Glycogen Storage Diseases

Question 1

Glycogenesis

Answer 1

• To start the process of glycogenesis, glucose is phosphorylated by glucokinase (liver) or hexokinase (muscle) to produce glucose-6-phosphate (glucose6P).
• After a meal, glucose is diverted to the synthesis of hepatic glycogen to replace what has been lost since the last meal.
• This response is controlled largely by increased amounts of insulin in the blood as well as by the marked increased concentration of glucose6P in the liver cell that occurs after a carbohydrate meal.
• In muscle, glycogen is replaced after intense exercise during which glycogen has been used.
• The glucose6P is then converted to glucose-1-phosphate (reverse of the reaction used during glycogenolysis).
• glucose 1P + uridine monophosphate (UMP —> UDP - glucose

-The UMP is derived from UTP.

•UDP-glucose is the substrate for glycogen synthase, the principal and regulated enzyme of glycogenesis.

• Glycogen synthase is active in its dephosphorylated state by the action of protein phosphatase, which is activated by insulin.
• Any glycogen synthase that remains phosphorylated is activated allosterically by glucose6P.

•These combined effects ensure that glycogen, which had been utilized to maintain glucose homeostasis since the last meal or for driving muscle contractions is replenished.

Question 2

Glycogenesis - Adding Branches

Answer 2

• The highly branched structure of glycogen permits exclusion of water to decrease a tissue osmotic effect and to increases its efficiency as a substrate for glycogen phosphorylase, which catalyzes the removal of glucose units from the ends of branches.
• The formation of branches is catalyzed by branching enzyme that moves seven glucose residues from the end of a growing chain to an interior area where a branch can be attached.

Question 3

Glycogenolysis

Answer 3

• Glycogen phosphorylase [GP] is the key regulated enzyme that removes sugar residues from glycogen.
• GP catalyzes hydrolysis of glucose residues from the ends of branches and phosphorylation of these residues.
• This enzyme contains binding sites for its substrates (glycogen, Pi), a cofactor (pyridoxal phosphate), an allosteric activator (AMP), and allosteric inhibitors (ATP, glucose, glucose-6-phosphate).
• Certain hormone signals [i.e., glucagon, epinephrine] activate GP by phosphorylation of the enzyme.
• The product of the reaction is glucose-1-phosphate that is rearranged to glucose6P.
• In liver, to ensure the glucose6P is dephosphorylated to glucose via glucose 6-phosphatase (G6Pase), glycolysis is inhibited by fructose-2,6-bisphosphate (F2,6BP) at phosphofructokinase-1 (PFK-1) under conditions of food deprivation.
• Glucose-6-phosphatase is unique to tissues producing glucose (i.e., liver and kidney).
• Other tissues, such as muscle, lack G6Pase so that glucose6P from glycogenolysis proceeds directly through glycolysis to produce pyruvate that is either converted to lactate via lactate dehydrogenase (LDH) under anaerobic conditions or aerobically to CO2 via pyruvate dehydrogenase (PDH) and the citric acid cycle (CAC)

Question 4

Glcogenolysis - Debranching

Answer 4

• The combined actions of a debranching enzyme and a transferase move the final four residues of a branch to the end of a chain so that they can be removed by glycogen phosphorylase.
• Glucose-1-phosphate, the product from glycogen phosphorylase, is converted to glucose6P via phosphoglucomutase.
• The final residue that forms the alpha-1,6 linkage is removed by a 1,6-glucosidase enzyme releasing free glucose directly.

Question 5

Glycogenolysis in the Lysosome

Answer 5

• Lysosomes can store some glycogen. Its conversion to glucose is catalyzed by the lysosomal acid maltase (alpha-1,4-glucosidase).
• Homozygous deficiency of this enzyme causes accumulation of lysosomal glycogen in all types of cells.

Question 6

Glycogen Storage Diseases

Answer 6

• Type II - Pompe disease – lysosomal glucosidase
• Type I – Von Gierke disease – glucose-6-Pase
• Type III – Cori disease – debranching enzyme
• Type V – McArdle disease – muscle phosphorylase
• Type VI – Hers disease – liver phosphorylase
• Type 0 – glycogen synthase
• Type IV – Andersen disease – branching enzyme

Question 7

GSD Type II Pompe Disease

Answer 7

*Defect of lysosomal storage of glycogen; acid maltase: alpha-1,4-glucosidase

*Affects wide range of cell types

• Infants: hypotonia, weakness, areflexia, cardiomegaly, hypertrophic cardiomyopathy, some hepatomegaly [no hypoglycemia]
• Juvenile/adult form: motor delay; progressive myopathy – skeletal muscle only
• Heart failure leads to early death
• Enzyme replacement therapy - alglucosidase alfa [lumizyme]*

*For 2016, Lumizyme was ranked the costliest drug per patient, average of $630,159

Question 8

Type II Pompe Disease Histology

Answer 8

Question 9

GSD Type I Von Gierke Disease

Answer 9

• IA: Glucose-6-phosphatase [most common form]
• IB: Glucose-6P transporter

Question 10

Workup for GSD Type I Von Gierke Disease

Answer 10

• Glucose (fasting hypoglycemia; monitoring therapy)
• Liver enzymes – AST and ALT (hepatomegaly)
• Plasma lactate elevated (lactic acidosis)
• Plasma bicarbonate (decreased due to acidosis)
• Uric acid (decreased due to acidosis)
• Plasma lipids (elevated cholesterol and triglyceride)
• Hb/Hct (anemia due to chronic hepatic disease)
• Serum alpha-fetoprotein (hepatocellular carcinoma marker - adenoma)
• Imaging:
• Hepatic ultrasonography (diagnosis and monitoring therapy)
• Renal ultrasonography (nephrolithiasis)
• CT/MRI (monitor adenomas)

Question 11

GSD Type I Von Gierke Disease Overview

Answer 11

• GSD Type I (von Gierke disease) usually involves a lack or reduced activity of glucose-6- phosphatase (Type Ia) that is located in the endoplasmic reticulum).
• Less frequently the disease can be a consequence of a deficiency in the transporter for glucose6P (Type Ib).

-In Type Ib the substrate fails to reach the glucose-6-phosphatase enzyme in the ER lumen.

• Overall GSD type I occurs in about 1 per 100,000 live births.
• The disease is inherited as an autosomal recessive disorder.
• A variety of mutations have been identified in Caucasians, Hispanics, Chinese, and the Ashkenazi Jews; the most common being a R83C mutation found to be prevalent in all groups listed except Chinese. Amongst the non-Ashkenazi Jews in North Africa the incidence is reportedly as much as 1 in 5500. Overall about 25% of the cases of GSD are type I.

Question 12

GSD Type I Von Gierke Disease Clinical Features

Answer 12

The disease presents in infants with major symptoms that include:

•Hepatomegaly leading to a protruding abdomen.

-The hepatomegaly contributes to development of at least one hepatic adenoma, usually in the teen years, in as high as 75% of the patients but less commonly do these adenomas become malignant (10% of adenomas).

• Hepatomegaly may also lead to pancreatitis that is another factor which, along with hepatomegaly and nephrolithiasis, can cause abdominal pain.
• Metabolic derangements are common and include hypoglycemia, lactic acidosis and hyperuricemia.

-The extent of hypoglycemia varies but can lead to serious complications ranging from seizures to coma and death.

•Recall that the kidney contains glucose-6-phosphatase activity, so that glycogen accumulates in this organ as well.

-Elevated uric acid (90% of patients) due to the acidosis leads to gouty arthritis.

•Type Ia patients almost always exhibit dyslipidemia with markedly elevated serum triacylglycerol (hypertriglyceridemia – nearly 100%), and moderately increased VLDL, LDL and cholesterol (hypercholesterolemia – 75%).

-The elevated lipids can manifest as xanthomas and contribute to pancreatitis.

•Patients often exhibit platelet dysfunction.

• Anemia is found in ~80% of patients.
• Type Ib patients may have neutropenia and neutrophil abnormalities.

• GI:

-Infections, abscesses and inflammatory bowel disease are common in type Ib but less so in type Ia patients.

• Endocrine:

• Growth failure, even in treated patients is common (90%) with final height being in the 5th -10th percentiles.
• Less commonly features can include muscle hypotonia, delayed psychomotor development and recurrent infections, the latter being most common in type Ib (41%) compared to type Ia (3%).
• Hormonal imbalances also can lead to bone disorders (osteopenia or fractures – 25%). These imbalances likely also account for delayed onset of puberty and subsequent development.
• Polycystic ovary disease may also be present in females.

• Renal:

• Nephrolithiasis is common. Kidney damage (focal segmental glomerulosclerosis) can lead to further complications of proteinuria (65%), hypertension and chronic renal failure.
• Damage due to both uric acid stones and kidney accumulation of glycogen leads to decreased creatinine clearance.

• Mortality has become less of an issue with the development of therapies that help reduce the severe complications.

Question 13

Biochemistry of GSD Type I Von Gierke Disease

Answer 13

• Glucose-6-phosphatase is an essential enzyme for both glycogenolysis and gluconeogenesis.
• In GSD Type I, glycogenolysis occurs up to the production of glucose6P; carbons are then pushed through the glycolytic pathway.
• So why does glycogen accumulate leading to hepatomegaly?
• The capacity for glycolysis to process glucose6P following food deprivation is limited by the hormonal controls that decrease glycolysis and enhance gluconeogenesis.
• This capacity is not zero because there is always residual enzymatic activity even in an ‘inhibited’ state.

•The limitation of glycolysis causes an increase in the concentration of glucose6P, which counteracts to some extent for the activation of glycogenolysis by glucagon following food deprivation.

Question 14

Biochemistry of GSD Type I Von Gierke Disease Part II

Answer 14

The limitation of glycolysis causes an increase in the concentration of glucose6P, which counteracts to some extent for the activation of glycogenolysis by glucagon following food deprivation.

Question 15

Biochemistry of GSD Type I Von Gierke Disease Part III

Answer 15

• The inability to convert lactate or alanine to glucose means that lactic acidemia and hyperalaninemia become a consequence of food deprivation.
• The acidosis created by the lactic acid lowers the solubility and hence excretion of uric acid by the kidney; hence the development of hyperuricemia.
• Lactate, alanine and carbons from limited glycogen breakdown all will end up as pyruvate that is converted to acetyl CoA.

-Acetyl CoA is a precursor to synthesis of fatty acids and cholesterol that contribute to the formation and secretion of VLDL; hence the development of hypertriglyceridemia and hypercholesterolemia

Question 16

GSD Type I Von Gierke Disease and Growth Failure

Answer 16

• In terms of growth failure, hypoglycemia reduces the secretion of insulin-like growth factor (IGF) by liver.
• IGF production and secretion is controlled by growth hormone, whose primary role is metabolic in promoting an increase of blood glucose.
• In the face of fasting hypoglycemia, the metabolic effects of growth hormone are retained in an attempt to maintain glucose homeostasis.
• Concurrently its stimulation of IGF-I secretion is curtailed because of the energy costs associated with growth; a second measure to preserve blood glucose.

Question 17

GSD Type I Von Gierke Disease Histology

Answer 17

• Deficiency of glucose-6-phosphatase results in accumulation of glycogen in hepatocytes (left – compare to normal on right).
• The liver is enlarged. The hepatocytes are swollen and a mosaic histological pattern with compression of the sinusoids is seen.

Question 18

GSD Type I Von Gierke Disease Treatment

Answer 18

• Avoid fasting
• Nasogastric tube feeding – young infants
• Avoiding excessive carb intake to prevent lactic acidemia.
• Uncooked cornstarch

-The raw cornstarch is a complex glucose polymer, which is acted on slowly by pancreatic amylase over about a 6-hour period

• Avoid sat. fats/cholesterol because of hyperlipidemia
• Surgical removal of adenomas

Liver resection in glycogen storage disease type Ia. Multiple tumor nodules with smooth borders; uninvolved parenchyma pale ; bar = 5cm

Question 19

GSD Type III Cori Disease

Answer 19

• IIIA/B: Debranching enzyme
• IIIC: Glucosidase
• IIID: Transferase
• GSD Type III (Cori disease) is caused by a lack or reduced activity of the debranching enzyme leaving glycogen with short branches of 2-4 glucose residues.
• There are four types of clinical manifestations.
• Most patients (80%) have type IIIa that affects both liver and muscle.
• Type IIIb affects liver only.
• Type IIIc is associated with a defect of the glucosidase activity
• Type IIId a defect of the transferase activity.
• The disease is inherited as an autosomal recessive disorder.
• The incidence is about 1 in 25,000 births. GSD Type III accounts for about 25% of all GSD cases. Frequency of the disease is high in the following populations: Inuits and Sephardic Jews originating in North Africa (~1:5000).

Question 20

GSD Type III Cori Disease Clinical Features

Answer 20

• The disease is diagnosed in infancy or early childhood with hepatomegaly and hypoglycemia as characteristics.
• Ketoacidosis can also occur.
• Some patients present with hyperlipidemia and growth retardation but not to the extent seen in GSD Type I.

-A key difference from GSD Type I is the muscle involvement in GSD Type III leading to hypotonia and muscle wasting though this feature is more likely seen in adults than children.

• Adult patients with GSD Type IIIa may also present with cardiomyopathy.
• Female adult patients may exhibit polycystic ovaries.

Question 21

Biochemistry of GSD Type III Cori Disease

Answer 21

• Because branches cannot be fully removed from the glycogen molecule, the short branches can interfere with glycogen phosphorylase action.
• Following food deprivation, limited glycogenolysis can occur leaving a glycogen molecule with stubby branches and incomplete hydrolysis.
• Consequently, hypoglycemia occurs. However, because the glycogen molecule is partially degraded, hypoglycemia is less severe.
• The presence of ketoacidosis, hyperlipidemia and growth retardation are less characteristic.
• Excessive storage of glycogen in muscle causes damage to the tissue leading to leakage of creatine kinase into the circulation.

Question 22

GSD Type III Cori Disease Workop

Answer 22

• Glucose (fasting hypoglycemia - mild)
• Liver enzymes – AST/ALT (hepatomegaly)
• Serum CK (muscle damage in type IIIa)
• Fibroblast enzyme activity 
• Imaging:
• Hepatic ultrasonography (liver size)
• Female pelvic ultrasonography (polycystic ovaries)
• Abdominal CT (hepatocellular carcinoma)
• Ischemic forearm muscle test (decreased lactate output)
• Electromyography (myopathy changes)

Question 23

Growth and Development GSD Type III Cori Disease

Answer 23

• Growth and development in a patient with type IIIb glycogen storage disease.
• Debrancher deficiency in liver but normal activity in muscle.
• Child: hepatomegaly, hypoglycemia, and growth retardation.
• After puberty: no hepatomegaly or hypoglycemia
• No muscle weakness or atrophy in contrast to type IIIa patients, who exhibit progressive myopathy in adulthood.

Question 24

GSD Type III Cori Disease Treatment

Answer 24

• Avoid fasting
• High protein diet – favors gluconeogenesis

Question 25

GSD Type V McArdle Disease

Answer 25

* affects muscle glycogen phosphorylase * Most patients first present in their teens or 20s. * It is associated with immediate morbidity as a consequence of severe exercise intolerance. * Initial symptoms include cramps, fatigue and/or pain after exercise. * Some adult patients develop a proximal weakness or even a fixed motor weakness. * no hypoglycemia

Question 26

Biochemistry of GSD Type V McArdle Disease

Answer 26

* Though these patients exhibit muscle fatigue within several minutes, their ability to exercise can become more easily tolerated due to a spontaneous “second-wind” phenomenon. * One possible explanation for this response is increased use of fatty acids but very likely is related to the positive effect of exercise on muscle glucose uptake. * Because the glycolytic pathway is intact in these patients, increased uptake of glucose would allow for energy production from anaerobic glycolysis with glucose as the fuel source in lieu of glycogen. * Indeed, these patients, unlike normal individuals, may show a decline in blood glucose during exercise. * Further support for this conclusion is that patients with Tarui disease (GSD type VII), in which muscle phosphofructokinase is defective, do not exhibit the second-wind phenomenon.

Question 27

GSD Type V McArdle Disease Histology

Answer 27

A. sub-sarcolemmal vacuoles seen on H&E stain B. dark-stained glycogen on PAS stain.

Question 28

GSD Type V McArdle Disease Workup

Answer 28

* Serum creatine kinase (elevated due to muscle damage) * Glucose (normal with fast) * Urine myoglobin (elevated due to rhabdomyolysis) * Ischemic forearm test (no increase lactate from muscle) * Muscle Biopsy (diminished or no myophosphorylase)

Question 29

GSD Type V McARdle Disease Treatment

Answer 29

* A high protein diet may improve exercise tolerance. * Creatine supplementation may increase exercise tolerance. -Creatine is converted to creatine phosphate that may help sustain the initial energy demands at the outset of exercise. •Avoidance of intense exercise is necessary.

Question 30

GSD Type VI Hers Disease

Answer 30

* caused by a lack or reduced activity of hepatic glycogen phosphorylase * The disease presents in early childhood (ages 1-5) and is one of the milder forms of hepatic GSD. * Patients exhibit hepatomegaly and growth retardation. * Splenomegaly does not occur in GSD VI. * Symptoms of hypoglycemia, hyperlipidemia and ketosis are generally mild. * Although postprandial lactic acidemia occurs in GSD VI, it is not severe enough to cause hyperuricemia. * The disease conditions improve with age. * The disease is best confirmed by analyzing enzyme activity in a liver biopsy sample.

Question 31

Biochemisrty of GSD Type VI Hers Disease

Answer 31

* Symptoms are those expected when hepatic glycogenolysis is impaired. * That the disease is typically mild suggests there is remaining significant enzymatic activity.

Question 32

GSD Type VI Hers Disease Workup

Answer 32

* Blood glucose (mild hypoglycemia with a 3-5 h fast) * Urinary/serum ketone bodies (mild elevation may be seen with a fast) * Serum lipids (mild hyperlipidemia; serum cholesterol elevated more than triglycerides) * MRI or CT scans (evaluate liver volume)

Question 33

GSD Type VI Hers Disease Treatment

Answer 33

* Dietary restrictions are sufficient because the disease is mild. * Frequent feedings are only recommended for patients who develop fasting hypoglycemia. * Many patients require no intervention.

Question 34

GSD Type V vs Type VI

Answer 34

* GSD Type VI (Hers disease) is caused by a lack or reduced activity of hepatic glycogen phosphorylase and is a distinctly different disease from GSD Type V (McArdle disease) that only affects muscle glycogen phosphorylase. * The two diseases are distinctly different because the liver and muscle enzymes are products of different genes and hence are isoforms of each other. * Both forms are inherited as autosomal recessive disorders. * GSD Type VI comprises about 30% of all GSD cases making it amongst the most common forms of this group of disorders. -Hers disease is most commonly found amongst the Mennonites with a frequency of ~0.1%. •The frequency of McArdle disease is estimated at 2-3 in 100,000.

Question 35

GSD Type 0 Glycogen Synthase Defect

Answer 35

* GSD type 0 is a consequence of a defect of glycogen synthase (GYS2 isoform). * The disease is autosomal recessive. GSD Type 0 represents just 1% of all cases of GSD.

Question 36

GSD Type 0 Glycogen Synthase Defect Clinical Features

Answer 36

•Patients present with fasting hypoglycemia and ketosis with initial occurrence in infancy to early childhood. -When severe and frequent this is the major morbidity. * Consequently, patients often exhibit morning fatigue that responds to feeding. * Fasting may also cause both blood alanine and lactate to be abnormally low. * Following a meal, dietary glucose cannot be readily stored as glycogen leading to postprandial hyperglycemia and even lactic acidemia. * Lack of treatment in these patients may lead to short stature and osteopenia (abnormally low bone mineral density). * Neurological damage may also occur due to the dependency of nervous tissue on glucose as fuel. * Such damage can lead to delay in development and intellectual insufficiency.

Question 37

Biochemistry of GSD Type 0 Glycogen Synthase Defect

Answer 37

•As a consequence of a glycogen synthase defect, the content of glycogen in the liver will be low but of normal structure. - Small amounts of glycogen still form because the defective enzyme has some minimal activity though in some patients it may too low to be accurately measured. - In tissues that have the GYS1 isoform (e.g., skeletal muscle) the enzyme activity is normal as is the content of glycogen. * During fasting, hypoglycemia results from the insufficient amounts of glycogen that can be mobilized for maintenance of blood glucose. * Because growth hormone is released at night and growth depends on adequate blood glucose concentrations, untreated disease will lead to diminished growth and hence short stature. - Fasting without proper blood glucose homeostasis has a negative effect on the secretion of insulin-like growth factor (IGF) by the liver. - It is IGF that mediates the effects of growth hormone on bone, cartilage and muscle cell proliferation. •The mechanism as to why fasting hypoglycemia is accompanied by ketosis remains unproven. - One possibility is that with reduced fuel availability under hypoglycemic conditions, lipolysis will be accelerated even more, especially because blood insulin will be low even for a fasting state. - Normally in starvation, ketosis is prevented because elevated ketone bodies promote a small release of insulin from the pancreatic beta-cells. Insulin in turn inhibits lipolysis. - However, in these patients, insulin secretion is suppressed because of hypoglycemia and hence there may be poor feedback response to elevated ketone bodies. •Because of reduced production of glucose from glycogen in fasting, initial dependence on gluconeogenesis following food deprivation becomes more critical. Consequently, the blood concentrations of lactate and alanine may be lower than normal since they are the two major gluconeogenic precursors. Postprandial lactic acidemia likely results from dietary glucose being diverted to lactic acid because of the limited ability of liver to form glycogen.

Question 38

GSD Type 0 Glycogen Synthase Defect Workup

Answer 38

Laboratory Tests: * Serum glucose (testing for hypoglycemia) * Serum electrolytes (testing for metabolic acidosis based on anion gap) * Urine ketones (testing for ketosis) * Fasting serum lactate * Liver enzymes – AST/ALT (mild hepatocellular damage may be evident) * Fasting plasma amino acid analysis (testing for hypoalaninemia) Imaging Studies: • Skeletal radiography (testing for osteopenia) Other Tests: • Oral loading of hexose sugars (in patients elicits a marked increase in blood lactate)

Question 39

GSD Type 0 Glycogen Synthase Defect Treatment

Answer 39

•It is critical to avoid fasting. -Hence infants/children must receive frequent feedings especially of protein-rich meals. * Avoiding excess carbohydrate intake is important to limit the possibility of lactic acidemia. * Once the pancreatic amylase activity becomes high enough after birth, a child can be given uncooked cornstarch in the evening to facilitate sleeping through the night. -Raw cornstarch is a complex glucose polymer acted on slowly by pancreatic amylase over about a 6- h period.

Question 40

GSD Type IV Anderson Disease Branching Enzyme Defect

Answer 40

* Like GSD Type 0, GSD Type IV (Andersen disease) affects glycogen synthesis. * However, two predominant differences are that GSD- Type IV presents with abnormal glycogen structure and hypoglycemia is uncommon in the early stages of the disease. * The disease is inherited as autosomal recessive and accounts for about 3% of all GSD cases.

Question 41

GSD Type IV Anderson Disease Branching Enzyme Defect Clinical Features

Answer 41

* The disease presents in early childhood. * Patients develop severe liver disease presenting even in early infancy with hepatomegaly and a failure to thrive. * Ultimately the disease can lead to terminal liver failure with cirrhosis by age 5. * The liver damage leads to portal hypertension with portosystemic blood shunting resulting in esophageal varices, encephalopathy, splenomegaly, ascites and/or diminished renal function. * In rare instances, patients have developed hepatocellular carcinoma. * Liver biopsy reveals excessive accumulation of glycogen as fibrillar aggregates. * Serious morbidity is most often associated with hepatic failure due to cirrhosis and hepatosplenomegaly. * Less frequently cardiomyopathy may occur.

Question 42

Biochemistry of GSD Type IV Anderson Disease Branching Enzyme Defect

Answer 42

•With a deficiency of branching enzyme, glycogen structure will be similar to plant amylose; long glucose polymers lacking branches. - The lack of branches works well in plants as a way of storing water (e.g., potatoes). - However, normally the highly branched structure of glycogen excludes water because of the hydrogen bonding that occurs between glucose residues on parallel branches. Instead lacking or with much fewer branches, the hydroxyl groups of the glucose residues instead become hydrated. - This excessive water storage in the liver causes hepatomegaly because the cells become swollen. * Because there is glycogen stored in the liver, albeit abnormally structured, glucose mobilization from glycogen will respond to fasting so that patients do not present with fasting hypoglycemia early in the disease. * However, the liver damage caused by the hepatomegaly eventually leads to impaired metabolism as cells die. -Consequently, later in the course of the disease patients may exhibit hypoglycemia following food deprivation.

Question 43

GSD Type IV Anderson Disease Branching Enzyme Defect Workup

Answer 43

* Unlike GSD Type 0, GSD Type IV is evident in fibroblasts. Therefore, cultured fibroblasts can be tested for the level of branching enzyme activity as a definitive diagnosis. * When genetic counseling shows the possibility of a fetus having the disease, DNA analysis can be performed on either cultured amniocytes or chorionic villi. * Prenatal diagnosis of placental biopsies has also become a possibility. In instances where patients present with neuromuscular involvement, serum creatine kinase will be elevated. * Laboratory Tests: * Serum creatine kinase (testing for possible neuromuscular involvement) * Fasting hypoglycemia (some indication of the disease progress if present) * Liver enzymes – AST/ALT (hepatocellular damage evident due to hepatomegaly) * Enzyme analysis in fibroblasts Imaging Studies: • Analysis for hepatosplenomegaly Other Tests: * Liver biopsy (evidence of progressive liver dysfunction) * Ischemic forearm test (lack of lactate production with exercise)

Question 44

GSD Type IV Anderson Disease Branching Enzyme Defect Treatment

Answer 44

* Treatment options are limited. * Except for liver transplant, little can be done. * Diet therapy may limit hepatomegaly, hypoglycemia and lessen symptoms but with only a partially successful outcome.

Question 45

GSD Type IV Anderson Disease Branching Enzyme Defect Histology

Answer 45

* Liver section from a patient with GSD IV stained with periodic acid-Schiff (PAS) after diastase treatment. Coarsely clumped cytoplasmic material representing accumulated abnormal glycogen resists diastase treatment; readily stained with PAS. * Normally diastase removes glycogen