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Glycogen Storage Disease

GSD

There are numerous forms of glycogen storage diseases, but the common end-result is inability to store glycogen in either the liver and/or muscles due to enzyme deficiencies that are transmitted by an autosomal recessive pattern of inheritance. Symptoms are diverse, but hepatosplenomegaly, failure to thrive and hypoglycemia are the most common. The diagnosis is confirmed by genetic testing, while treatment depends on the subtype.


Presentation

Clinical presentation somewhat depends on the type of GSD and a broad classification into liver and muscle glycogenoses aids the physician in differentiating between various forms [8]. Symptoms may appear at any age, but peak in childhood, adulthood and mid-adolescence. Liver disease is present in patients with type I, III, IV, VI, IX, XI, and 0, hepatomegaly being the most prominent symptom [12]. Hypoglycemia, hyperlipidemia and growth retardation are commonly observed, but some symptoms are specific for certain subtypes, such as elevated blood lactate (type I), profound neutropenia (type Ib), ketosis (types VI and 0) and cardiomyopathy (type II). On the other hand, skeletal glycogenoses (types V, VII) are characterized by muscle cramping, fatigue, myoglobinuria during strenuous exercise and anemia. Pompe disease (type II) has a distinct clinical presentation, encompassing both muscular and hepatic manifestations, together with rapidly progressive cardiac and respiratory failure [4].

Congestive Heart Failure
  • heart failure Arrhythmia Variant with no cardiac involvement: Longer survival Liver involvement Pulmonary: Pneumonia Motor Hypotonia (88%) Respiratory distress (80%) Weakness (60%) Anesthesia 18 Succinylcholine: Increased risk Arrhythmia Hyperkalemia[neuromuscular.wustl.edu]
Exertional Syncope
  • We report a new muscle GSD0 patient, a Japanese girl, who had been suffering from recurrent attacks of exertional syncope accompanied by muscle weakness and pain since age 5 years until she died of cardiac arrest at age 12.[ncbi.nlm.nih.gov]
Decreased Diastolic Blood Pressure
Hepatomegaly
  • GSD should be suspected in a child with unexplained hepatomegaly and investigated accordingly.[ncbi.nlm.nih.gov]
  • They were ultimately found to have hepatomegaly, fasting hypoglycemia, mild elevation of transaminases and ketosis.[ncbi.nlm.nih.gov]
  • Most patients with the disease are thought to outgrow the childhood manifestations, which include hepatomegaly, poor growth, and ketosis with or without hypoglycemia.[ncbi.nlm.nih.gov]
  • Abdominal examination of all cases revealed abdominal distention and soft hepatomegaly which had bright echogenicity by ultrasound. Hypertriglyceridaemia was present in 93.6%, hyperlactacidaemia in 51.6% and hyperuricaemia in 19.4%.[ncbi.nlm.nih.gov]
  • Cardinal symptoms include fasting hypoglycemia, lactic acidosis and hepatomegaly as well as neutropenia.[ncbi.nlm.nih.gov]
Hand Stiffness
  • We report a 25-year-old man with glycogenosis III who presented with a progressive 2 year history of fatigue, hand stiffness and cramping.[ncbi.nlm.nih.gov]
Hand Muscle Weakness
  • Intrinsic hand muscle weakness is likely due to a combination of nerve and muscle dysfunction, a finding that may have implications for treatment.[ncbi.nlm.nih.gov]
Skin Lesion
  • We report a glycogen storage disease type 1b girl with biotin deficiency caused by an exclusive glucose-containing glycogen storage disease formula for years, presenting with the appearance of severe skin lesions, and diagnosed by urinary organic acid[ncbi.nlm.nih.gov]
Cesarean Section
  • Thus, a cesarean section was performed at 26 weeks of gestation. The delivered male infant weighing 412 g died at 2 days after birth. The patient's blood pressure had normalized within 3 months after delivery, while proteinuria persisted.[ncbi.nlm.nih.gov]
Neurologic Manifestation
  • In this study, we aimed to study the genetic and clinical characteristics of four patients with GSD IIIa from China, especially the neurological manifestations.[ncbi.nlm.nih.gov]

Workup

Making the diagnosis of GSD may be difficult, but patients with progressive liver disease and/or muscle cramping, fatigue and poor general condition without an identifiable cause, a high suspicion to one of the GSDs should be present. Initial laboratory findings may reveal elevated liver transaminases and impaired synthetic function, anemia, as well as hypoglycemia, elevated triglycerides, cholesterol, and lactate. The gold standard, however, is either biopsy or detection of reduced enzymatic activity in the target tissue, while magnetic resonance imaging (MRI) can provide important clues as well [11].

Fasting Hypoglycemia
  • The management of glycemic control remains a clinical challenge, requiring management of both fasting hypoglycemia from glycogen storage disease, as well as post-prandial hyperglycemia from diabetes mellitus.[ncbi.nlm.nih.gov]
  • Cardinal symptoms include fasting hypoglycemia, lactic acidosis and hepatomegaly as well as neutropenia.[ncbi.nlm.nih.gov]
  • Most affected individuals exhibit resolution of hepatomegaly, hypotonia, muscle weakness, risk of fasting hypoglycemia, and abnormal biochemical parameters before or at puberty.[emedicine.medscape.com]
  • The clinical presentation of GSD1b is characterized by hepatomegaly, failure to thrive, fasting hypoglycemia, and dyslipidemia.[ncbi.nlm.nih.gov]
Hypertriglyceridemia
  • […] be produced by glomerular hyperfiltration, TGF-beta expression which is induced by renin-angiotensin-aldosterone system (RAS) and uric acid, and the increase in both small dense LDL and modified LDL which is characteristic of GSD Iota(a) as well as hypertriglyceridemia[ncbi.nlm.nih.gov]
  • At age 18 years of age, she had marked hypertriglyceridemia (3860 mg/dL) and eruptive xanthomas and was treated with fenofibrate, atorvastatin, and fish oil.[ncbi.nlm.nih.gov]
  • Biological findings include hypoglycemia without acidosis, hypertriglyceridemia, and hypertransaminasemia during childhood.[orpha.net]
  • […] into alternative pathways resulting in 3 major metabolic consequences: [2] Hyperlacticacidemia, which develops as a byproduct of enhanced glycolysis Hyperuricemia, which arises due to shunting of glucose-6-phosphate into the pentose phosphate pathway Hypertriglyceridemia[online.epocrates.com]
  • […] treatment Management aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch), acidosis (restricted fructose and galactose intake, oral supplementation in bicarbonate), hypertriglyceridemia[orpha.net]
Glucose Decreased
  • In fact, consuming carbohydrates exacerbates exercise intolerance because glucose decreases the blood concentration of alternative fuels such as free fatty acids and ketones by increasing insulin concentrations.[doi.org]

Treatment

Treatment principles almost strictly depend on the type of GSD:

  • Management of type I depends on symptomatic therapy and dietary changes that comprise introduction of raw, uncooked cornstarch, which is profoundly effective in correcting hypoglycemia.
  • Type II (Pompe disease), although being one of the most severe forms, is one of the first GSDs to be successfully treated using recombinant human enzymes [4]. It is given every two weeks and its introduction into medical practice has significantly increased survival rates of patients with respiratory and cardiac symptoms [8].
  • Adequate dietary management of hypoglycemia is sufficient for the majority of patients suffering from type III GSD [5].
  • Treatment of type IV (Andersen disease) GSD relies on palliative care, since a rapidly progressive course is seen in many patients and terminal liver failure is often seen. In fact, liver transplantation is frequently necessary.
  • Prevention of strenuous exercise while maintaining an adequate level of physical activity is key in managing type V GSD in order to reduce the incidence of rhabdomyolysis but preserve physiological muscle tone. Numerous substances have been tested, including creatine, sucrose, ramipril and various dietary regimens, but a significant correlation with improvement has not been established [15].

Management of hypoglycemia through dietary changes and additional symptoms is imperative for other GSDs, but in general, this approach is favored across all subtypes so that the metabolic needs for glycogen and energy are fulfilled.

Prognosis

The prognosis of patients with GSDs significantly depend on the subtype. Type Ib patients may develop recurrent infections that can be fatal due to persistent neutropenia, while Pompe disease is often fatal during childhood due to respiratory and cardiac failure [4] [13]. Rapid liver failure that necessitates transplantation is seen in type IV patients, whereas a mild and relatively benign clinical course may be observed in type III and type VI [8]. Some types (I and VI) have been associated with hepatocellular carcinoma [14]. In all other forms, disease manifestations may range from benign and mild to severe and severely debilitating. For these reasons, it is important to identify the exact subtype in order to instate appropriate therapy and prevent further complications.

Etiology

Enzyme deficiency that impairs normal glycogen degradation is the principal cause of all GSDs (except in type 0, where glycogen synthase deficiency results in impaired glycogen storage in the liver) [10]. Enzyme deficiencies are acquired through autosomal recessive pattern of inheritance in virtually all types, but rare cases (type IX) have shown to occur as a result of X-linked transmission [8]. For all diseases, the exact enzyme deficiencies have been identified. Glucose-6-phosphatase (type I), acid alpha-glucosidase (type II), glycogen debranching enzyme (type III), glycogen branching enzyme (type IV), glycogen phosphorylase (type V), liver phosphorylase (type IV), phosphofructokinase (type VII), liver phosphorylase kinase (type IX) GLUT2 (type XI), glycogen synthase (type 0) and several other enzyme deficiencies have been established.

Epidemiology

Incidence and prevalence rates significantly depend on the subtype, but overall estimations suggest that 1 per 25,000 individuals develop some form of GSD [11]. Type II (Pompe disease) is estimated to develop in 1 per 40,000 births, whereas type III occurs in approximately 1 per 5,400 births, with a significant predilection toward Sephadric Jews of North Africa [4] [5]. On the other hand, some subtypes have shown to be extremely rare, like type XI and 0, as only a handful of cases described in literature [9] [10]. Gender distribution is usually diverse, but in type V, a male predominance is observed [8].

Sex distribution
Age distribution

Pathophysiology

The pathogenesis across all subtypes invariably includes inability to utilize glycogen as a source of energy due to deficiencies of enzymes that are either a part of its degradation or synthesis (type 0) [10]. Under physiological circumstances, excess glucose ingested by food is up to a certain extent converted to glycogen by the action of glycogen synthase (enzyme deficient in type 0) and stored principally in the liver, while the skeletal muscles are also a site of its storage [12]. Glycogen is further stored until the tissues in which it is stored reach maximal capacity (which is impaired in patients suffering from type IV GSD, as the enzyme responsible for its assembly, branching enzyme is deficient), but its conversion back to glucose in metabolic needs is an important source of fuel and provided rapid energy utilization. Various enzymes are involved in its breakdown and conversion to glucose, including debranching enzyme, liver and muscle phosphorylase kinases, acid maltase, phosphofructokinase, glucose-6-phosphatase and GLUT2 transporter [11]. All of these enzymes are deficient in certain types of GSDs, with the common end-result being inability of the liver and muscles to degrade glycogen and provide the necessary energy for metabolic functions, which manifests in a variety of symptoms, depending on the subtype and the severity of enzyme deficiency.

Prevention

Although exact enzyme deficiencies have been determined in virtually all subtypes, prevention of GSDs is currently not possible, as the triggers that are responsible for their development are unknown. Genetic counseling may be advisable for families with first-degree relatives that have GSDs, but prevention strategies should be focused on ensuring long-term management through adequate treatment.

Summary

Glycogen storage diseases (GSDs) result in impaired utilization of glycogen as a result of various enzyme deficiencies. Glycogen is converted from glucose in liver and skeletal muscles to some extent and these two organs are principally affected [1]. Because of its role in energy production and utilization by many tissues, numerous symptoms may be encountered. Up to today, 23 GSDs have been established [2], and are classified into [1-15]:

  • Type I, also known as Von Gierke disease, occurs either due to glucose-6-phosphatase (type Ia, seen in 90% of cases) or glucose-6-phosphatase translocase deficiency (type Ib), leading to symptoms such as growth retardation, hepatomegaly, hyperlipidemia, hypoglycemia, lactic acidemia and renal enlargement [3]. Additionally, impaired function of neutrophils is reported in patients with type Ib and severe neutropenia may lead to recurrent and potentially severe infections, as well as mucosal ulcerations [3]. Additional subtypes that have been included in this group include pyrophosphate translocase (type Ic) and glucose translocase deficiencies (type Id).
  • Type II (Pompe disease) develops as a result of acid alpha-glucosidase deficiency, a glycogen-degrading lysosomal enzyme, for which it is often classified into the group of lysosomal storage diseases (LSDs) [4]. Consequently, intralysosomal accumulation of glycogen occurs and causes a severe clinical presentation consisting of cardiac and respiratory failure that may be fatal within a few years after their onset [4].
  • Type III (known as either Forbes of Cori disease) is characterized by glycogen debranching enzyme deficiency, which is essential for glycogen degradation from the liver and muscles. Type IIIa (seen in 85% of individuals) is distinguished by both hepatic and skeletal system manifestations accompanied by hypoglycemia and progressive cardiac disease, whereas type IIIb includes liver symptoms only [5].
  • Type IV (Andersen disease) stems from glycogen branching enzyme deficiency and the clinical course is rapidly progressive and often fatal in most patients. Liver transplantation is frequently indicated, as severe hepatic disease ensues within a short period of time [6].
  • Type V (McArdle disease) is a GSD in which the skeletal muscles are principally affected, as the enzyme that is supposed to break down glycogen, myophosphorylase (or glycogen phosphorylase), is not present, leading to cramping, myalgia, profound premature fatigue and elevations of creatine kinase (CK) [7]. For unknown reasons, a gender predilection toward males is observed [8].
  • Type VI (Hers disease) manifests similarly to other GSDs, including hyperlipidemia, hypoglycemia and ketosis, but it is often considered a benign form of disease. Deficiency of liver phosphorylase is the underlying cause [8].
  • Type VII (Tarui disease) is most commonly seen in Ashkenazi Jews and the Japanese. Deficiency of phosphofructokinase is the main pathological mechanism [8].
  • Type IX GSD, unlike all other forms, is transmitted both by autosomal recessive and X-linked patterns of inheritance. Type IX stems from deficiency of liver phosphorylase kinase. Clinically, it is almost identical to type VI, but the course of disease ranges from mild to severe and life-threatening.
  • Type XI (Fanconi-Bickel syndrome) is an extremely rare GSD that develops due to impaired function of glucose transporters (GLUT2) [9].
  • Type 0 (glycogen synthase deficiency) is distinguished from all other GSDs by absence of liver symptoms, since glycogen synthase is responsible for storage of glycogen in the liver [10]. This GSD is even more rare than type XI and only about 20 cases have been reported in literature [10].

Although each type is distinguished by deficiency of different enzymes, signs and symptoms that reflect hepatic and skeletal pathology without an evident cause can rise clinical suspicion. The initial diagnosis can be made by clinical criteria, whereas confirmation can be determined by genetic testing that may reveal mutated genes that led to enzyme deficiencies. Treatment depends on the subtype [8]. For some GSDs, moderate exercise, vitamin supplementation and appropriate dietary changes are only options. Maintenance of blood glucose through introduction of corn starch is highly effective for type III and type I, although fructose and galactose intake should be limited for type I patients. On the other hand, enzyme supplementation has been introduced to patients suffering from type II GSD and has markedly improved patient outcomes [4]. In general, the prognosis of GSDs range from mild to severe and rapidly fatal across different subtypes [8], but early recognition of the disease may prevent complications such as hepatic, respiratory and cardiac failure, which will invariably prolong the patient's life.

Patient Information

Today, more than 20 glycogen storage diseases (GSDs) are described in literature and they all cause the same metabolic disturbance - disruption of normal glycogen storage and inability of the body to utilize this source of energy for its needs. Glycogen is synthesized when excess concentrations of glucose are introduced through food, but the body can store limited amounts of glycogen. The liver and the skeletal muscles are sites where glycogen can be stored, but in the setting of various GSDs, enzymes that are involved in its creation from glucose are deficient. Consequently, impaired glycogen conversion to glucose leads to very low glucose levels (hypoglycemia), one of the most important manifestations of this group of diseases. Enzyme deficiencies occur as a result of genetic mutations that are transferred from parent to their child through an autosomal recessive pattern of inheritance. This means that the disease is present only if both parent transfer have a defective gene copy and transfer it to their child, whereas only one transferred copy implies that the child is a carrier but does not develop any symptoms. GSDs roughly develop in approximately 1 per 25,000 individuals and gender distribution is mostly equal. Based on clinical symptoms, GSDs are roughly divided into those that involve the liver and those in whom symptoms are mostly related to skeletal muscles, but both organs may be affected across various types. Liver enlargement, increased circulating values of lipids, and decreased blood sugar are the most common manifestations of GSDs, while muscle cramping, profound fatigue and weakness are also frequently encountered. Making the diagnosis may be quite difficult, but liver or skeletal muscle symptoms together with hypoglycemia that do not have an identifiable cause should rise suspicion toward GSDs. A definite diagnosis can be made by either biopsy or genetic testing for deficient enzymes. Treatment principles depend on the subtype. Changes in dietary habits through introduction of uncooked cornstarch is a very useful method to recover from persistent low sugar levels, whereas symptomatic therapy and even use of recombinant human enzymes has been accomplished in some subtypes. Many patients, however, suffer a poor prognosis, as several subtypes can be fatal within years due to heart or liver failure, which is why early recognition of this disease is imperative in prolonging survival rates.

References

Article

  1. Shin YS. Glycogen storage disease: clinical, biochemical, and molecular heterogeneity. Semin Pediatr Neurol. 2006;13(2):115-120.
  2. Vega AI, Medrano C, Navarrete R, Desviat LR, Merinero B, Rodriguez-Rombo P, et al. Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing. Genetics in Medicine. 2016; Feb 25 [Epub ahead of print].
  3. Chou JY. The molecular basis of type 1 glycogen storage diseases. Curr Mol Med. 2001;1(1):25-44.
  4. Schoser B, Hill V, Raben N. Therapeutic approaches in glycogen storage disease type II/pompe disease. Neurotherapeutics. 2008;5(4):569-578.
  5. Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med. 2010;12(7):446-463.
  6. Moses SW, Parvari R. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies. Curr Mol Med. 2002;2(2):177-188.
  7. Andreu A, Nogales-Gadea G, Cassandrini D, Arenas J, Bruno C. McArdle disease: molecular genetic update. Acta Myologica. 2007;26(1):53-57.
  8. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
  9. Santer R, Steinmann B, Schaub J. Fanconi-Bickel syndrome--a congenital defect of facilitative glucose transport. Curr Mol Med. 2002;2(2):213-227.
  10. Weinstein DA, Correia CE, Saunders AC, Wolfsdorf JI. Hepatic glycogen synthase deficiency: an infrequently recognized case of ketotic hypoglycemia. Molecular genetics and metabolism. 2006;87(4):284-288.
  11. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011
  12. Aster, JC, Abbas, AK, Robbins, SL1, Kumar, V. Robbins basic pathology. Ninth edition. Philadelphia, PA: Elsevier Saunders; 2013.
  13. Kannourakis G. Glycogen storage disease. Semin Hematol. 2002;39(2):103-106.
  14. Manzia TM, Angelico R, Toti L, Cillis A, Ciano P, Orlando G, Anselmo A, Angelico M, Tisone G. Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case reports. Transplant Proc. 2011;43(4):1181-1183.
  15. Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). Cochrane Database Syst Rev. 2014;(11):CD003458.

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Last updated: 2019-07-11 20:37