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Ann Neurol 2013;74:914-9. PMID 23798481
101: Nogales-Gadea G, Pinos T, Lucia A, et al. Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. Brain 2012;135(Pt 7):2048-57. PMID 22730558
102: Nogales-Gadea G, Santalla A, Brull A, de Luna N, Lucia A, Pinos T. The pathogenomics of McArdle disease – genes, enzymes, models, and therapeutics implications. J Inherit Metab Dis 2015;38(2):221-30. PMID 25053163
103: Orhan Akman H, Emmanuele V, Gulkan Kurt Y, et al. A novel mouse model that recapitulates adult-onset glycogenosis type IV. Hum Mol Genet 2015;24(23):6801-10. PMID 26385640
104: Orho M, Bosshard NU, Buist NR, et al. Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. J Clin Invest 1998;102(3):507-15. PMID 9691087
105: Papadimitriou A, Manta P, Divari R, Karabetsos A, Papadimitriou E, Bresolin N. McArdle's disease: two clinical expressions in the same pedigree. J Neurol 1990;237(4):267-70. PMID 2391551
106: Paradas C, Akman HO, Ionete C, et al. Branching enzyme deficiency: expanding the clinical spectrum. JAMA Neurol 2014;71(1):41-7. PMID 24248152
107: Phoenix J, Hopkins P, Bartram C, Beynon RJ, Quinlivan RC, Edwards RH. Effect of vitamin B6 supplementation in McArdle's disease: a strategic case study. Neuromusc Disord 1998;8(3-4):210-2. PMID 9631404
108: Piirila P, Simila ME, Palmio J, et al. Unique exercise lactate profile in muscle phosphofructokinase deficiency (Tarui Disease): difference compared with McArdle disease. Front Neurol 2016;7:82. PMID 27303362
109: Preisler N, Orngreen MC, Echaniz-Laguna A, et al. Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease. Neurology 2012;78(4):265-8. PMID 22238410
110: Preisler N, Laforet P, Madsen KL, et al. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology 2015;84(17):1767-71. PMID 25832663
111: Quinlivan R, Buckley J, James M, et al. McArdle disease: a clinical review. J Neurol Neurosurg Psychiaty 2010;81(11):1182-8. PMID 20861058
112: Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (glycogen storage disease type V). Cochrane Database Syst Rev 2014;2014(11):CD003458. PMID 25391139
113: Raaschou-Pedersen DE, Madsen KL, Løkken N, et al. No effect of triheptanoin in patients with phosphofructokinase deficiency. Neuromuscul Disord 2022;32(4):295-304. PMID 35241345
114: Raben N, Danon M, Lu N, et al. Surprises of genetic engineering: a possible model of polyglucosan body disease. Neurology 2001;56(12):1739-45. PMID 11425943
115: Raben N, Sherman J, Miller F, Mena H, Plotz P. A 5' splice junction mutation leading to exon deletion in an Ashkenazi Jewish family with phosphofructokinase deficiency (Tarui disease). J Biol Chem 1993;268(7):4963-7. PMID 8444874
116: Roscher A, Patel J, Hewson S, et al. The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada. Mol Genet Metab 2014;113(3):171-6. PMID 25266922
117: Rubio JC, Martin MA, Bautista J, Campos Y, Segura D, Arenas J. Association of genetically proven deficiencies of myophosphorylase and AMP deaminase: a second case of "double trouble". Neuromuscul Disord 1997;7(6-7):387-9. PMID 9327403
118: Sadeh M, Yosovich K, Dabby R. Glycogen debrancher enzyme deficiency myopathy. J Clin Neuromuscul Dis 2021;22(4):224-7. PMID 34019008
119: Sagnelli A, Savoiardo M, Marchesi C, et al. Adult polyglucosan body disease in a patient originally diagnosed with Fabry's disease. Neuromuscul Disord 2014;24(3):272-6. PMID 24380807
120: Salameh J, Goyal N, Choudry R, Camelo-Piragua S, Chong PS. Phosphoglycerate mutase deficiency with tubular aggregates in a patient from Panama. Muscle Nerve 2013;47(1):138-40. PMID 23169535
121: Santalla A, Nogales-Gadea G, Encinar AB, et al. Genotypic and phenotypic features of all Spanish patients with McArdle disease: a 2016 update. BMC Genomics 2017;18(Suppl 8):819. PMID 29143597
122: Sato S, Ohi T, Nishino I, Sugie H. Confirmation of the efficacy of vitamin B6 supplementation for McArdle disease by follow-up muscle biopsy. Muscle Nerve 2012;45(3):436-40. PMID 22334182
123: Scalco RS, Stemmerik M, Løkken N, et al. Results of an open label feasibility study of sodium valproate in people with McArdle disease. Neuromuscul Disord 2020;30(9):734-41. PMID 32811700
124: Schmidt B, Servidei S, Gabbai AA, et al. McArdle's disease in two generations: autosomal recessive transmission with manifesting heterozygote. Neurology 1987;37(9):1558-61. PMID 3476861
125: Semplicini C, Hézode-Arzel M, Laforêt P, et al. The role of electrodiagnosis with long exercise test in mcardle disease. Muscle Nerve 2018. Epub ahead of print. PMID 29350794
126: Seol J, Jung S, Koh H, Jung J, Kang Y. Echocardiographic assessment of patients with glycogen storage disease in a single center. Int J Environ Res Public Health 2023;20(3):2191. PMID 36767559
127: Serratrice G, Monges A, Roux H, Aquaron R, Gambarelli D. [Myopathic form of phosphofructokinase deficiency] [Article in French]. Rev Neurol (Paris) 1969;120(4):271-7. PMID 4241954
128: Sherman JB, Raben N, Nicastri C, et al. Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenosis VII--and their population frequency. Am J Hum Genet 1994;55(2):305-13. PMID 8037209
129: Simila ME, Auranen M, Piirilä PL. Beneficial effects of ketogenic diet on phosphofructokinase deficiency (glycogen storage disease type VII). Front Neurol 2020;11:57. PMID 32117019
130: Sotiriou E, Greene P, Krishna S, Hirano M, DiMauro S. Myopathy and parkinsonism in phosphoglycerate kinase deficiency. Muscle Nerve 2010;41(5):707-10. PMID 20151463
131: Sparks J, Michelassi F, Thompson JLP, et al. A United States-based patient-reported adult polyglucosan body disease registry: initial results. Ther Adv Rare Dis 2024;5:26330040241227452. PMID 38445267
132: Spiegel R, Gomez EA, Akman HO, Krishna S, Horovitz Y, DiMauro S. Myopathic form of phosphoglycerate kinase (PGK) deficiency: a new case and pathogenic considerations. Neuromusc Disord 2009;19(3):207-11. PMID 19157875
133: Stemmerik MG, Madsen KL, Laforêt P, Buch AE, Vissing J. Muscle glycogen synthesis and breakdown are both impaired in glycogenin-1 deficiency. Neurology 2017;89(24):2491-4. PMID 29142088
134: Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 2017;136(6):665-77. PMID 28349240
135: Stojkovic T, Vissing J, Petit F, et al. Muscle glycogenosis due to phosphoglucomutase 1 deficiency. N Engl J Med 2009;361(4):425-7. PMID 19625727
136: Sugie H, Sugie Y, Ito M, Fukuda T, Nonaka I, Igarashi Y. Genetic analysis of Japanese patients with myophosphorylase deficiency (McArdle's disease): single-codon deletion in exon 17 is the predominant mutation. Clin Chim Acta 1995;236(1):81-6. PMID 7664468
137: Sukigara S, Liang WC, Komaki H, et al. Muscle glycogen storage disease 0 presenting recurrent syncope with weakness and myalgia. Neuromuscul Disord 2012;22(2):162-5. PMID 21958591
138: Swoboda KJ, Specht L, Jones HR, Shapiro F, DiMauro S, Korson M. Infantile phosphofructokinase deficiency with arthrogryposis: clinical benefit of a ketogenic diet. J. Pediatr 1997;131:932-4. PMID 9427905
139: Taratuto AL, Akman HO, Saccoliti M, et al. Branching enzyme deficiency/glycogenosis storage disease type IV presenting as a severe congenital hypotonia: muscle biopsy and autopsy findings, biochemical and molecular studies. Neuromusc Dis 2010;20(12):783-90. PMID 20833045
140: Tarui S, Okuno G, Ikura Y, Tanaka T, Suda M, Nishikawa M. Phosphofructokinase deficiency in skeletal muscle. A new type of glycogenosis. Biochem Biophys Res Comm 1965;19:517-23. PMID 14339001
141: Tay SK, Akman HO, Chung WK, et al. Fatal infantile neuromuscular presentation of glycogen storage disease type IV. Neuromuscul Disord 2004;14(4):253-60. PMID 15019703
142: Tiberia E, Turnbull J, Wang TJ, et al. Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease. J Biol Chem 2012;287(30):25650-9. PMID 22669944
143: Tonin P, Bruno C, Cassandrini D, et al. Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M gene. Neuromuscul Disord 2009;19(11):776-8. PMID 19783439
144: Tonin P, Lewis P, Servidei S, DiMauro S. Metabolic causes of myoglobinuria. Ann Neurol 1990;27(2):181-5. PMID 2156480
145: Toscano A, Tsujino S, Vita G, Shanske S, Messina C, DiMauro S. Molecular basis of muscle phosphoglycerate mutase (PGAM-M) deficiency in the Italian kindred. Muscle Nerve 1996;19(9):1134-7. PMID 8761269
146: Tsujino S, Shanske S, Brownell A, Haller RG, DiMauro S. Molecular genetic studies of muscle lactate dehydrogenase deficiency in white patients. Ann Neurol 1994;36(4):661-5. PMID 7944300
147: Tsujino S, Shanske S, Carroll JE, Sabina RL, DiMauro S. Double trouble: combined myophosphorylase and AMP deaminase deficiency in a child homozygous for nonsense mutations at both loci. Neuromuscul Disord 1995;5(4):263-6. PMID 7580237
148: Tsujino S, Shanske S, DiMauro S. Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease). New Engl J Med 1993;329(4):241-5. PMID 8316268
149: Valenzuela PL, Santalla A, Alejo LB, et al. Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability:iInsights from McArdle disease. J Sport Health Sci 2023:S2095-546(23)00115-1. PMID 38030066
150: Vieitez I, Teijeira S, Fernandez JM, et al. Molecular and clinical study of McArdle's disease in a cohort of 123 European patients. Identification of 20 novel mutations. Neuromuscul Disord 2011;21(12):817-23. PMID 21802952
151: Vissing J, Haller RG. A diagnostic cycle test for McArdle's disease. Ann Neurol 2003a;54(4):539-42. PMID 14520671
152: Vissing J, Haller RG. Mechanism of exertional fatigue in muscle glycogenoses. Neuromusc Dis 2012;22 Suppl 3:S168-71. PMID 23182633
153: Vissing J, Haller RG. The effect of oral sucrose on exercise tolerance in patients with McArdle's disease. N Engl J Med 2003b;349(26):2503-9. PMID 14695410
154: Vissing J, Quistorff B, Haller RG. Effects of fuels on exercise capacity in muscle phosphoglycerate mutase deficiency. Arch Neurol 2005;62(9):1440-3. PMID 16157752
155: Vissing J, Schmalbruch H, Haller RG, Clausen T. Muscle phosphoglycerate mutase deficiency with tubular aggregates: effect of dantrolene. Ann Neurol 1999;46(2):274-7. PMID 10443898
156: Vissing J, Vissing SF, MacLean DA, Saltin B, Quistorff B, Haller RG. Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies. J Clin Invest 1998;101(8):1654-60. PMID 9541495
157: Vives-Corrons JL, Koralkova P, Grau JM, Manu Pereira Mdel M, Van Wijk R. First description of phosphofructokinase deficiency in Spain: identification of a novel homozygous missense mutation in the PFKM gene. Front Physiol 2013;4:393. PMID 24427140
158: Voermans NC, Preisler N, Madsen KL, et al. PGM1 deficiency: substrate use during exercise and effect of treatment with galactose. Neuromuscul Disord 2017;27(4):370-6. PMID 28190645
159: Vorgerd M, Grehl T, Jager M, et al. Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol 2000;57(7):956-63. PMID 10891977
160: Vucic S, Pamphlett R, Wills EJ, Yiannikas C. Polyglucosan body disease myopathy: an unusual presentation. Muscle Nerve 2007;35(4):536-9. PMID 17221878
161: Wary C, Nadaj-Pakleza A, Laforet P, et al. Investigating glycogenosis type III with multi-parametric functional NMR imaging and spectroscopy. Neuromuscul Disord 2010;20(8):548-58. PMID 20620060
162: Weinstein DA, Correia CE, Saunders AC, Wolfsdorf JI. Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia. Mol Genet Metab 2006;87(4):284-8. PMID 16337419
163: Witting N, Duno M, Piraud M, Vissing J. Severe axial myopathy in McArdle disease. JAMA Neurol 2014;71(1):88-90. PMID 24216972
164: Yao DC, Tolan DR, Murray MF, et al. Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase. Blood 2004;103(6):2401-3. PMID 14615364
165: Yatsuga S, Fujita Y, Ishii A, et al. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol 2015;78(5):814-23. PMID 26463265

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ezequiel A Piccione MD

Dr. Piccione of University of Nebraska has no relevant financial relationships to disclose.
See Profile

Editor

Aravindhan Veerapandiyan MD

Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
See Profile

Former Authors

Hasan O Akman PhD
Salvatore DiMauro MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female,>2:1
Heredity: heredity may be a factor

heredity typical

autosomal recessive
Population groups selectively affected: None selectively affected.
Occupation groups selectively affected: None selectively affected.

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Nonlysosomal muscle glycogenoses

Associated Disorders

Acute renal failure
Compensated hemolytic anemia
Hyperuricemia with or without gouty arthritis
Sudden infant death syndrome (SIDS)

Also Relevant

Carnitine palmitoyltransferase II deficiency
Lafora disease
Myoadenylate deaminase deficiency
Myoglobinuria

Clinical Categories

Neuromuscular Disorders

Patient Handouts

Pompe disease

Nonlysosomal muscle glycogenoses …

Nonlysosomal muscle glycogenoses

Introduction

Overview

Key points

Historical note and nomenclature

Glycogenoses causing exercise intolerance and myoglobinuria

Myophosphorylase deficiency (glycogenosis type V, McArdle disease)

Phosphofructokinase (PFK) deficiency (glycogenosis type VII, Tarui disease)

Table 1. Clinical Differences Between McArdle Disease (GSD V) and Tarui Disease (GSD VII)

Aldolase (ALD) deficiency (glycogenosis type XII)

Phosphoglycerate kinase (PGK) deficiency

Phosphoglycerate mutase (PGAM) deficiency (glycogenosis type X)

Beta-enolase deficiency (glycogenosis type XIII)

Phosphoglucomutase-1 deficiency (glycogenosis type XIV)

Lactate dehydrogenase (LDH) deficiency (glycogenosis type XI)

Muscle glycogen synthetase (GS) deficiency (glycogenosis type 0)

Differential diagnosis

Glycogenoses causing fixed weakness

Differential diagnosis

Conclusion

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Chronic progressive external ophthalmoplegia

Drug-induced myasthenic syndromes

Distal myopathies

Amyotrophic lateral sclerosis

ALS-like disorders of the Western Pacific

Nonlysosomal muscle glycogenoses

Introduction

Overview

Key points

Historical note and nomenclature

Glycogenoses causing exercise intolerance and myoglobinuria

Myophosphorylase deficiency (glycogenosis type V, McArdle disease)

Phosphofructokinase (PFK) deficiency (glycogenosis type VII, Tarui disease)

Table 1. Clinical Differences Between McArdle Disease (GSD V) and Tarui Disease (GSD VII)

Aldolase (ALD) deficiency (glycogenosis type XII)

Phosphoglycerate kinase (PGK) deficiency

Phosphoglycerate mutase (PGAM) deficiency (glycogenosis type X)

Beta-enolase deficiency (glycogenosis type XIII)

Phosphoglucomutase-1 deficiency (glycogenosis type XIV)

Lactate dehydrogenase (LDH) deficiency (glycogenosis type XI)

Muscle glycogen synthetase (GS) deficiency (glycogenosis type 0)

Differential diagnosis

Glycogenoses causing fixed weakness

Differential diagnosis

Conclusion

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Chronic progressive external ophthalmoplegia

Drug-induced myasthenic syndromes

Distal myopathies

Amyotrophic lateral sclerosis

ALS-like disorders of the Western Pacific

This is an article preview.
Start a Free Account
to access the full version.