Glycogen Storage Disease(s) By Alaa Haseeb, MS.c Points of

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Glycogen Storage Disease(s)

• By
• Alaa Haseeb, MS.c

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Points of discussion

• - Basic biochemistry of glucose and glycogen
  metabolism.
• - Definition and pathophysiology of GSD.
• - Incidence inheritance.
• - Classification and clinical types.
• - Hepatic glycogenoses.
• - Muscle glycogenoses.

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Basic biochemistry

• - Glucose is the principle substrate of energy
  metabolism in humans.
• - The ultimate fate of glucose depends on body
  needs thus glucose may be
• - Oxidized to give energy or
• - Stored as glycogen (muscles, liver) or
• - Converted to triglycerides, amino acids and
• proteins.

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Cont.

• Glycogen is a glucose polymer joined in
• straight chains by alpha 1,4 linkages and
• branched at intervals of 4 to 6 residues by
• alpha 1,6 linkages. It forms a tree like
• molecule and can have a molecular weight
• of many millions. Glycogen is the storage
• form of glucose and is found in abundance in the
• liver, muscles and kidneys.

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Glycogen polymer
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Biochemical terms

• Glycolysis
• - The oxidation of glucose to pyruvate with
• generation of ATP for energy ( 2 moles of ATP per
• glucose molecule).
• - Takes place in the cytoplasm of the cell.
• - May also occur in the absence of O2, in which
  case pyruvate is converted to lactate.

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Cont.

• Glycogenesis
• - The conversion of excess glucose to
• glycogen for storage.
• - Begins with the phosphorylation of glucose to
  glucose-6-phosphate, which is then isomerized to
  glucose-1-phosphate and added to a glycogen
  primer, uridine diphosphoglucose (UDPG).
• - Catalyzed by glycogen synthetase, which exists
  in 2 forms an active (D or dependent) form and
  an inactive
• (L or independent) form.

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Cont.

• Glycogenolysis
• - The degradation of glycogen to glucose.
• - A phosphorylase enzyme splits the alpha 1,4
• linkage releasing glucose-1-phosphate, a
  debranching enzyme then splits the alpha 1,6
  linkage.
• - The phosphorylase enzyme has two forms an
• inactive form (phosphorylase b) and an active
• form (phosphorylase a). Conversion to the active
• form is catalyzed by phosphorylase b kinase.

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Cont.

• The glucose-1-phosphate can then be
• isomerized to glucose-6-phosphate and
• either enter glycolysis or be hydrolysed to
• free glucose.
• The latter step is catalyzed by a glucose-6
• phosphatase enzyme and facilitated by a
• translocase that transports glucose-6-phosphate
• across the microsomal membrane.

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Glycogenolysis
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Regulation of glycogen metabolism

• - Cyclic AMP activates a cAMP-dependent protein
  kinase which in turn activates both phosphorylase
  b kinase ( to promote glycogenolysis) and
  glycogen synthetase kinase (to promote
  glycogenesis) thus keeping a state of balance in
  glycogen turnover.
• - Adrenaline and glucagon activate glycogenolysis
  and inhibit glycogenesis, while insulin does the
  opposite.

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Definition of GSD and their
pathophysiology

• A group of inherited disorders caused by a
• defect in glycogen metabolism characterized
• by impaired conversion of glycogen to free
• glucose resulting in the accumulation of
• normal and abnormal glycogen in tissues.
• Disruption of glycogen metabolism also affects
• other biochemical pathways as the body seeks
• alternative fuel sources. Accumulation of
  abnormal
• metabolic by-products can damage other organs.

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Cont.

• The system for glycogen metabolism relies on a
• complex system of enzymes. These enzymes are
• responsible for creating glycogen from glucose,
• transporting the glycogen to and from storage
• areas within cells, and extracting glucose from
  the
• glycogen as needed. Both creating and tearing
• down the glycogen macromolecule are multistep
• processes requiring a different enzyme at each
• step. If one of these enzymes is defective and
  fails to
• complete its step, the process halts.

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Incidence and mode of inheritance

• The overall frequency of all forms of GSD is
• approximately one in 20,000-25,000 live births.
• The most common forms of GSD are Types I, II,
• III, V and IX, which may account for more than
• 90 of all cases. The most common form is Type
• Ia, or Von Gierke disease, which occurs in one
  out
• of every 100,000 births. Other forms are so rare
• that reliable statistics are not available.

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Cont.

• All GSD are inherited as an autosomal
• recessive trait except two phosphoglycerate
• kinase deficiency (a muscle glycogenoses)
• and one form of phosphorylase kinase
• deficiency ( a hepatic glycogenoses), both of
• which are X-linked diseases. Most are
• childhood disorders, only few (like type V,
  McArdle
• disease) are adult disorders.

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Classification and clinical types

• -Historically, GSD were categorized numerically
  in the order
• in which the enzymatic defects were identified (
  type I,
• II, III etc.) and named after the person who
  discovered
• each type (Von Gierke, Pompe, Cori etc.).
• -Clinically, GSD are classified according to the
  main organ
• involved and two main categories are born
• GSD involving principally the liver (hepatic
  glycogenoses)
• and those principally involving the muscles
  (muscle
• glycogenoses). Almost 20 diseases are described.

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Hepatic glycogenosis

• - Principally involve the liver.
• - Four common clinical findings
• 1) Hepatomegaly, which may be massive.
• 2) Recurrent hypoglycemia.
• 3) Growth retardation and delayed puberty.
• 4) Abnormal blood results involving any of the
  following cholesterol, triglycerides, uric acid,
  aminotransferases, blood lactate or neutrophils.

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Cont.

• - Other findings are disease specific.
• - Development of cirrhosis is rare, except in
  type IV (Andersen disease) in which development
  of cirrhosis, liver cell failure and death is
  before the fifth year of life in many cases, and
  in some cases with type IIIa (Cori disease).

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Von Gierke disease (Type Ia GSD)

• - Caused by glucose-6-phosphatase deficiency in
  liver, kidneys and small intestine.
• - Children often have doll-like faces with fat
• cheeks, relatively thin extremities, short
  stature
• and a protuberant abdomen. The kidneys are
• enlarged, but the heart and spleen are of normal
• size. There is a prolonged bleeding time as a
  result
• of defective platelets aggregation/adhesion.

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Cont.

• -Virtually all females have polycystic ovaries,
  as an
• ultrasound finding, but without clinical features
  of acne or
• hirsutism.
• - Long term complications (2nd and 3rd decade of
  life)
• include hyperuricemia and gout, dyslipidemia,
• atherosclerosis, osteopenia and bone fractures,
  hepatic
• adenomas, which can turn malignant and renal
• impairement and proteinuria, which might progress
  to renal
• failure requiring dialysis or transplantation.

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Diagnosis of hepatic glycogenoses

• 1) Glucagon challenge (historical)
• Intra-muscular administration of glucagon
• results in poor blood glucose level elevation,
• and elevates levels of lactate.
• 2) Liver biopsy
• The biopsy sample is tested for its glycogen
• content (which is increased) and assayed for
• enzyme activity and presence (which is
• defective or absent).

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Cont.

• - Liver histology reveals ,in addition, steatosis
  typically with absence of fibrosis.
• 3) DNA based gene mutation analysis
• The genes for many enzymes , which their
• defects or deficiencies are responsible for GSD
• have been encoded and mutations have been
• identified. Molecular technologies
• have provided a non-invasive way of diagnosis,
• and pre-natal diagnosis is being developed as
  well.

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Treatment of hepatic glycogenoses

• Some types are relatively easy to control
• through symptom management and
• dietary therapy. In more severe cases,
• receiving an organ transplant (e.g. liver) is
• the only option. In the most severe cases, there
• are no available treatments and the victim
• dies within the first few years of life.

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Cont.

• The key to managing hepatic glycogenoses is to
• maintain normal levels of blood glucose through a
• combination of
• 1) Nocturnal high carbohydrate enteral feeding ,
  through a
• nasogastric tube if necessary, (usually for
  infants and
• children).
• 2) Frequent high-carbohydrate meals during the
  day.
• 3) Regular oral doses of uncooked cornstarch
  (slow release
• form of glucose) every 4 - 6 hours at a dose of
  2g/kg.

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Cont.

• - Fructose and galactose can not be
• converted to glucose so their dietary intake
• should be restricted.
• - Dietary supplement of vitamins and calcium may
  be required.
• - Symptomatic treatment of dyslipidemias, gout
  and other metabolic abnormalities.

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Muscle glycogenoses

• - Principally involve the muscles (skeletal
  and/or cardiac).
• Two groups
• 1) Muscle-energy impairment
• - Exercise intolerance and muscle cramps.
• - Rhabdomyolysis and myoglubinuria on strenuous
  exercise.
• - Evidence of hemolysis and hemolytic anemia in
  some cases.

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Cont.

• 2) Progressive skeletal myopathy and/or
  cardiomyopathy
• - Skeletal muscle weakness and atrophy.
• - Cardiomyopathy with cardiac enlargement and
  heart failure.
• Both groups show elevated CK levels at rest
  with
• further rise after exercise. Exercise also
  elevates
• levels of blood ammonia, inosine, hypoxanthine
• and uric acid.

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Diagnosis

• 1) Lack of an increase in blood lactate and
• exaggerated blood ammonia elevations after
• an ischemic exercise test are indicative of
• muscle glycogenoses and suggest a defect
• in the conversion of glycogen or glucose to
• lactate.
• 2) Muscle biopsy with enzymatic assay of
• responsible enzymes.
• 3) DNA based gene mutation analysis.

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Treatment of muscle glycogenoses

• - Definitive therapy is not currently available
• - Avoidance of strenuous exercise can
• prevent major episodes of rhabdomyolysis.
• - High protein diet.
• - Creatine supplements have improved muscle
  function in some patients.
• - Clinical trials of enzyme replacement therapy
• have begun. Preliminary data have shown
  improvement in some patients.
• - Gene therapy is still experimental in these
  cases.

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Prenatal diagnosis of GSD

• Through chorionic villi sampling and
• amniocentesis the disorder can be detected
• prior to birth. Some types of GSD can be detected
• even before conception occurs, if both parents
  are
• tested for the presence of the defective gene.
• Before undergoing such testing, the prospective
• parents should meet with a genetic counselor and
• other professionals in order to make an informed
• decision.

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Screening for GSD

• Just like all other genetically inherited
• disorders, relatives of the victim must be
• screened for the presence of the abnormal
• gene so that early recognition and early
• intervention, if necessary can be implicated.

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Thank you

• Alaa Haseeb, MS.c