GLCOGEN STORAGE DISORDERS

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GLCOGEN STORAGE DISORDERS

  1. 1. GLYCOGEN STORAGE DISORDERS
  2. 2. GSD  Inherited disorders of glycogen metabolism.  Any Enzyme can be involved.  Can affect synthesis and degradation .  glycogen in abnormal quantity or quality or both .  Categorized as numeric type in chronological order they discovered.  Frequency of all forms 1 in 20,000 live births.
  3. 3. TYPESOF GSD  The glycogen storage diseases (GSDs) and related disorders are caused by defects of glycogen degradation, glycolysis and, paradoxically, glycogen synthesis.  They are all called glycogenoses, although not all affect glycogen breakdown.  Glycogen, an important energy source, is found in most tissues, but is especially abundant in liver and muscle.  In the liver, glycogen serves as a glucose reserve for the maintenance of normoglycemia.  In muscle, glycogen provides energy for muscle contraction.  Despite some overlap, the GSDs can be divided in three main groups: those affecting liver, those affecting muscle, and those which are generalized .  GSDs are denoted by a Roman numeral that reflects the historical sequence of their discovery, by the deficient enzyme, or by the name of the author of the first description.
  4. 4. liver glycogen storage disorders  GSD I, the hepatic presentations of GSD III, GSD IV, GSD VI, the liver forms of GSD IX, and GSD 0.  GSD I, III, VI, and IX present with hypoglycemia, marked hepatomegaly,and growth retardation.  GSD I is the most severe affecting both glycogen breakdown and gluconeogenesis. In GSD Ib there is additionally a disorder of neutrophil function.  Most patients with GSD III have a syndrome that includes hepatopathy, myopathy, and often cardiomyo pathy.  GSD VI and GSD IX are the least severe: there is only a mild tendency to fasting hypoglycemia, liver size normalises with age, and patients reach normal adult height.  GSD IV manifests in most patients in infancy or childhood as hepatic failure with cirrhosis leading to end-stage liver disease.  GSD 0 presents in infancy or early childhood with fasting hypoglycemia and ketosis and, in contrast, with postprandial hyperglycemia and hyperlactatemia.  Treatment is primarily dietary and aims to prevent hypoglycemia and suppress secondary metabolic decompensation. This usually requires frequent feeds by day, and in GSD I and in some patients with GSD III, continuous nocturnal gastric feeding.
  5. 5. muscle glycogenoses  two clinical groups.  The first comprises GSD V, GSD VII, the muscle forms of GSD IX, phosphoglycerate kinase deficiency , GSD X, GSD XI, GSD XII and GSD XIII.  Characterised by exercise intolerance with exercise-induced myalgia and cramps, which are often followed by rhabdomyolysis and myoglobinuria; all symptoms are reversible with rest.  Disorders in the second group, consisting of the myopathic form of GSD III, and rare neuromuscular forms of GSD IV, manifest as sub-acute or chronic myopathies, with weakness of trunk, limb, and respiratory muscles.  Involvement of other organs (erythrocytes, central or peripheral nervous system, heart, liver) is possible, as most of these enzymes defects are not confined to skeletal
  6. 6. Generalized glycogenoses  GSD II, caused by the deficiency of a lysosomal enzyme, and Danon disease due to the deficiency of a lysosomal membrane protein.  Recent work on myoclonus epilepsy with Lafora bodies ( Lafora disease) suggests that this is a glycogenosis, probably due to abnormal glycogen synthesis.  GSD II can be treated by enzyme replacement therapy, but there is no specific treatment for Danon and Lafora disease
  7. 7. THE LIVER GLYCOGENOSES
  8. 8. The Liver Glycogenoses  The liver GSDs comprise GSD I, the hepatic presentations of GSD III, GSD IV, GSD VI, the liver forms of GSD IX, and GSD 0.  GSD I, III, VI, and IX present with similar symptoms during infancy, with hypoglycemia, marked hepatomegaly, and retarded growth.  GSD I is the most severe of these four conditions because not only is glycogen breakdown impaired, but also gluconeogenesis.  Most patients with GSD III have a syndrome that includes hepatopathy, myopathy, and often cardiomyopathy.  GSD IV manifests in most patients in infancy or childhood as hepatic failure with cirrhosis leading to end-stage liver disease.  GSD VI and the hepatic forms of GSD IX are the mildest forms: there is only a mild tendency to fasting hypoglycemia, liver size normalises with age, and patients reach normal adult height.  GSD 0 presents in infancy or early childhood with fasting hypoglycemia and ketosis contrasting with postprandial hyperglycemia and hyperlactatemia.
  9. 9. Glycogen Storage Disease Type I (Glucose-6-Phosphatase of Translocase Deficiency)  GSD I, first described by von Gierke.  GSD Ia caused by deficiency of the catalytic subunit of glucose-6- phosphatase (G6Pase).  GSD Ib, due to deficiency of the endoplasmic reticulum (ER) glucose-6-phosphate (G6P) translocase.  There is controversy about the existence of ER phosphate translocase deficiency (GSD Ic) and ER glucose transporter deficiency (GSD Id) as distinct entities.  The term GSD Ib includes all GSD I non-a forms.
  10. 10. Clinical Presentation  Neonate-hypoglycemia , lactic acidosis.  Infancy- hepatomegaly , hypoglycemic seizures .  Doll like features-obesity , prominent cheeks , thin extremities ,protuberent abdomen, hypotrophic muscles, and growth delay .  Profound hypoglycemia and lactic acidosis elicited by trivial events.  Liver changes.  Renomegaly.  Spleen normal.  Bleeding tendency.  Skin xanthomas.  Gouty arthritis.  patients with GSD Ib develop neutropenia .  GSD Ib patients show symptoms of inflammatory bowel disease (IBD).
  11. 11. Metabolic Derangement  Hypoglycemia occurs during fasting as soon as exogenous sources of glucose are exhausted.  Hyperlactatemia is a consequence of excess G6P that cannot be hydrolysed to glucose and is further metabolised in the glycolytic pathway, ultimately generating pyruvate and lactate.  Substrates such as galactose, fructose and glycerol need liver G6Pase to be metabolised to glucose. Consequently ingestion of sucrose and lactose results in hyperlactatemia, with only a small rise in blood glucose .  serum of untreated patients has a milky appearance due to hyperlipidemia.  Hyperuricemia is a result of both increased production and decreased renal clearance.  Halmarks of disease are hypoglycemia,lactic acidosis,hyperlipidemia,hyperurecemia.
  12. 12. Genetics&Diagnosis  GSD Ia and Ib are autosomal recessive disorders.  gene encoding G6Pase (G6PC) was identified on chromosome 17q21.  the gene encoding the G6P transporter (G6PT) was identified on chromosome 11q23.  enzyme studies in liver tissue obtained by biopsy are now usually un-necessary since the diagnosis can be based on clinical and biochemical findings combined with DNA investigations in leukocytes.  Identification of mutations in either G6PC or G6PT alleles of a GSD I index case allows reliable prenatal DNAbased diagnosis in chorionic villus samples.
  13. 13. Dietary Treatment  The goal of treatment is, as far as possible, to prevent hypoglycemia, thus limiting secondary metabolic derangements.  Initially, treatment consisted of frequent carbohydrate- enriched meals during day and night.  In 1974, continuous nocturnal gastric drip feeding (CNGDF) via a nasogastric tube was introduced, allowing both patients and parents to sleep during the night .  In 1984 uncooked cornstarch (UCCS), from which glucose is more slowly released than from cooked starch, was introduced .  stringent maintenance of normolactatemia by complete avoidance of lactose and fructose ingestion.  Special attention should be directed to calcium (limited milk intake) and vitamin D.  Increased carbohydrate metabolism needs an adequate supply of vitamin B1.  During surgery,-iv fluids.
  14. 14. Pharmacological Treatment  Until recently, (sodium)bicarbonate was recommended to reduce hyperlactatemia. Bicarbonate also induces alkalisation of the urine, thereby diminishing the risk of urolithiasis and nephrocalcinosis.  However, it was found that a progressive worsening of hypocitraturia occurs so that alkalisation with citrate may be even more beneficial in preventing or ameliorating urolithiasis and nephrocalcinosis.  Uric acid is a potent radical scavenger and it may be a protective factor against the development of atherosclerosis . Consequently, it is recommended to accept a serum uric acid concentration within the high normal range. To prevent gout and urate nephropathy, however, a xanthine-oxidase inhibitor (allopurinol) should be started if it exceeds this.  If persistent microalbuminuria is present, a (long-acting) angiotensin converting enzyme (ACE) inhibitor should be started to reduce or prevent further deterioration of renal function. Additional blood pressure lowering drugs should be used if blood pressure remains above the 95th percentile for age.  triglyceride- lowering drugs (nicotinic acid, fibrates) are indicated only if severe hypertriglyceridemia persists.  prophylaxis with cotrimoxazol may be of benefit in symptomatic patients or in those with a neutrophil count < 500 .  granulocyte colony-stimulating factor GCSF
  15. 15. Follow-up, Complications, Prognosis,  Proximal and distal renal tubular as well as glomerular functions are at risk.  Single or multiple liver adenomas may develop in the second or third decade.  Osteopenia.  Anemia.  Polycystic ovaries (PCOs).  Despite severe hyperlipidemia, cardiovascular morbidity and mortality is infrequent.  Depressive illness.
  16. 16. Glycogen Storage Disease Type III (Debranching Enzyme Deficiency)  The release of glucose from glycogen requires the activity of both phosphorylase and glycogen debranching enzyme (GDE).  known as Cori or Forbes disease.  Autosomal recessive disorder due to deficiency of GDE which causes storage of glycogen with an abnormally compact structure, known as phosphorylase limit dextrin.
  17. 17. Clinical Presentation  Hepatic Presentation  Hepatomegaly, short stature, hypoglycemia, and hyperlipidemia predominate in children, may be indistinguishable from GSD I.  Splenomegaly can be present.  kidneys are not enlarged and renal function is normal.  With increasing age, these symptoms improve in most GSD III patients and may disappear around puberty.
  18. 18. Myopathic Presentation  Clinical myopathy may not be apparent in infants or children, although some show hypotonia and delayed motor milestones.  Myopathy often appears in adult life, long after liver symptoms have subsided.  Adult-onset myopathies may be distal or generalised.  Patients with distal myopathy develop atrophy of leg and intrinsic hand muscles, often leading to the diagnosis of motor neurone disease or peripheral neuropathy .  The course is slowly progressive and the myopathy is rarely crippling.
  19. 19. Contd,  Muscle biopsy typically shows a vacuolar myopathy.  The vacuoles contain PAS-positive material and corresponds to large pools of glycogen, most of which is free in the cytoplasm.  However, some of the glycogen is present within lysosomes.  Biochemical analysis shows greatly increased concentration of phosphorylase- limit dextrin, as expected.
  20. 20. Metabolic Derangement  GDE is a bifunctional enzyme, with two catalytic activities, oligo1,4- glucantransferase and amylo-1,6- glucosidase.  After phosphorylase has shortened the peripheral chains of glycogen to about four glycosyl units, these residual stubs are removed by GDE in two steps.  A maltotriosyl unit is transferred from a donor to an acceptor chain (transferase activity), leaving behind a single glucosyl unit, which is hydrolysed.
  21. 21. Metabolic Derangement  During infancy and childhood patients suffer from fasting hypoglycemia, associated with ketosis and hyperlipidemia.  Serum transaminases are also increased in childhood but decrease to (almost) normal values with increasing age.  In contrast to GSD I, blood lactate concentration is normal.  Elevated levels of serum creatine kinase (CK) and aldolase suggest muscle involvement, but normal values do not exclude the future development of myopathy.
  22. 22. Genetics& Diagnosis  The gene for GDE (GDE) is located on chromosome 1p21.  Diagnosis is based on enzyme studies in leukocytes, erythrocytes and/or fibroblasts, combined with DNA investigations in leukocytes.  Prenatal diagnosis is possible by identifying mutations in the GDE gene if these are already known.
  23. 23. Treatment  The main goal of dietary treatment is prevention of hypoglycemia and correction of hyperlipidemia.  Dietary management is similar to GSD Ia but, since the tendency to develop hypoglycemia is less marked, only some younger patients will need continued nocturnal gastric drip feeding, and a late evening meal and/or uncooked corn starch will be sufficient to maintain normoglycemia during the night.  In GSD III (as opposed to GSD I), restriction in fructose and galactose is unnecessary .  Dietary protein intake can be increased since no renal dysfunction exists. This would not only have a beneficial effect on glucose homeostasis, but also on atrophic myopathic muscles.
  24. 24. Complications, Prognosis  With increasing age, both clinical and biochemical abnormalities gradually disappear in most patients; parameters of growth normalise, and hepatomegaly usually disappears after puberty.  In older patients, however, liver fibrosis may develop into cirrhosis.  In about 25% of these patients, liver adenoma may occur, and transformation into hepatocellular carcinoma has been described, although this risk is apparently small.  Liver transplantation has been performed in patients with end-stage cirrhosis and/or hepatocellular carcinoma .
  25. 25. Glycogen Storage Disease Type IV (Branching Enzyme Deficiency)  GSD IV, or Andersen Disease, is an autosomal recessive disorder due to a deficiency of glycogen branching enzyme (GBE).  Deficiency of GBE results in the formation of an amylopectin-like compact glycogen molecule with fewer branching points and longer outer chains.  Patients with the classical form of GSD IV develop progressive liver disease early in life.  The non-progressive hepatic variant of GSD IV is less frequent and these patients usually survive into adulthood.  Besides these liver related presentations, there are rare neuro muscular forms of GSD IV.
  26. 26. Clinical Presentation Hepatic Forms  Patients are normal at birth and present generally in early childhood with hepatomegaly, failure to thrive, and liver cirrhosis.  The cirrhosis is progressive and causes portal hypertension, ascites, and oesophageal varices.  Some patients may also develop hepatocellular carcinoma .  Life expectancy is limited due to severe progressive liver failure and – without liver transplantation – death generally occurs when patients are 4 to 5 years of age .  Patients with the non-progressive form present with hepatomegaly and sometimes elevated transaminases.  Although fibrosis can be detected in liver biopsies, this is apparently non-progressive.  No cardiac or skeletal muscle involvement is seen.  These patients have normal parameters for growth.
  27. 27. Neuromuscular Forms  four clinical presentations according to the age of onset.  A neonatal form, which is extremely rare, presents as fetal akinesia deformation sequence (FADS), consisting of arthrogryposis multiplex congenita, hydrops fetalis, and perinatal death.  A congenital form presents with hypotonia, cardiomyopathy, and death in early infancy.  A third form manifests in childhood with either myopathy or cardiomyopathy.  Adult form may present as a myopathy or as a multisystemic disease also called adult polyglucosan body disease (APBD) .  APBD is characterised by progressive upper and lower motor neurone dysfunction (sometimes simulating amyotrophic lateral sclerosis), sensory loss, sphincter problems and, inconsistently, dementia.  In APBD, polyglucosan bodies have been described in processes of neurones and astrocytes in both grey and white matter.  Muscle biopsy in the neuromuscular forms shows the typical foci of polyglucosan accumulation, intensely PASpositive and diastase-resistant.  Similar deposits are seen in the cardiomyocytes of children with cardiomyopathy and in motor neurones of infants with Werdnig-Hoffmann-like presentation
  28. 28. Metabolic Derangement  Hypoglycemia is rarely seen, and only in the classical hepatic form, when liver cirrhosis is advanced, and detoxification and synthesis functions become impaired.  The clinical and biochemical findings under these circumstances are identical to those typical of other causes of cirrhosis, with elevated liver transaminases and abnormal values for blood clotting factors, including prothrombin and thromboplastin generation time.  The GBE gene has been mapped to chromosome 3p14.  The diagnosis is usually only suspected at the histological examination of a liver or muscle biopsy which shows large deposits that are periodic-acid-Schiff-staining but partially resistant to diastase digestion.  The enzymatic diagnosis is based on the demonstration of GBE deficiency in liver, muscle, fibroblasts, or leukocytes.
  29. 29. Treatment  There is no specific dietary treatment for GSD IV.  Dietary treatment focuses on the maintenance of normoglycemia by frequent feedings and a late evening meal.  Liver transplantation is the only effective therapeutic approach at present for GSD IV patients with the classic progressive liver disease.
  30. 30. Glycogen Storage Disease Type VI ( Glycogen Phosphorylase Deficiency)  GSD VI or Hers disease is an autosomal recessive disorder due to a deficiency of the liver isoform of glycogen phosphorylase. Phosphorylase breaks the straight chains of glycogen down to glucose-1-phosphate in a concerted action with debranching enzyme. Glucose-1-phosphate in turn is converted into glucose-6-phosphate and then into free glucose.  Rare disorder with a generally benign course.  Present with hepatomegaly and growth retardation in early childhood. Cardiac and skeletal muscles are not involved. Hepatomegaly decreases with age and usually disappears around puberty. Growth usually normalises after puberty.  The tendency towards hypoglycemia is not as severe as seen in GSD I or GSD III and usually appears only after prolonged fasting in infancy. Hyperlipidemia and hyperketosis are usually mild. Lactic acid and uric acid are within normal limits.  The gene encoding the liver isoform, PYGL, is on chromosome 14q21- q22.  Deficient phosphorylase activity can be documented in liver tissue.
  31. 31. Glycogen Storage Disease Type IX (Phosphorylase Kinase Deficiency)  GSD IX, or phosphorylase kinase (PHK) deficiency, is the most frequent glycogen storage disease.  According to the mode of inheritance and clinical presentation six different subtypes are distinguished. (1) X-linked liver glycogenosis (XLG or GSD IXa), by far the most frequent subtype. (2) combined liver and muscle PHK deficiency (GSD IXb). (3) autosomal liver PHK deficiency (GSD IXc). (4) X-linked muscle glycogenosis (GSD IXd). (5) autosomal muscle PHK deficiency (GSD IXe). (6) heart PHK deficiency (GSD IXf) probably due to AMP kinase mutations.
  32. 32. Clinical Presentation  Hepatic Presentation  hepatomegaly due to glycogen storage, growth retardation, elevated liver transaminases, and hypercholesterolemia and hypertriglyceridemia.  Symptomatic hypoglycemia and hyperketosis are only seen after long periods of fasting in young patients. The clinical course is generally benign.  Clinical and biochemical abnormalities disappear with increasing age and after puberty most patients are asymptomatic.  Myopathic Presentation  The myopathic variants present clinically similar to a mild form of McArdle disease , with exercise intolerance, cramps, and recurrent myoglobinuria in young adults.  Less frequent presentations include infantile weakness and respiratory insufficiency or late-onset weakness.  Muscle morphology shows subsarcolemmal deposits of normal-looking glycogen.
  33. 33. Treatment and Prognosis  Treatment of the hepatic form is symptomatic, and consists of preventing hypoglycemia using a high- carbohydrate diet and frequent feedings; a late evening meal is unnecessary except for young patients.  Growth improves without specific treatment with age.  XLG patients have a specific growth pattern characterised by initial growth retardation, a late growth spurt, and complete catch-up in final height occurring after puberty .  Prognosis is generally favourable for the hepatic types, and more uncertain for the myopathic variants.
  34. 34. Glycogen Storage Disease Type 0 ( Glycogen Synthase Deficiency)  The first symptom of GSD 0 is fasting hypoglycemia which appears in infancy or early childhood.  Patients can remain asymptomatic. Recurrent hypoglycemia often leads to neurological symptoms.  Developmental delay is seen in a number of GSD 0 patients and is probably associated with these periods of hypoglycemia typically occurring in the morning before breakfast.  The size of the liver is normal, although steatosis is frequent. Some patients display stunted growth, which improves after dietary measures to protect them from hypoglycemia.  The small number of patients reported in the literature may reflect underdiagnosis, since the symptomatology is usually mild and the altered metabolic profile is not always interpreted correctly.  GSD 0 is caused by a deficiency of glycogen synthase (GS), a key-enzyme of glycogen synthesis.  Consequently, patients with GS deficiency have decreased liver glycogen concentration, resulting in fasting hypoglycemia.  This is associated with ketonemia, low blood lactate concentrations, and mild hyperlipidemia.  Post-prandially, there is often a characteristic reversed metabolic profile, with hyperglycemia and elevated blood lactate.  The gene that encodes GS, GYS2, is located on chromosome 12p12.2, and several mutations are known.  Patients with GSD 0 may be misdiagnosed as having diabetes mellitus, especially when glucosuria and ketonuria are also present.  Diagnosis of GSD 0 is based on the demonstration of decreased hepatic glycogen content and deficiency of the GS enzyme in a liver biopsy or by DNA analysis.  Treatment is symptomatic, and consists of preventing hypoglycemia with a high- carbohydrate diet, frequent feedings and, in young patients, late evening meals.
  35. 35. FANCONI-BICKEL SYNDROME  Hepatic glycogenesis with renal fanconi syndrome.  Rare AR disorder.  Deficiency of GLUT-2 in hepatocytes , pancreatic beta cells, intestinal and renal epithelial cells.  Proximal renal tubular dysfunction.  Presents in 1st year of life as FTT , rickets , hepatomegaly , renomegaly.  Glycosuria,phosphaturia , amino aciduria , bicarbonate wasting,hypophosphatemia , ricketic radiological findings.  Fasting hypoglycemia , hyperlipidaemia may be seen.  No specific treatment.  Symptomatic treatment with fluids , electrolytes , vit D, frequent small
  36. 36. MUSCLE GLYCOGENOSES
  37. 37. Muscle Glycogenoses  At rest, muscle utilizes predominantly fatty acids.  During submaximal exercise, it additionally uses energy from blood glucose, mostly derived from liver glycogen.  In contrast, during very intense exercise, the main source of energy is anaerobic glycolysis following breakdown of muscle glycogen.  When the latter is exhausted, fatigue ensues.  Enzyme defects within the pathway affect muscle function.
  38. 38. Glycogen Storage Disease Type V (Myophosphorylase Deficiency)  Clinical Presentation  GSD V, decribed in 1951 by McArdle is characterised by exercise intolerance, with myalgia and stiffness or weakness of exercising muscles, which is relieved by rest.  Two types of exertion are more likely to cause symptoms: brief intense isometric exercise, such as pushing a stalled car, or less intense but sustained dynamic exercise, such as walking in the snow. Moderate exercise, for example walking on level ground, is usually well tolerated.  Strenuous exercise often results in painful cramps, which are true contractures as the shortened muscles are electrically silent.  An interesting constant phenomenon is the second wind that affected individuals experience when they rest briefly at the first appearance of exercise-induced myalgia.  Myoglobinuria (with the attendant risk of acute renal failure) occurs in about half of the patients. Electromyography (EMG) can be normal or show non-specific myopathic features at rest, but documents electrical silence in contracted muscles.  As in most muscle glycogenoses, resting serum CK is consistently elevated in McArdle patients.  After carnitine palmitoyl transferase II (CPT II) deficiency, McArdle disease is the second most common cause of recurrent myoglobinuria in adults .  Clinical variants of McArdle disease include the fatal infantile myopathy described in a few cases, and fixed weakness in older patients .  However, some degree of fixed weakness does develop in patients with typical McArdle disease as they grow older and is associated with chronically elevated serum CK level  There are three isoforms of glycogen phosphorylase: brain/heart, liver, and muscle, all encoded by different genes. GSD V is caused by deficient myophosphorylase activity.
  39. 39. Genetics&Diagnosis  GSD V is an autosomal recessive disorder. The gene for the muscle isoform (PYGM) has been mapped to chromosome 11q13.  The forearm ischemic exercise (FIE) test is informative but is being abandoned as it is neither reliable, reproducible, nor specific, and is painful.  Alternative diagnostic tests include a non-ischemic version of the FIE , and a cycle test based on the unique decrease in heart rate shown by McArdle patients between the 7th and the 15th minute of moderate exercise, a reflection of the second wind phenomenon .  Muscle histochemistry shows subsarcolemmal accumulation of glycogen that is normally digested by diastase.  A specific histochemical stain for phosphorylase can be diagnostic except when the muscle specimen is taken too soon after an episode of myoglobinuria.  Myophosphorylase analysis of muscle provides the definitive answer, but muscle biopsy may be avoided altogether in Caucasian patients by looking for the common mutation (R49X) in genomic DNA.
  40. 40. Treatment  There is no specific therapy.  Probably, the most important therapy is aerobic exercise .  Oral sucrose improved exercise tolerance, and may have a prophylactic effect when taken before planned activity.  This effect is explained by the fact that sucrose is rapidly split into glucose and fructose; both bypass the metabolic block in GSD V and hence contribute to glycolysis
  41. 41. Glycogen Storage Disease Type VII (Phosphofructokinase Deficiency)  Clinical Presentation  Clinically, GSD VII, first described by Tarui, is indistinguishable from McArdle disease, except for the absence of the second wind phenomenon.  Some laboratory results are useful in the differential diagnosis, including an increased bilirubin concentration and reticulocyte count, reflecting a compensated hemolysis.  The diagnosis of PFK deficiency is based on the combination of muscle symptoms and compensated hemolytic anemia: the only other muscle glycogenosis with these features is phosphoglycerate kinase deficiency .  There are two clinical variants, one manifesting as fixed weakness in adult life (although most patients recognise having suffered from exercise intolerance in their youth), the other affecting infants or young children, who have both generalised weakness and symptoms of multisystem involvement (seizures, cortical blindness, corneal opacifications, or cardiomyopathy) .  The infantile variant, in which no mutation in the PFK-M gene has been documented is probably genetically different from the typical adult myopathy.  PFK is a tetrameric enzyme under the control of three autosomal genes. A gene (PFK- M) on chromosome 12 encodes the muscle subunit; a gene (PFK-L) on chromosome 21 encodes the liver subunit; and a gene (PFK-P) on chromosome 10 encodes the platelet subunit.
  42. 42. Diagnosis&Treatment  Muscle histochemistry shows predominantly subsarcolemmal deposits of normal glycogen, most of which stains normally with the PAS and is normally digested by diastase.  Patients with PFK deficiency also accumulate increasing amounts of polyglucosan, which stains intensely with the PAS reaction but is resistant to diastase digestion and – in the electron microscope – appears composed of finely granular and filamentous material, similar to the storage material in branching enzyme deficiency and in Lafora disease.  There is no specific therapy.  Contrary to McArdle disease, sucrose should be avoided, but aerobic exercise might be useful.  The astute observation that patients with PFK deficiency noticed worsening of their exercise intolerance after high-carbohydrate meals was explained by the fact that glucose lowers the blood concentration of free fatty acids and ketone bodies, alternative muscle fuels.
  43. 43. Phosphoglycerate Kinase Deficiency  Phosphoglycerate kinase (PGK) is a single polypeptide encoded by a gene (PGK1) on Xq13 for all tissues except spermatogenic cells.  Although this enzyme is virtually ubiquitous, clinical presentations depend on the isolated or associated involvement of three tissues, erythrocytes (hemolytic anemia), central nervous system (CNS, with seizures, mental retardation, stroke), and skeletal muscle (exercise intolerance, cramps, myoglobinuria).  The most common association, seen in 8 of 27 reported patients, is nonspherocytic hemolytic anemia and CNS dysfunction, followed by isolated myopathy (7 patients), isolated blood dyscrasia (6 patients), and myopathy plus CNS dysfunction (3 patients) .  There was only one patient with myopathy and hemolytic anemia, while two patients showed involvement of all three tissues.  The seven myopathic cases were clinically indistinguishable from McArdle disease, but muscle biopsies showed less severe glycogen accumulation .  Mutations in PGK1 were identified in 4 of the 7 myopathic patients.  The different involvement of single or multiple tissues remains unexplained but it may have to do with leaky mutations allowing for some residual PGK activity in some tissues.
  44. 44. Glycogen Storage Disease Type X (Phosphoglycerate Mutase Deficiency)  GSD X or phosphoglycerate mutase (PGAM) deficiency is an autosomal recessive disorder.  Phosphoglycerate mutase is a dimeric enzyme: different tissues contain various proportions of a muscle (MM) isozyme, a brain (BB) isozyme, and the hybrid (MB) isoform.  Normal adult human muscle has a marked predominance of the MM isozyme, whereas in most other tissues PGAM-BB is the only isozyme demonstrable by electrophoresis .  A gene (PGAMM) on chromosome 7 encodes the M subunit.  The clinical picture is stereotypical: exercise intolerance and cramps after vigorous exercise, often followed by myoglobinuria.  Manifesting heterozygotes have been identified in several families.  The muscle biopsy shows inconsistent and mild glycogen accumulation, accompanied in one case by tubular aggregates . Four different mutations in the PGAMM gene have been identified .
  45. 45. Glycogen Storage Disease Type XII (Aldolase A Deficiency)  GSD XII or aldolase A deficiency is an autosomal recessive disorder.  Aldolase exists in three isoforms (A, B, and C).  skeletal muscle and erythrocytes contain predominantly the A isoform, which is encoded by a gene (ALDOA) on chromosome 16.  The only reported patient with aldolase A deficiency was a 4 1/2-year-old boy, who had episodes of exercise intolerance and weakness following febrile illnesses.
  46. 46. Glycogen Storage Disease Type XIII (β-Enolase Deficiency)  GSD XIII or-β enolase deficiency is an autosomal recessive disorder.  β -Enolase is a dimeric enzyme and exists in different isoforms resulting from various combinations of three subunits,ALFA,BETA, and GAMMA.  The β subunit is encoded by a gene (ENO3) on chromosome 17.  GSD XIII is still represented by a single patient, a 47-year-old Italian man with adult onset but rapidly progressive exercise intolerance and myalgia, and chronically elevated serum CK
  47. 47. Glycogen Storage Disease Type XI (Lactate Dehydrogenase Deficiency)  autosomal recessive disorder. Lactate dehydrogenase is a tetrameric enzyme composed of two subunits, M (or A) and H (or B.  The gene for LDH-M (LDHM) is on chromosome 11.  The first case was identified on the basis of an apparently paradoxical laboratory finding: during an episode of myoglobinuria, the patient had the expected high levels of serum CK, but extremely low level of LDH.  All have exercise intolerance, cramps, with or without myoglobinuria.
  48. 48. THE GENERALIZED GLYCOGENOSES AND RELATED DISORDERS
  49. 49. Glycogen Storage Disease Type II (Acid Maltase Deficiency)  GSD II is a lysosomal storage disorder, caused by the generalized deficiency of the lysosomal enzyme, acid maltase .  The enzyme defect results in the accumulation of glycogen within the lysosomes of all tissues, but particularly in muscle and heart, resulting in muscle weakness. Serum levels of transaminases , CK and CK-myocardial band (in the infantile form) are elevated.  Acid maltase is encoded by a gene (GAA) on chromosome 17q25.  Frequency 1 in 40,000 live births.
  50. 50. Clinical Presentation  Manifests as three different clinical phenotypes: infantile, juvenile, and adult.  The infantile form is generalised, and usually fatal by 1 year of age.  The diagnosis is suggested by the association of profound hypotonia from muscle weakness, (floppy infant syndrome), hyporeflexia and an enlarged tongue.  The heart is extremely enlarged, and the electrocardiogram is characterised by huge QRS complexes and shortened PR intervals.  The liver has a normal size unless enlarged by cardiac decompensation.  The cerebral development is normal.  The clinical course is rapidly downward, and the child dies from
  51. 51. juvenile form,& adult form  The juvenile form starts either in infancy or in childhood, presents with retarded motor milestones and causes severe proximal, truncal, and respiratory muscle weakness (sometimes with calf hypertrophy, which, in boys, can raise the suspicion of Duchenne muscular dystrophy), but shows no overt cardiac disease.  Myopathy deteriorates gradually leading to death from respiratory failure in the second or third decade.  The adult form is also confined to muscle and mimics other myopathies with a long latency.  Decreased muscle strength and weakness develop in the third or fourth decade of life.  Cardiac involvement is minimal or absent.  The slow, progressive weakness of the pelvic girdle, paraspinal muscles and diaphragm simulates limb-girdle muscular dystrophy or polymyositis and results in walking difficulty and respiratory insufficiency, but old age can be attained.  The early and preferential involvement of truncal and respiratory muscles is an important clinical characteristic
  52. 52. Diagnosis  In the infantile form, a tentative diagnosis can be based on the typical abnormalities in the electrocardiogram.  Muscle biopsy shows a severe vacuolar myopathy with accumulation of both intralysosomal and free glycogen in both the infantile and childhood variants.  Another clue to the correct diagnosis in myopathic Pompe disease is the EMG, which shows, – besides myopathic features – fibrillation potentials, positive waves, and myotonic discharges, more easily seen in paraspinal muscles.  For confirmation, acid maltase should be determined in tissues containing lysosomes. The preferred tissues are fibroblasts or muscle, but lymphocytes may be usable.
  53. 53. Treatment  Palliative therapy includes respiratory support, dietary regimens (e.g. high-protein diet), and aerobic exercise.  Enzyme replacement therapy using recombinant human alfa-glucosidase, obtained in large quantities from rabbit milk has been used successfully.  Alglucosidase alfa (Myozyme), a recombinant analog of human alfa-glucosidase manufactured in CHO cell lines, has now available for use in both the infantile and later onset forms.  It appears to be important to start enzyme replacement therapy as early as possible.
  54. 54. Danon Disease  Danon Disease or GSD IIb, or pseudo-Pompe disease, is an X-linked dominant lysosomal storage disease due to deficiency of LAMP-2 (lysosomal-associated membrane protein 2).  The disease starts after the first decade, is extremely rare and affects cardiac and skeletal muscle. Acid maltase activity is normal, muscle biopsy shows vacuolar myopathy with vacuoles containing glycogen and cytoplasmatic degradation products .  Some patients are mentally retarded.  As expected, hemizygous females are also affected, but generally show the first symptoms at a later age.  No specific therapy is available, but cardiac transplantation should be considered .  The gene encoding LAMP2 was mapped to Xq28
  55. 55. Lafora Disease  Lafora disease (myoclonus epilepsy with Lafora bodies) is characterised by seizures, myoclonus, and dementia. Onset is in adolescence and the course is rapidly progressive, with death occurring almost always before 25 years of age.  The pathologic hallmark of the disease are the Lafora bodies, round, basophilic, strongly PAS-positive intracellular inclusions seen only in neuronal perikarya, especially in the cerebral cortex, substantia nigra, thalamus, globus pallidus, and dentate nucleus.  Polyglucosan bodies are also seen in muscle, liver, heart, skin, and retina, showing that Lafora disease is a generalised glycogenosis.  However, the obvious biochemical suspect, branching enzyme, is normal.  Linkage analysis localised the gene responsible for Lafora disease (EPM2A) to chromosome 6q24 and about 30 pathogenic mutation have been identified .  The protein encoded by EPM2A, dubbed laforin, may play a role in the cascade of phosphorylation/dephosphorylation reactions controlling

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