Glycogen Storage Disorders

Overview

Definition

Glycogen storage disorders (GSDs) are genetic defects causing enzyme deficiencies that result in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, muscle, or heart disease from abnormal glycogen deposition in tissues and episodic hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia (in most disorders), as the body cannot use glycogen as a source of energy.

Epidemiology

• Overall approximately 1 case per 20,000–40,000 live births in the US
• GSD I incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 100,000 births
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency 1 in 20,000 Ashkenazi Jews
  • Affects both sexes equally
• GSD III more frequent in individuals of North African Jewish descent
• GSD VI more common in the Old Order Mennonite population than the general population

Classification

• GSD 0: Glycogen synthase Glycogen synthase An enzyme that catalyzes the transfer of d-glucose from udp glucose into 1, 4-alpha-d-glucosyl chains. Glycogen Metabolism deficiency
• GSD I (von Gierke disease): lack of the enzyme glucose-6-phosphatase Glucose-6-phosphatase An enzyme that catalyzes the conversion of d-glucose 6-phosphate and water to d-glucose and orthophosphate. Gluconeogenesis (G6Pase)
• GSD II (Pompe disease): deficiency of the enzyme alpha-1,4-glucosidase
• GSD III (Cori disease): deficiency of glycogen debranching enzyme Debranching enzyme 1, 4-alpha-d-glucan-1, 4-alpha-d-glucan 4-alpha-d-glucosyltransferase/dextrin 6 alpha-d-glucanohydrolase. An enzyme system having both 4-alpha-glucanotransferase and amylo-1, 6-glucosidase activities. As a transferase it transfers a segment of a 1, 4-alpha-d-glucan to a new 4-position in an acceptor, which may be glucose or another 1, 4-alpha-d-glucan. As a glucosidase it catalyzes the endohydrolysis of 1, 6-alpha-d-glucoside linkages at points of branching in chains of 1, 4-linked alpha-d-glucose residues. Amylo-1, 6-glucosidase activity is deficient in glycogen storage disease type III. Glycogen Metabolism
• GSD IV (Andersen disease): deficiency of glycogen branching enzyme Branching enzyme An enzyme that catalyzes the formation of udp glucose from utp plus glucose 1-phosphate. Glycogen Metabolism
• GSD V (McArdle disease): deficiency of muscle glycogen Muscle glycogen Glycogen Metabolism phosphorylase
• GSD VI (Hers disease): hepatic glycogen phosphorylase Glycogen phosphorylase An enzyme that catalyzes the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1, 4-glycosidic bond. This enzyme exists in two forms: an active phosphorylated form ( phosphorylase A) and an inactive un-phosphorylated form (phosphorylase B). Both A and B forms of phosphorylase exist as homodimers. In mammals, the major isozymes of glycogen phosphorylase are found in muscle, liver and brain tissue. Glycogen Metabolism deficiency
• GSD VII (Tarui disease): phosphofructokinase (PFK) deficiency
• GSD IX: deficiency in phosphorylase kinase
• GSD X: deficiency in phosphoglycerate (PG) mutase
• GSD XI: deficiency of muscle lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma ( LDH LDH Osteosarcoma)
• GSD XII: aldolase Aldolase Becker Muscular Dystrophy A deficiency
• GSD XIII: beta-enolase deficiency
• GSD XV: glycogenin-1 deficiency

Von Gierke Disease

Glycogen storage disorder I (von Gierke disease) is caused by mutations that lead to enzyme deficiencies; these result in excess glycogen and fat accumulation in tissues and hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia.

Etiology

• Both are autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance
• GSD type 1a: 
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in G6PC gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics → deficiency of the enzyme G6Pase in 80% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • A mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the SLC37A4   gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics causes the same deficiency in the other 20%.
• GSD type 1b: mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in glucose-6-phosphate Glucose-6-phosphate An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. Gluconeogenesis transporter

Clinical presentation

• Generally similar between both types
• Type Ib is also associated with:
  • Chronic neutropenia Chronic neutropenia Severe Congenital Neutropenia
  • Recurrent bacterial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Oral and intestinal mucosal ulcers 
• Manifestations:
  • Mostly related to liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy issues:
    • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
    • Hepatomegaly
  • Delayed growth and puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea caused by pseudocolitis; steatorrhea Steatorrhea A condition that is characterized by chronic fatty diarrhea, a result of abnormal digestion and/or intestinal absorption of fats. Diarrhea
  • Epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis due to impaired platelet function
  • Abdominal distension
  • Round cheeks Cheeks The part of the face that is below the eye and to the side of the nose and mouth. Melasma (caused by fat deposits)
  • Xanthomas Xanthomas Lipid Disorders on extremities due to hyperlipidemia (HLD)
  • Aphthous ulcers
  • HLD

Diagnosis

• Laboratory studies after a monitored fast:
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Lactic acidosis Lactic Acidosis Oxazolidinones
  • Low insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
  • ↑ Fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance and beta-hydroxybutyrate Beta-hydroxybutyrate Butyric acid substituted in the beta or 3 position. It is one of the ketone bodies produced in the liver. Ketone Body Metabolism
  • ↑ Glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions
  • ↑ Cortisol Cortisol Glucocorticoids
  • ↑ Growth hormone (GH)
• Glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions and epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs fail to increase the blood glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance level (BGL)
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma with genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies or assay for G6Pase level

Management

• Frequent meals and snacks to prevent hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Continuous nocturnal gastric infusion
  • Nighttime feedings (cornstarch)
• Dietary avoidance of galactose Galactose An aldohexose that occurs naturally in the d-form in lactose, cerebrosides, gangliosides, and mucoproteins. Deficiency of galactosyl-1-phosphate uridyltransferase causes an error in galactose metabolism called galactosemia, resulting in elevations of galactose in the blood. Lactose Intolerance and fructose (require G6Pase for metabolism)
• Allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs for hyperuricemia Hyperuricemia Excessive uric acid or urate in blood as defined by its solubility in plasma at 37 degrees c; greater than 0. 42 mmol per liter (7. 0 mg/dl) in men or 0. 36 mmol per liter (6. 0 mg/dl) in women. Gout

Complications

• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
• Renal stones or failure
• Gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or “gout flare,” followed later by chronic deforming arthritis. Gout
• Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• Respiratory distress due to metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
• Hepatic adenoma Hepatic adenoma A benign epithelial tumor of the liver. Benign Liver Tumors

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Early diagnosis and treatment can result in normal growth and puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty.
• Affected women have had successful pregnancies and childbirth.

Pompe Disease

Glycogen storage disorder II (Pompe disease) is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance lysosomal storage disorder caused by a pathogenic variant in GAA. The defect results in an enzyme deficiency of alpha-glucosidase, with subsequent glycogen accumulation Glycogen Accumulation Cellular Accumulations in cardiac and skeletal muscle.

Clinical presentation

• Infantile onset: 
  • Part of the newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care panel in many states in the US
  • Onset before 12 months of age with:
    • Hypotonia Hypotonia Duchenne Muscular Dystrophy
    • Generalized muscle weakness
    • Feeding difficulties
    • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive ( FTT FTT Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive)
    • Respiratory distress
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia due to hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy ( HCM HCM Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy)
• Late onset:
  • After 12 months of age (or before 12 months of age without cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types (CM))
  • Characterized by:
    • Proximal muscle weakness Proximal Muscle Weakness Lambert-Eaton Myasthenic Syndrome
    • Respiratory insufficiency
    • No significant cardiac involvement
• No hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia (as in GSD I); this disorder affects mostly muscle and heart

Diagnosis

• Newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn testing of acid alpha-glucosidase enzyme activity on dried blood spots
• Confirmation by pathogenic variants in GAA on molecular genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies

Management

• Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID) treatment (ERT) with alglucosidase alfa
  • Reduces death by 79%–95%
  • Reduces need for invasive ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing
  • Improves cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology skills
• Respiratory support if needed: continuous positive airway Airway ABCDE Assessment pressure ( CPAP CPAP A technique of respiratory therapy, in either spontaneously breathing or mechanically ventilated patients, in which airway pressure is maintained above atmospheric pressure throughout the respiratory cycle by pressurization of the ventilatory circuit. Noninvasive Ventilation), BiPap BiPAP Noninvasive Ventilation, and/or tracheostomy Tracheostomy Surgical formation of an opening into the trachea through the neck, or the opening so created. Laryngomalacia and Tracheomalacia
• Physical and occupational therapy Occupational Therapy Skilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living. Fetal Alcohol Spectrum Disorder for muscle weakness
• Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies for families
• Prevent secondary complications by:
  • Managing infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease aggressively
  • Keeping immunizations up to date
  • Prophylaxis Prophylaxis Cephalosporins for respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus ( RSV RSV Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus): palivizumab Palivizumab A humanized monoclonal antibody and antiviral agent that is used to prevent respiratory syncytial virus infections in high risk pediatric patients. Respiratory Syncytial Virus until age 2
• Routine monitoring:
  • Respiratory, cardiovascular, and musculoskeletal status
  • Nutrition and feeding
  • Renal function
  • Hearing testing for sensorineural hearing loss Sensorineural hearing loss Hearing loss resulting from damage to the cochlea and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the auditory nerve and its connections in the brainstem. Hearing Loss (SNHL)
• Avoid harmful circumstances:
  • Volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration
  • Exposure to infection
  • Agents that worsen left ventricular outflow obstruction Ventricular Outflow Obstruction Occlusion of the outflow tract in either the left ventricle or the right ventricle of the heart. This may result from congenital heart defects, predisposing heart diseases, complications of surgery, or heart neoplasms. Tetralogy of Fallot:
    • Digoxin Digoxin A cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. Cardiac Glycosides
    • Inotropes Inotropes Hypoplastic Left Heart Syndrome (HLHS)
    • Diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
    • Afterload-reducing agents
• Experimental gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics therapy strategies: currently being developed

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Infantile onset:
  • Death from heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) before 1 year if not treated
  • ERT improves survival.
• Late-onset disease:
  • If diagnosed in childhood → survival up to age 30
  • If diagnosed in adulthood → survival to 50–60 years of age

Cori Disease

Glycogen storage disorder III (Cori disease) is caused by a deficiency in glycogen debranching enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes and leads to glycogen deposition in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, muscle, and heart.

Etiology

• Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations to amylo-alpha-1,6-glucosidase ( debranching enzyme Debranching enzyme 1, 4-alpha-d-glucan-1, 4-alpha-d-glucan 4-alpha-d-glucosyltransferase/dextrin 6 alpha-d-glucanohydrolase. An enzyme system having both 4-alpha-glucanotransferase and amylo-1, 6-glucosidase activities. As a transferase it transfers a segment of a 1, 4-alpha-d-glucan to a new 4-position in an acceptor, which may be glucose or another 1, 4-alpha-d-glucan. As a glucosidase it catalyzes the endohydrolysis of 1, 6-alpha-d-glucoside linkages at points of branching in chains of 1, 4-linked alpha-d-glucose residues. Amylo-1, 6-glucosidase activity is deficient in glycogen storage disease type III. Glycogen Metabolism)
• Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance

Clinical presentation

• Symptoms start in the 1st few years of life.
• Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
• Hepatomegaly, elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
• Cardiomegaly Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly

Diagnosis

• Elevated CK levels
• Muscle of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 
• Genetic analysis

Management

• Dietary: high-protein diet
• Medications
  • IV glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance if needed
  • Vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies to prevent bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types disease
• Referrals: nutritional consult 
• Surgery: hepatic transplant for severe cases

Complications

• Hepatic adenomas and carcinomas
• Cardiac arrhythmias
• Polycystic ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy without impact on fertility (successful pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care is possible)

McArdle Disease

Glycogen storage disease Glycogen storage disease A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. Benign Liver Tumors V (McArdle disease), also known as myophosphorylase deficiency, is an autosomal-recessive disorder caused by mutations in the muscle isoform of phosphorylase ( muscle glycogen Muscle glycogen Glycogen Metabolism phosphorylase, or PYGM) located at 11q13.

Clinical presentation

• Symptoms begin in childhood between infancy and 11 years of age; diagnosis is often delayed until adulthood.
  • Exercise-induced muscle pain Muscle Pain Ion Channel Myopathy and cramps Cramps Ion Channel Myopathy in the 1st few minutes
  • “2nd wind”: 
    • After brief exercise causing pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, can resume with little or no discomfort
    • Occurs after the 1st 10 minutes of exertion due to alternative energy source utilization (e.g., fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance)
  • Often misdiagnosed as “growing pains”—psychological or other rheumatic/neuromuscular disorders
• Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis → acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury from myoglobinuria Myoglobinuria The presence of myoglobin in urine usually as a result of rhabdomyolysis. Rhabdomyolysis
• Laboratory findings:
  • Myoglobinuria Myoglobinuria The presence of myoglobin in urine usually as a result of rhabdomyolysis. Rhabdomyolysis 
  • Elevated CK

Diagnosis

• Forearm Forearm The forearm is the region of the upper limb between the elbow and the wrist. The term “forearm” is used in anatomy to distinguish this area from the arm, a term that is commonly used to describe the entire upper limb. The forearm consists of 2 long bones (the radius and the ulna), the interosseous membrane, and multiple arteries, nerves, and muscles. Forearm: Anatomy exercise test 
  • Nonischemic test of 1-second handgrips every other second for 1 minute
  • A flat venous lactate curve with an increase in ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance is diagnostic.
• Muscle biopsy Muscle Biopsy Trichinella/Trichinellosis: 
  • Histologic staining shows a lack of myophosphorylase.
  • May have up to 10% normal residual enzyme activity
  • A biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma may also show regenerating fibers with a fetal isozyme that is immunologically different from mature muscle phosphorylase.
• Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies ( DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure sequencing): mutations in the PYGM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics

Management

• Supervised exercise to gradually increase exercise capacity
• Minimal benefit in exercise tolerance Tolerance Pharmacokinetics and Pharmacodynamics with:
  • Oral sucrose or carbohydrate-rich diet
  • Supplementation with creatine Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury (controversial)

Complications

• Kidney failure
• Compartment syndrome Compartment Syndrome Compartment syndrome is a surgical emergency usually occurring secondary to trauma. The condition is marked by increased pressure within a compartment that compromises the circulation and function of the tissues within that space. Compartment Syndrome (CS)

Comparison Table