Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs)
Abstract
:1. Background
2. Glycogen Storage Disorders (GSDs) an Overview
3. Mitochondrial Metabolic Dysfunction
3.1. Overproduction of ROS and Oxidative Stress
3.2. Mitochondrial Biogenesis
3.3. Autophagy and Mitophagy
3.4. Apoptosis and Mitochondrial Dysfunction
3.5. Mitochondrial Myopathy
4. Diagnosis and Therapeutic Strategies in GSDs
4.1. Diagnosis
4.2. Current Treatment Options and Therapies
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Disorders (Common Name) | Enzyme | Gene/Chromosome/-Inheritance | Clinical Manifestation |
---|---|---|---|
GSD 0a | Glycogen synthase in Liver | GYS2/12p12.1/AR | Fasting ketotic hypoglycemia, reactive hyperglycemia and lactate elevation [15,16] |
GSD 0b | Glycogen synthase in muscle | GYS1/19q13.33/AR | Hypertrophic cardiomyopathy exercise intolerance, and adult-onset myopathy without cardiomyopathy [17,18] |
GSD Ia (von Gierke disease) | Glucose-6-phosphatase | G6PC/17q21.31/AR | Hypoglycemia, lactic acidosis, Hypertriglyceridemia, hepatomegaly, renal dysfunction [19] |
GSD Ib | Glucose-6-phosphate translocase | SLC37A4/11q23.3/AR | Neutropenia, neutrophil dysfunction and inflammatory bowel disease [20] |
GSD II (PD) | alpha-1,4-glucosidase | GAA/17q25.3/AR | Hypertrophic cardiomyopathy, hypotonia, and motor delay [21] |
GSD III (Cori or Forbes disease) | Glycogen debranching (amylo-1,6 glucosidase) | AGL/1p21.2/AR | Hypoglycemia, elevated ketosis in hyperlipidemia, hepatomegaly, elevated liver enzyme myopathy, variable muscle and cardiac phenotype [11] |
GSD IV (Andersen or Adult polyglucosan body disease) | Glycogen branching enzyme- amylo (1,4-1,6) transglucosidase | GBE1/3p12.2/AR | Hepatosplenomegaly, liver dysfunction, progressive cirrhosis, cardiomyopathy, hypotonia, gait difficulty, progressive neurogenic bladder, autonomic dysfunction, sensory loss, and variable cognitive difficulty [22,23,24] |
GSD 5 (McArdle disease) | Myophosphorylase | PYGM/11q13.1/AR | Exercise induces fatigue, cramps, tachypnoea and tachycardia, rhabdo-myolysis, myoglobinuria [25] |
GSD 6 (Hers disease) | Liver glycogen phosphorylase | PYGL/14q22.1/AR | Hepatomegaly, hypoglycemia, with ketosis, elevated liver transaminases, hyperlipidemia, osteoporosis, and liver fibrosis [26,27] |
GSD 7 (Tarui disease) | Muscle phosphofructokinase | PFKM/12q13.11/AR | Hemolytic anemia, muscle weakness, exercise-induced muscle cramping, exertional Myopathy, and gout/hyperuricemia [28,29] |
GSD 9A1 (formerly GSD 8) | Alpha-2 subunit of liver phosphorylase kinase | PHKA2/Xp22.13 XL | Hepatomegaly, growth retardation, motor developmental delay. Hypercholesterolmia, hypertriglyceridemia, elevated liver enzymes; fasting hyperketosis [30] |
GSD 9B (GSD IXb) | Beta subunit of liver and muscle phosphorylase | PHKB/16q12.1/AR | Short stature, hepatomegaly, diarrhea, muscle weakness, hypotonia [3,31] |
GSD 9C (GSD IXc) | Hepatic and testis isoform gamma subunit of phosphorylase kinase | PHKG2/16p11.2/AR | Growth retardation, hepatomegaly, hypotonia; cognitive delay [32,33] |
GSD 9D (GSD IXd) | Alpha subunit of muscle phosphorylase kinase | PHKA1/Xq13.1/XL | Muscle weakness, exercise-induced muscle pain and stiffness, muscle atrophy, elevated CK [3,30,32] |
GSD 10 (GSD X) | Muscle phosphoglycerate mutase | PGAM2/7p13/AR | Exercise intolerance with cramp or pain, rhabdo-myolysis, myoglobinuria, hyperuricemia, coronary arteriosclerosis [2,34] |
GSD 11 (GSD XI) | Lactate dehydrogenase A | LDHA/11p15.1/AR | Exercise-induced muscle cramps and pain, uterine muscle stiffness in pregnancy, psoriatic skin lesions, Elevated serum CK during myoglobinuria, with low serum lactate dehydrogenase [35,36,37] |
GSD 12 (GSD XII) | Fructose-1,6- bisphosphate aldolase | ALDOA/16p11.2/AR | Short stature dysmorphic face, myopathy; mental retardation; delayed puberty; hemolytic anemia, hepatosplenomegaly; rhabdomyolysis with febrile illness [38,39] |
GSD 13 (GSD XIII) | Beta-enolase | ENO3/17p13.2/AR | Exercise intolerance, myalgia, rhabdomyo-lysis with fatty infiltration [40,41] |
GSD 15 (GSD XV) | Glycogenin-1 | GYG1/3q24/AR | Weakness, arrhythmias, skeletal myopathy, cardiomyopathy [42,43] |
GSD 14 (Previously GSDXIV) | Phosphoglucomutase-1 | PGM1/1p31.3/AR | Hematological anomalies, hypoglycemia, growth retardation, and dilated cardio-myopathy [44,45] |
Fanconi–Bickel syndrome (GSD XI) | SLC2A2 | GLUT2/3q26.2/AR | Postprandial elevations of glucose and galactose, fasting hypoglycemia, hepatomegaly, proximal tubular nephropathy, glucosuria, short stature [46,47] |
PGK deficiency | PGK1 | PGK/Xq21.1/XL | Nonspherocytic hemolytic anemia, myopathy with rhabdomyolysis and neurological features, myopathy, rhabdomyolysis [48,49] |
Type of GSDs | General Lab Test and Imaging | Diagnostic Test | Genetic Test | Treatment and Management |
---|---|---|---|---|
GSD 0a | NA | NA | Biallelic PLP GYS2 variants | Protein-rich meals and bedtime consumption of uncooked cornstarch |
GSD 0b | NA | NA | Biallelic PLP GYS1 variants | |
GSD I | Kidney and liver function tests, lipids and uric acid levels, a complete blood count, and iron studies. Liver and kidney imaging, echocardiography | GSD Ia, G6Pase enzyme activity in liver tissue | Biallelic PLP G6PC1 variants (GSD Ia), biallelic PLP SLC37A4 (GSD Ib) | Angiotensin receptor blockers, low-purine diet, and Allopurinol for gout, G-CSF, and empagliflozin Liver transplantation |
GSD II | CK, AST, ALT, urine Glc4, BNP, and, when receiving ERT, IgG against recombinant protein levels. ECG, Echo, Chest X-Ray | GAA activity testing in blood, fibroblast, or muscle | Biallelic PLP variants in GAA | ERT, Respiratory muscle training, maximize clearance of airway secretions |
GSD III | Liver function tests, coagulation, Lipid, CK levels, echocardiography | GDE activity assay for liver and muscle, can be measured in leukocytes, erythrocytes, or cultured fibroblasts | Biallelic PLP AGL variants | Dietary management, hypoglycemia monitoring and muscle health support |
GSD IV | liver function tests, PT/INR, albumin, renal function panel, complete blood count, ammonia levels, AFP levels, USG, Bone density scan, physical therapy/occupational therapy | GBE activity assay in on fibroblast, liver or muscle and PB accumulation by PAS staining | Biallelic PLP GBE1 variants | Hepatitis A and B vaccinations. Prophylactic antibiotics for small bowel infections and urinary tract infections. Physical therapy and occupational therapy. Routinely screen for dysphagia (difficulty swallowing). Liver transplant if required |
GSD 5 | Serum CK and uric acid levels, Hb A1c, lipid profile. weakness and muscle evaluation. Assess ADLs and QoL | Myophosphorylase activity | Biallelic PLP PYGM | Carbohydrate rich diet, Sucrose to improve exercise tolerance. Exercise is helpful for chronic pain |
GSD 6 | AST, ALT, serum albumin and γ-glutamyl transferase levels, coagulation, blood glucose, and serum β-hydroxybutyrate monitoring | Phosphorylase activity in liver specimens | Biallelic PLP variants in PYGL | Dietary and symptomatic treatment |
GSD 7 | Phosphofructokinase activity in muscle | Biallelic PLP PFKM variants | Low-carbohydrate ketogenic diet. Exercise to avoid chronic pain | |
GSD 9 | AST, ALT, serum albumin and γ-glutamyl transferase levels, coagulation DEXA, and heart imaging. Blood glucose and serum β-hydroxybutyrate monitoring | Phosphorylase b kinase activity can be measured in liver, blood, and muscle (based on subtype). Enzyme activity in blood can be normal | Hemizygous PLP variant in PHKA2 (GSD IX A) biallelic PLP variants in PHKB (GSD IX B) | Dietary and symptomatic treatment |
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Mishra, K.; Kakhlon, O. Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs). Biomolecules 2024, 14, 1096. https://doi.org/10.3390/biom14091096
Mishra K, Kakhlon O. Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs). Biomolecules. 2024; 14(9):1096. https://doi.org/10.3390/biom14091096
Chicago/Turabian StyleMishra, Kumudesh, and Or Kakhlon. 2024. "Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs)" Biomolecules 14, no. 9: 1096. https://doi.org/10.3390/biom14091096