RARE DISEASE
Glycogen storage disease due to muscle glycogen phosphorylase deficiency
Glycogen storage disease due to muscle glycogen phosphorylase deficiency
Glycogen storage disease due to muscle glycogen phosphorylase deficiency
Synonyms: GSD due to muscle glycogen phosphorylase deficiency, GSD type 5, GSD type V, Glycogen storage disease type 5, Glycogen storage disease type V, Glycogenosis due to muscle glycogen phosphorylase deficiency, Glycogenosis type 5, Glycogenosis type V, McArdle disease, Myophosphorylase deficiency
Synonyms: GSD due to muscle glycogen phosphorylase deficiency, GSD type 5, GSD type V, Glycogen storage disease type 5, Glycogen storage disease type V, Glycogenosis due to muscle glycogen phosphorylase deficiency, Glycogenosis type 5, Glycogenosis type V, McArdle disease, Myophosphorylase deficiency
Synonyms: GSD due to muscle glycogen phosphorylase deficiency, GSD type 5, GSD type V, Glycogen storage disease type 5, Glycogen storage disease type V, Glycogenosis due to muscle glycogen phosphorylase deficiency, Glycogenosis type 5, Glycogenosis type V, McArdle disease, Myophosphorylase deficiency
Drug discovery
2
drugs
With orphan designations
Overview
Glycogen storage disease due to muscle glycogen phosphorylase deficiency (GSD V/McArdle disease) is an autosomal recessive metabolic disorder caused by PYGM gene mutations, leading to impaired glycogen breakdown in skeletal muscle. It presents with exercise intolerance, myalgia, and rhabdomyolysis triggered by anaerobic activity, often accompanied by the "second wind" phenomenon. Diagnosis involves non-ischemic forearm exercise testing (blunted lactate rise), elevated serum CK, and genetic confirmation [3][12][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
147 drug discovery papers about Glycogen storage disease due to muscle glycogen phosphorylase deficiency, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
147 drug discovery papers about Glycogen storage disease due to muscle glycogen phosphorylase deficiency, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-03-01 | Clinical Features in Children with Persistent Toe Walking Who Carry Heterozygous PYGM Variants: A Cross-Sectional Study.
Persistent toe walking (TW) in children is often idiopathic but may conceal subtle neuromuscular or metabolic causes. This cross-sectional, retrospective study investigated clinical and genetic characteristics of children carrying PYGM variants to explore potential subclinical phenotypes among heterozygous carriers. Seventy-two (72) children meeting criteria for idiopathic TW were evaluated using a standardized clinical protocol and a validated 49-gene next-generation sequencing neuromuscular panel. Variants were classified as pathogenic, likely pathogenic, or of uncertain significance according to ACMG/AMP guidelines. Analyses were descriptive. Among 1,300 screened patients, 72 were identified as PYGM variant carriers. Toe walking was bilateral in all cases, with severe dorsiflexion restriction (≤ 5°) in 80.5%. Pes cavus was observed in 93% of patients, and muscle symptoms-pain, fatigue, or cramps-occurred in approximately one-third. VUS carriers displayed comparable, slightly milder muscle symptom frequencies than P/LP carriers. 12.5% could perform heel walking. Speech difficulties were reported in 56.9% of cases. While causality cannot be inferred, these findings suggest that heterozygous PYGM variants may contribute to subtle neuromuscular phenotypes. Genetic testing can be considered in persistent TW when clinical findings raise suspicion for an underlying neuromuscular/metabolic condition.
2018-01-18 | Neuropathic and Myopathic Pain.
The evaluation and management of childhood pain syndromes of neuromuscular origin have distinct challenges, as the patterns of disease presentation and the ability of a child to describe symptoms may differ from that of an adult. Advances in scientific and clinical knowledge are leading to significant progress in the care of affected children. The genetic origins of Fabry disease and the inherited form of erythromelalgia are better understood. The increasing interest in neuroimmunology among pediatric neurologists has led to more sophisticated diagnostic and therapeutic approaches. Treatment protocols for complex regional pain syndrome have become more standardized. In addition, investigations continue into potential new interventions for metabolic muscle diseases such as McArdle disease and carnitine palmitoyl transferase deficiency type II. In the years to come, children with pain of neuromuscular origin will have access to more precise diagnostic tools and novel therapies that would alleviate this particularly distressing category of disease.
2015-05-29 | Minimally symptomatic mcardle disease, expanding the genotype–phenotype spectrum
ABSTRACT Introduction: We report the clinical, biochemical, and molecular findings in a Cypriot family with minimally symptomatic McArdle disease. Methods : Myophosphorylase in muscle was assessed by histochemistry, quantitative spectrophotometry, and western blot analysis. Mutation identification was performed by PCR amplification of all PYGM exons, followed by bidirectional sequencing. Screening for the new mutation was performed by restriction enzyme analysis. Results : We found that a novel c.1151C>T transition in exon 10 of the myophosphorylase gene ( PYGM ) is associated with minimally symptomatic McArdle disease. Homozygous carriers displayed an ischemic exercise response characterized by a blunted increase in post‐exercise blood lactate levels in conjunction with an exaggerated increase in ammonia. Myophosphorylase activity in muscle was 3.75% of normal, whereas the size and abundance of the enzyme were unaffected. Conclusions : These findings expand the genotype–phenotype spectrum of McArdle disease and suggest that enzymatic activity as low as 4% may be sufficient to ameliorate the phenotype. Muscle Nerve 52 : 891–895, 2015
2014-02-01 | Phosphorylase re-expression, increase in the force of contraction and decreased fatigue following notexin-induced muscle damage and regeneration in the ovine model of McArdle disease
McArdle disease is caused by a deficiency of myophosphorylase and currently a satisfactory treatment is not available. The injection of notexin into, or the layering of notexin onto, the muscles of affected sheep resulted in necrosis followed by regeneration of muscle fibres with the expression of both non-muscle isoforms of phosphorylase within the fibres and a reduction of the amount of glycogen in the muscle with an increase in the strength of contraction and a decrease in fatiguability in the muscle fibres. The sustained re-expression of both the brain and liver isoforms of phosphorylase within the muscle fibres provides further emphasis that strategies to enhance the re-expression of these isoforms should be investigated as a possible treatment for McArdle disease.
2012-10-02 | Advances in neuromuscular disease 2003: the year in review.
During 2003, numerous research advances in both clinical neuromuscular disease and in the basic pathophysiology of these disorders were published and/or presented. In this review, we present a few categorical highlights of the year, discussing a new potential treatment of McArdle's disease, proposed new diagnostic criteria for the inflammatory myopathies and their clinical implications, the emerging anti-MuSK antibody syndrome in patients with myasthenia gravis, potential new therapies for the most common hereditary neuropathy (Charcot-Marie-Tooth type 1A), the successful pharmacologic manipulation and its therapeutic implications of the genetic mechanisms underlying spinal muscular atrophy, and several emerging therapeutic strategies in amyotrophic lateral sclerosis. As these reports indicate, clinical and basic research in neuromuscular disease continues to yield important and clinically relevant insights, which are now being rapidly translated into new clinical trials showing therapeutic promise for diseases previously thought untreatable.
small molecules
2026-03-16 | The Impact of Muscle Fatigue on McArdle Disease: A Case Report.
McArdle disease (McA) is a rare metabolic disorder of autosomal recessive inheritance caused by pathogenic variants in the PYGM gene, which lead to a deficiency of the myophosphorylase enzyme. This enzymatic defect impairs muscle glycogenolysis, typically resulting in exercise intolerance, premature fatigue, and exertional cramps triggered by anaerobic or high-intensity physical activity starting in childhood or adolescence. However, the diagnosis is frequently delayed due to the heterogeneous and non-specific presentation of these symptoms. The authors report a case of a 61-year-old woman with a lifelong history of exercise intolerance and disproportionate muscle fatigue that restricted her physical activity since her youth. She presented with persistent, idiopathic elevations of creatine kinase (CK) over several years. The patient had no history of myoglobinuria and showed preserved renal function and no evidence of acute rhabdomyolysis, despite marked hyperCKemia. Cardiac involvement was also excluded. After excluding more common secondary causes of hyperCKemia, such as statin-induced myopathy and inflammatory conditions, the persistence of marked hyperCKemia and specific exercise-induced symptoms suggested a metabolic myopathy, such as McArdle disease. Molecular analysis was performed, identifying the homozygous pathogenic variant c.280C>T (p.Arg94Trp) in the PYGM gene and confirming the diagnosis of McArdle disease.
2026-01-31 | An exercise intervention in children and young adults with McArdle disease: feasibility, acceptability, and clinical outcomes
Abstract Introduction Patients with McArdle disease have reduced exercise capacity. Structured exercise programs in adults with McArdle disease can improve aerobic capacity and strength. However, structured exercise has not been evaluated in younger populations. Our aim was to determine the safety, feasibility, and acceptability of an exercise intervention in children and young adults with McArdle disease. Methods Children and young adults aged 5–30 years with McArdle disease were recruited through metabolic clinics in New South Wales, Australia, to complete a remote, supervised 12-week exercise intervention. Pre and/or post intervention, participants completed a treadmill cardiopulmonary exercise test (CPET), strength testing, habitual physical activity monitoring, a quality-of-life questionnaire, acceptability questionnaire, muscular Near Infrared Spectroscopy (NIRS), and blood samples. Results Five out of 10 eligible participants, with a median age of 17 years (range 13–29), were enrolled. Four met the feasibility target of 70% completed exercise sessions. Four episodes of mild rhabdomyolysis were reported during the study, but no participant required hospital admission. All participants reported they would participate in similar programs in the future. No significant changes were found in aerobic capacity, strength, habitual physical activity levels or quality of life. Trends were observed for lower perceived pain during CPET, and improved leg press. NIRS indicated a possible trend for improved muscle oxygen utilisation. Conclusion A 12-week remotely delivered exercise intervention was found to be feasible, safe, and acceptable to children and young adults with McArdle disease. Although improvements to aerobic capacity and strength were not elicited, individual clinical benefits may have occurred. One sentence take home message An exercise intervention in children and young adults with McArdle disease is feasible, safe, and acceptable, and may elicit individual clinical benefits.
2025-12-14 | Lactate-induced mitochondrial magnesium uptake and its metabolic implications in the McArdle disease model.
McArdle disease, caused by mutations in the pygm encoding myophosphorylase, impairs muscle glycogenolysis and lactate production during exercise, leading to severe energy deficits. Here, we report that the decreased lactate production in McArdle disease regulates mitochondrial magnesium (mMg2+) uptake, with major metabolic consequences in skeletal muscle. Using a CRISPR/Cas9-generated pygm knockout (KO) rat model, we demonstrate that KO rats fail to elevate lactate during static muscle contraction and exhibit diminished mMg2+ uptake, disrupted ATP synthesis, and impaired mitochondrial respiration. In vitro, caffeine-stimulated KO myotubes showed preserved Ca2+ oscillations but lacked lactate production and mMg2+ uptake. Restoration of lactate levels via glucose supplementation rescued mMg2+ transport and improved metabolic output. These findings underscore the significance of lactate as a crucial regulator of mMg2+ homeostasis and provide valuable mechanistic insights into the metabolic dysfunction observed in McArdle disease.
2025-10-16 | Clinical Benefits of Exogenous Ketosis in Adults with Disease: A Systematic Review.
Ketone bodies are increasingly studied for their potential therapeutic effects, particularly through exogenous ketosis, in a variety of diseases. This systematic review aimed to rigorously assess the clinical efficacy of exogenous ketosis in adults with medical conditions. Following PRISMA guidelines, we systematically searched MEDLINE and Scopus databases. Our inclusion criteria were defined according to the PICOS framework, focusing on studies involving exogenous ketosis in adult patients with specific diseases. The study is registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42023492846). After a stringent selection process, fifty-one studies were analyzed. Twenty-two studies focused on neurological disorders, one on psychiatric disorders, twenty-two on metabolic disorders, five on cardiovascular disorders, and one on an inflammatory disorder. Exogenous ketosis demonstrated potential benefits across multiple conditions, including Alzheimer's disease, mild cognitive impairment, McArdle's disease, various forms of heart failure, cardiogenic shock, pulmonary hypertension, and COVID-19-related acute respiratory distress syndrome, although evidence is mostly limited to surrogate endpoints with insufficient hard outcome data. Subtherapeutic ketone concentrations induced by medium-chain triglycerides and limited follow-up periods often precluded firm conclusions regarding clinically meaningful outcomes. Exogenous ketosis shows potential in neurological, metabolic, and cardiovascular disorders, while evidence in psychiatric and inflammatory conditions remains scarce and preliminary. Ketone esters appear preferable for effective and tolerable ketosis. Future research should focus on identifying responsive patient populations, optimizing treatment regimens, and conducting long-term clinical trials with hard endpoints to validate these findings.
2025-07-01 | Biochemistry and molecular genetics of human glycogenoses
Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes of glycogenolysis (myophosphorylase ( PYGM ), glycogen debranching enzyme ( AGL ), phosphorylase b -kinase ( PHKB )) and glycolysis (phosphofructokinase ( PFK ), phosphoglyceromutase ( PGAM 2), aldolase A ( ALDOA ), β -enolase ( ENO 3)); however, 3 of them involve glycogen synthesis (glycogenin-1 ( GYG 1), glycogen synthase ( GSE ), and debranching enzyme ( GBE 1)). Many present with exercise-induced cramps and rhabdomyolysis with more intense exercise (ie, PYGM , PFK , PGAM 2), while others present with muscle wasting and weakness ( GYG 1, AGL , GBE 1). Failure of serum lactate to rise with exercise, with an exaggerated response to ammonia, is a common but not invariant feature. Serum creatine kinase ( CK ) levels are often elevated in myopathic forms and PYGM deficiency , but may be normal and elevated only in rhabdomyolysis ( PGAM 2, PFK , ENO 3). Therapy for glycogen storage diseases that result in exercise-induced symptoms involves lifestyle adaptations and carefully selected exercises. Immediate carbohydrate ingestion before exercise improves symptoms in glycogenolytic defects (i.e., PYGM), but may worsen symptoms in glycolytic defects (i.e., PFK ). Low-dose creatine monohydrate may provide modest improvement in PYGM mutations.
cell therapies
2025-07-18 | Impact of individualized and supervised strength training on muscle physiology, metabolic control and quality of life in metabolic myopathies
Metabolic myopathies impair muscle energy metabolism. Exercise is challenging, as patients may suffer from rhabdomyolysis attacks. This study investigated long-term effects of an individualized strength training program. Eighteen patients (12-45 years) with fatty acid oxidation disorders and glycogen storage diseases (types III and V) participated in a supervised progressive strength exercise program over two periods: biweekly assessments for 12 weeks and monthly in the second 12 weeks. Clinical assessments (anthropometry, food intake, laboratory tests), muscle strength/endurance (isokinetic tests), balance (postural stability tests), aerobic capacity (exercise duration, anaerobic threshold rate, maximal oxygen consumption), and quality of life (calculated in eight subscales) were assessed at baseline, 12, and 24 weeks. Biweekly nutritional and medical adjustments were made based on physiological responses, including modifications in caloric intake, macronutrient composition, pre-exercise sucrose and creatine supplementation. Significant improvements in strength (p < 0.001), balance (p < 0.05), and aerobic capacity (p < 0.001) were observed after 12 weeks and persisted for 24 weeks. No patients experienced rhabdomyolysis. Quality of life improved, particularly in the subscales of emotional role limitations, pain, and general health (p < 0.05). These findings suggest that dynamic, multidisciplinary, and individualized exercise program, combined with medical nutrition therapy and pharmacological adjustments, is effective and safe for patients with metabolic myopathies.
2012-07-25 | Resistance (Weight Lifting) Training in an Adolescent With McArdle Disease
Owing to the risk of severe rhabdomyolysis, clinicians advise McArdle disease patients to refrain from strenuous exercise, particularly weight lifting. A 15-year-old male McArdle disease patient performed a 6-week, supervised, light- to moderate-intensity (∼65-70% of one-repetition-maximum) resistance (weight lifting) training program (2 sessions/week). Training resulted in ∼27% and ∼6% increase in one-repetition-maximum bench press and multipower squat performance while inducing no myoglobinuria. The patient changed to a lower disease severity class, that is, he became virtually asymptomatic in terms of exercise limitations. The authors’ preliminary data suggest that supervised, light to moderate resistance training is feasible in children with McArdle disease and has potential clinical benefits.
1997-07-01 | A splice-site mutation causing ovine McArdle's disease
McArdle's disease is an autosomal recessive myopathy with symptoms of exercise intolerance caused by deficiency of the enzyme muscle glycogen phosphorylase which releases glucose for contraction during exercise. The human cDNA has been sequenced and disease-causing mutations identified. An ovine equivalent of McArdle's disease has been diagnosed and the mutation responsible identified by PCR-amplification of the ovine glycogen myophosphorylase cDNA in six overlapping fragments followed by single strand conformation polymorphism (SSCP) analysis. Two fragments showed SSCPs in the glycogen myophosphorylase cDNA from affected sheep. The SSCP in fragment one was a silent polymorphism, while that in fragment six, was an eight base deletion at the 5′ end of exon 20. This deletion will cause a frame-shift, a premature stop codon and remove the last 31 amino-acid residues from the protein. The cDNA deletion suggested that the genomic mutation most likely involved a splice-site. Sequencing intron 19 identified the mutation as an adenine for guanine substitution at the intron 19 3′ splice-site. This eliminated an XbaI site present in normal sheep allowing diagnosis of normal, affected and carrier sheep. This ovine model of McArdle's disease is now available for therapeutic trials.
proteins
2026-03-01 | Clinical Features in Children with Persistent Toe Walking Who Carry Heterozygous PYGM Variants: A Cross-Sectional Study.
Persistent toe walking (TW) in children is often idiopathic but may conceal subtle neuromuscular or metabolic causes. This cross-sectional, retrospective study investigated clinical and genetic characteristics of children carrying PYGM variants to explore potential subclinical phenotypes among heterozygous carriers. Seventy-two (72) children meeting criteria for idiopathic TW were evaluated using a standardized clinical protocol and a validated 49-gene next-generation sequencing neuromuscular panel. Variants were classified as pathogenic, likely pathogenic, or of uncertain significance according to ACMG/AMP guidelines. Analyses were descriptive. Among 1,300 screened patients, 72 were identified as PYGM variant carriers. Toe walking was bilateral in all cases, with severe dorsiflexion restriction (≤ 5°) in 80.5%. Pes cavus was observed in 93% of patients, and muscle symptoms-pain, fatigue, or cramps-occurred in approximately one-third. VUS carriers displayed comparable, slightly milder muscle symptom frequencies than P/LP carriers. 12.5% could perform heel walking. Speech difficulties were reported in 56.9% of cases. While causality cannot be inferred, these findings suggest that heterozygous PYGM variants may contribute to subtle neuromuscular phenotypes. Genetic testing can be considered in persistent TW when clinical findings raise suspicion for an underlying neuromuscular/metabolic condition.
2018-01-18 | Neuropathic and Myopathic Pain.
The evaluation and management of childhood pain syndromes of neuromuscular origin have distinct challenges, as the patterns of disease presentation and the ability of a child to describe symptoms may differ from that of an adult. Advances in scientific and clinical knowledge are leading to significant progress in the care of affected children. The genetic origins of Fabry disease and the inherited form of erythromelalgia are better understood. The increasing interest in neuroimmunology among pediatric neurologists has led to more sophisticated diagnostic and therapeutic approaches. Treatment protocols for complex regional pain syndrome have become more standardized. In addition, investigations continue into potential new interventions for metabolic muscle diseases such as McArdle disease and carnitine palmitoyl transferase deficiency type II. In the years to come, children with pain of neuromuscular origin will have access to more precise diagnostic tools and novel therapies that would alleviate this particularly distressing category of disease.
2015-05-29 | Minimally symptomatic mcardle disease, expanding the genotype–phenotype spectrum
ABSTRACT Introduction: We report the clinical, biochemical, and molecular findings in a Cypriot family with minimally symptomatic McArdle disease. Methods : Myophosphorylase in muscle was assessed by histochemistry, quantitative spectrophotometry, and western blot analysis. Mutation identification was performed by PCR amplification of all PYGM exons, followed by bidirectional sequencing. Screening for the new mutation was performed by restriction enzyme analysis. Results : We found that a novel c.1151C>T transition in exon 10 of the myophosphorylase gene ( PYGM ) is associated with minimally symptomatic McArdle disease. Homozygous carriers displayed an ischemic exercise response characterized by a blunted increase in post‐exercise blood lactate levels in conjunction with an exaggerated increase in ammonia. Myophosphorylase activity in muscle was 3.75% of normal, whereas the size and abundance of the enzyme were unaffected. Conclusions : These findings expand the genotype–phenotype spectrum of McArdle disease and suggest that enzymatic activity as low as 4% may be sufficient to ameliorate the phenotype. Muscle Nerve 52 : 891–895, 2015
2014-02-01 | Phosphorylase re-expression, increase in the force of contraction and decreased fatigue following notexin-induced muscle damage and regeneration in the ovine model of McArdle disease
McArdle disease is caused by a deficiency of myophosphorylase and currently a satisfactory treatment is not available. The injection of notexin into, or the layering of notexin onto, the muscles of affected sheep resulted in necrosis followed by regeneration of muscle fibres with the expression of both non-muscle isoforms of phosphorylase within the fibres and a reduction of the amount of glycogen in the muscle with an increase in the strength of contraction and a decrease in fatiguability in the muscle fibres. The sustained re-expression of both the brain and liver isoforms of phosphorylase within the muscle fibres provides further emphasis that strategies to enhance the re-expression of these isoforms should be investigated as a possible treatment for McArdle disease.
2012-10-02 | Advances in neuromuscular disease 2003: the year in review.
During 2003, numerous research advances in both clinical neuromuscular disease and in the basic pathophysiology of these disorders were published and/or presented. In this review, we present a few categorical highlights of the year, discussing a new potential treatment of McArdle's disease, proposed new diagnostic criteria for the inflammatory myopathies and their clinical implications, the emerging anti-MuSK antibody syndrome in patients with myasthenia gravis, potential new therapies for the most common hereditary neuropathy (Charcot-Marie-Tooth type 1A), the successful pharmacologic manipulation and its therapeutic implications of the genetic mechanisms underlying spinal muscular atrophy, and several emerging therapeutic strategies in amyotrophic lateral sclerosis. As these reports indicate, clinical and basic research in neuromuscular disease continues to yield important and clinically relevant insights, which are now being rapidly translated into new clinical trials showing therapeutic promise for diseases previously thought untreatable.
small molecules
2026-03-16 | The Impact of Muscle Fatigue on McArdle Disease: A Case Report.
McArdle disease (McA) is a rare metabolic disorder of autosomal recessive inheritance caused by pathogenic variants in the PYGM gene, which lead to a deficiency of the myophosphorylase enzyme. This enzymatic defect impairs muscle glycogenolysis, typically resulting in exercise intolerance, premature fatigue, and exertional cramps triggered by anaerobic or high-intensity physical activity starting in childhood or adolescence. However, the diagnosis is frequently delayed due to the heterogeneous and non-specific presentation of these symptoms. The authors report a case of a 61-year-old woman with a lifelong history of exercise intolerance and disproportionate muscle fatigue that restricted her physical activity since her youth. She presented with persistent, idiopathic elevations of creatine kinase (CK) over several years. The patient had no history of myoglobinuria and showed preserved renal function and no evidence of acute rhabdomyolysis, despite marked hyperCKemia. Cardiac involvement was also excluded. After excluding more common secondary causes of hyperCKemia, such as statin-induced myopathy and inflammatory conditions, the persistence of marked hyperCKemia and specific exercise-induced symptoms suggested a metabolic myopathy, such as McArdle disease. Molecular analysis was performed, identifying the homozygous pathogenic variant c.280C>T (p.Arg94Trp) in the PYGM gene and confirming the diagnosis of McArdle disease.
2026-01-31 | An exercise intervention in children and young adults with McArdle disease: feasibility, acceptability, and clinical outcomes
Abstract Introduction Patients with McArdle disease have reduced exercise capacity. Structured exercise programs in adults with McArdle disease can improve aerobic capacity and strength. However, structured exercise has not been evaluated in younger populations. Our aim was to determine the safety, feasibility, and acceptability of an exercise intervention in children and young adults with McArdle disease. Methods Children and young adults aged 5–30 years with McArdle disease were recruited through metabolic clinics in New South Wales, Australia, to complete a remote, supervised 12-week exercise intervention. Pre and/or post intervention, participants completed a treadmill cardiopulmonary exercise test (CPET), strength testing, habitual physical activity monitoring, a quality-of-life questionnaire, acceptability questionnaire, muscular Near Infrared Spectroscopy (NIRS), and blood samples. Results Five out of 10 eligible participants, with a median age of 17 years (range 13–29), were enrolled. Four met the feasibility target of 70% completed exercise sessions. Four episodes of mild rhabdomyolysis were reported during the study, but no participant required hospital admission. All participants reported they would participate in similar programs in the future. No significant changes were found in aerobic capacity, strength, habitual physical activity levels or quality of life. Trends were observed for lower perceived pain during CPET, and improved leg press. NIRS indicated a possible trend for improved muscle oxygen utilisation. Conclusion A 12-week remotely delivered exercise intervention was found to be feasible, safe, and acceptable to children and young adults with McArdle disease. Although improvements to aerobic capacity and strength were not elicited, individual clinical benefits may have occurred. One sentence take home message An exercise intervention in children and young adults with McArdle disease is feasible, safe, and acceptable, and may elicit individual clinical benefits.
2025-12-14 | Lactate-induced mitochondrial magnesium uptake and its metabolic implications in the McArdle disease model.
McArdle disease, caused by mutations in the pygm encoding myophosphorylase, impairs muscle glycogenolysis and lactate production during exercise, leading to severe energy deficits. Here, we report that the decreased lactate production in McArdle disease regulates mitochondrial magnesium (mMg2+) uptake, with major metabolic consequences in skeletal muscle. Using a CRISPR/Cas9-generated pygm knockout (KO) rat model, we demonstrate that KO rats fail to elevate lactate during static muscle contraction and exhibit diminished mMg2+ uptake, disrupted ATP synthesis, and impaired mitochondrial respiration. In vitro, caffeine-stimulated KO myotubes showed preserved Ca2+ oscillations but lacked lactate production and mMg2+ uptake. Restoration of lactate levels via glucose supplementation rescued mMg2+ transport and improved metabolic output. These findings underscore the significance of lactate as a crucial regulator of mMg2+ homeostasis and provide valuable mechanistic insights into the metabolic dysfunction observed in McArdle disease.
2025-10-16 | Clinical Benefits of Exogenous Ketosis in Adults with Disease: A Systematic Review.
Ketone bodies are increasingly studied for their potential therapeutic effects, particularly through exogenous ketosis, in a variety of diseases. This systematic review aimed to rigorously assess the clinical efficacy of exogenous ketosis in adults with medical conditions. Following PRISMA guidelines, we systematically searched MEDLINE and Scopus databases. Our inclusion criteria were defined according to the PICOS framework, focusing on studies involving exogenous ketosis in adult patients with specific diseases. The study is registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42023492846). After a stringent selection process, fifty-one studies were analyzed. Twenty-two studies focused on neurological disorders, one on psychiatric disorders, twenty-two on metabolic disorders, five on cardiovascular disorders, and one on an inflammatory disorder. Exogenous ketosis demonstrated potential benefits across multiple conditions, including Alzheimer's disease, mild cognitive impairment, McArdle's disease, various forms of heart failure, cardiogenic shock, pulmonary hypertension, and COVID-19-related acute respiratory distress syndrome, although evidence is mostly limited to surrogate endpoints with insufficient hard outcome data. Subtherapeutic ketone concentrations induced by medium-chain triglycerides and limited follow-up periods often precluded firm conclusions regarding clinically meaningful outcomes. Exogenous ketosis shows potential in neurological, metabolic, and cardiovascular disorders, while evidence in psychiatric and inflammatory conditions remains scarce and preliminary. Ketone esters appear preferable for effective and tolerable ketosis. Future research should focus on identifying responsive patient populations, optimizing treatment regimens, and conducting long-term clinical trials with hard endpoints to validate these findings.
2025-07-01 | Biochemistry and molecular genetics of human glycogenoses
Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes of glycogenolysis (myophosphorylase ( PYGM ), glycogen debranching enzyme ( AGL ), phosphorylase b -kinase ( PHKB )) and glycolysis (phosphofructokinase ( PFK ), phosphoglyceromutase ( PGAM 2), aldolase A ( ALDOA ), β -enolase ( ENO 3)); however, 3 of them involve glycogen synthesis (glycogenin-1 ( GYG 1), glycogen synthase ( GSE ), and debranching enzyme ( GBE 1)). Many present with exercise-induced cramps and rhabdomyolysis with more intense exercise (ie, PYGM , PFK , PGAM 2), while others present with muscle wasting and weakness ( GYG 1, AGL , GBE 1). Failure of serum lactate to rise with exercise, with an exaggerated response to ammonia, is a common but not invariant feature. Serum creatine kinase ( CK ) levels are often elevated in myopathic forms and PYGM deficiency , but may be normal and elevated only in rhabdomyolysis ( PGAM 2, PFK , ENO 3). Therapy for glycogen storage diseases that result in exercise-induced symptoms involves lifestyle adaptations and carefully selected exercises. Immediate carbohydrate ingestion before exercise improves symptoms in glycogenolytic defects (i.e., PYGM), but may worsen symptoms in glycolytic defects (i.e., PFK ). Low-dose creatine monohydrate may provide modest improvement in PYGM mutations.
cell therapies
2025-07-18 | Impact of individualized and supervised strength training on muscle physiology, metabolic control and quality of life in metabolic myopathies
Metabolic myopathies impair muscle energy metabolism. Exercise is challenging, as patients may suffer from rhabdomyolysis attacks. This study investigated long-term effects of an individualized strength training program. Eighteen patients (12-45 years) with fatty acid oxidation disorders and glycogen storage diseases (types III and V) participated in a supervised progressive strength exercise program over two periods: biweekly assessments for 12 weeks and monthly in the second 12 weeks. Clinical assessments (anthropometry, food intake, laboratory tests), muscle strength/endurance (isokinetic tests), balance (postural stability tests), aerobic capacity (exercise duration, anaerobic threshold rate, maximal oxygen consumption), and quality of life (calculated in eight subscales) were assessed at baseline, 12, and 24 weeks. Biweekly nutritional and medical adjustments were made based on physiological responses, including modifications in caloric intake, macronutrient composition, pre-exercise sucrose and creatine supplementation. Significant improvements in strength (p < 0.001), balance (p < 0.05), and aerobic capacity (p < 0.001) were observed after 12 weeks and persisted for 24 weeks. No patients experienced rhabdomyolysis. Quality of life improved, particularly in the subscales of emotional role limitations, pain, and general health (p < 0.05). These findings suggest that dynamic, multidisciplinary, and individualized exercise program, combined with medical nutrition therapy and pharmacological adjustments, is effective and safe for patients with metabolic myopathies.
2012-07-25 | Resistance (Weight Lifting) Training in an Adolescent With McArdle Disease
Owing to the risk of severe rhabdomyolysis, clinicians advise McArdle disease patients to refrain from strenuous exercise, particularly weight lifting. A 15-year-old male McArdle disease patient performed a 6-week, supervised, light- to moderate-intensity (∼65-70% of one-repetition-maximum) resistance (weight lifting) training program (2 sessions/week). Training resulted in ∼27% and ∼6% increase in one-repetition-maximum bench press and multipower squat performance while inducing no myoglobinuria. The patient changed to a lower disease severity class, that is, he became virtually asymptomatic in terms of exercise limitations. The authors’ preliminary data suggest that supervised, light to moderate resistance training is feasible in children with McArdle disease and has potential clinical benefits.
1997-07-01 | A splice-site mutation causing ovine McArdle's disease
McArdle's disease is an autosomal recessive myopathy with symptoms of exercise intolerance caused by deficiency of the enzyme muscle glycogen phosphorylase which releases glucose for contraction during exercise. The human cDNA has been sequenced and disease-causing mutations identified. An ovine equivalent of McArdle's disease has been diagnosed and the mutation responsible identified by PCR-amplification of the ovine glycogen myophosphorylase cDNA in six overlapping fragments followed by single strand conformation polymorphism (SSCP) analysis. Two fragments showed SSCPs in the glycogen myophosphorylase cDNA from affected sheep. The SSCP in fragment one was a silent polymorphism, while that in fragment six, was an eight base deletion at the 5′ end of exon 20. This deletion will cause a frame-shift, a premature stop codon and remove the last 31 amino-acid residues from the protein. The cDNA deletion suggested that the genomic mutation most likely involved a splice-site. Sequencing intron 19 identified the mutation as an adenine for guanine substitution at the intron 19 3′ splice-site. This eliminated an XbaI site present in normal sheep allowing diagnosis of normal, affected and carrier sheep. This ovine model of McArdle's disease is now available for therapeutic trials.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Glycogen storage disease due to muscle glycogen phosphorylase deficiency.
2 orphan drug designations for Glycogen storage disease due to muscle glycogen phosphorylase deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Valproic Acid | small molecules | EMA | — | Vall d'Hebron Institute of Research |
Triheptanoin | small molecules | EMA | Vall d'Hebron Institute of Research |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.