Glycogen Metabolism Disorders
Liver Glycogenoses:
Type 0 (Glycogen synthetase deficiency):
• The glycogen synthetase enzyme is deficient in the liver and is normal in muscle and blood cells. It manifests itself with hypoglycemic convulsions.
• Hyperglycemiaglucosuria and increased lactate are typical with normal insulin levels after meals.
• There is no hepatomegaly.
• Short stature and osteopenia can be seen. Prognosis is a good glycogen storage disease.
Type 1a (Von Gierke disease):
• Glucose-6-phosphatase activity is insufficient in the liver, kidney and intestine. Glucose-6-phosphatase is the final enzymatic step in glucose production through glycogenolysis and gluconeogenesis in the liver.
• In its deficiency, glucose-6-phosphate cannot be converted into glucose and accumulates in the tissues, and the blood glucose level decreases.
• Glucose-6-phosphate, which cannot be converted to glucose, is converted to purines and uric acid on the one hand, lactate via pyruvate, and acetyl coenzyme A, which is the main substrate in the synthesis of triglycerides and cholesterol.
• To compensate for hypoglycemia, lipolysis increases and fatty acids increase. Xanthoma, lipemia retinalis occurs. Plasma has a milky appearance due to high triglyceride levels.
• Hyperuricemia occurs as a result of increased uric acid synthesis and decreased renal urate clearance.
Clinic
• The clinical picture occurs with hepatomegaly, lactic acidosis, hypoglycemic convulsions and respiratory distress in the neonatal period. Symptoms become evident towards the end of the first year.
• Stone baby face (fat cheeks, thin limbs, short stature and abdominal swelling)
• Massive hepatomegaly, enlarged kidneys (spleen is of normal size)
• Growth retardation
• These patients are prone to bleeding because of impaired platelet adhesion and aggregation. Prolongation of bleeding time and nosebleeds are seen.
• Gout usually occurs after puberty as a result of hyperuricemia in patients. Xanthomas, pancreatitis and atherosclerosis may occur due to severe hyperlipidemia.
• There may be renal tubular dysfunction and hypercalciuria in childhood. Adults can develop progressive kidney damage in the form of focal segmental glomerulosclerosis and interstitial nephrosis, which usually starts with proteinuria after the age of 20.
• Negative calcium balance due to chronic lactic acidosis causes osteoporosis. Delayed puberty and polycystic ovaries may be seen.
• Hepatic adenoma, bleeding due to adenoma or hepatocellular carcinoma may develop in these patients at the age of 20-30 years.
Diagnosis:
• Hypoglycemia
• High cholesterol and triglyceride level
• Lactic acidosis
• Hyperuricemia
• There is no increase in blood glucose after intravenous glucagon. The lactate level increases.
• When fasting glucose is given, blood sugar increases, while a decrease in the high basal lactate value is typical. • Liver biopsy for definitive diagnosis has now been replaced by genetic mutation tests.
Treatment:
• Frequent feeding with glucose or glucose polymers is recommended for patients. Glucose, maltose or partially hydrolyzed starch solutions can be used for this purpose. In addition, frequent feeding with high-carbohydrate foods throughout the day is recommended.
• Since the conversion of fructose and galatose to glucose is impaired, sucrose and lactose are restricted. When the patient is 2-3 years old, raw corn starch is added to the diet at a dose of 1.75 g/kg at 6-hour intervals.
• Diet should be rich in protein.
• Allopurinol for hyperuricemia, statins for hyperlipidemia, ACE inhibitors for microalbuminuria and citrate to prevent nephrocalcinosis can be added to the treatment.
• Liver transplantation can be planned if there is malignancy in the liver and if there is no response to medical treatment.
Type 1b
• Infections are common in this type, as there is an additional tendency to neutropenia.
• In addition, intermittent diarrhea similar to inflammatory bowel disease is observed because the intestinal barrier is disrupted due to neutrophil dysfunction.
Type 3 (Cori disease; Borderline dextrinosis):
• This type of unbranching (amylo 1,6-glucosidase) enzyme is missing. Abnormal glycogen with a short chain called limit dextrin (limit dextrin) accumulates. Type IIIa involving both liver and muscle; The type that only affects the liver, which is 15% less common, is called IIIb.
• Initial findings are similar to type Ia; They present with hepatomegaly, hypoglycemia, growth retardation and hyperlipidemia.
• Differences from Type Ia;
- While splenomegaly is seen, renomegaly is not.
- Liver findings regress with age.
- In Type III, inflammatory changes in the liver and rarely cirrhosis can be seen.
- There may be myopathy or cardiomyopathy (ventricular hypertrophy, arrhythmias).
- Liver enzyme elevation is more prominent.
- Lactic acid and uric acid levels are usually normal.
Type 4 (Branching enzyme deficiency) (Andersen's disease) GBED
• Amylo 1,4-1,6 transglycosidase enzyme is deficient. Also known as amylopectinosis. It is the rarest form.
• It is normal at birth, but hepatomegaly, growth retardation and splenomegaly develops in a short time. The deposited substance is similar to amylopectin and causes a foreign body reaction in the tissue, causing cirrhosis (develops up to 18 months) and portal hypertension.
• Unlike Type 1, 3, VI and IX, hypoglycemia is not seen.
• Cirrhosis is the most important glycogen storage disease.
• In severe cases, death occurs within 5 years. There is no cure.
Muscle Glycogenoses:
Type 2 (Pompe Disease):
• Alpha 1,4-glucosidase enzyme is missing. It is the only glycogen storage disease due to lysosomal enzyme deficiency. This enzyme is normally a lysosomal enzyme that converts both the 1.6 and 1.4 junctions from glycogen to glucose.
• Since other enzymes are normal in the breakdown of glycogen in this enzyme deficiency, hypoglycemia does not occur, carbohydrate and lipid metabolism and other anomalies are not observed. There is no mental retardation.
• In its infantile form, hypotonia, hyporeflexia, muscle weakness, macroglossia, hepatomegaly and hypertrophic cardiomyopathy develop. Giant QRS wave and P-R shortening are important in ECG.
• Most babies die in the first year due to aspiration pneumonia, respiratory muscle insufficiency and heart failure.
• While serious cardiac involvement is not seen in the juvenile form, progressive muscle weakness especially involving the lower extremities, progressive respiratory failure due to respiratory muscle involvement, lingual weakness, ptosis and ascending aortic basilar artery aneurysms are seen.
• Enzymotherapy (alglucosidase alfa) should be started as soon as possible.
Type 5 (McArdle) and Type-7 (Tarui):
• Both diseases involve skeletal muscle and Type-V has muscle phosphorylase deficiency and TypeVII has muscle phosphofructokinase deficiency.
• Enzyme activity in the liver and smooth muscles is normal. The enzyme in the muscles cannot be used as an energy source. Muscle glycogen concentration is increased.
• The first symptom is fatigue and muscle cramps during exercise.
• Serum transaminase, aldolase and CPK levels increased after exercise.
• Patients are at risk of rhabdomyolysis and acute renal failure due to myoglobinuria.
Diagnosis
• After the ischemic exercise test, blood lactate does not increase and blood ammonia level increases are used for screening purposes. Definitive diagnosis is made by muscle biopsy, enzymatic and mutation analysis.
• Type 5 (McArdle) is the most common glycogen storage disease in adults.
• There is no effective treatment. It is recommended that patients do not do heavy activities. Sucrose or glucose intake before exercise, high protein diet, creatine and vitamin B6 replacements are recommended.
The differences between Tarui disease and Mc Ardle disease are as follows:
1. It is a more severe myopathy, the complaints do not regress with glucose infusion.
2. Hyperuricemia is seen.
3. In Type-VII, compensated hemolytic anemia is common because erythrocyte phosphofructokinase is also decreased.
4. Exercise intolerance may develop acutely after a carbohydrate-rich meal. Because glucose, which cannot be metabolized in the muscle, also inhibits lipolysis and reduces the fatty acid and ketone sources that the muscles will use for energy.
The most common glycogen storage diseases in childhood are types 1, 2, 3 and 4 (liver phosphorylase kinase deficiency).
Type 5 is the most common glycogen storage disease in adults.
Liver glycogenoses: Type 0, Type 1, 3, 6, 9 and 11 (glucose transporter 2 defect) (Hepatomegaly and hypoglycemia are seen in this group). The most common hepatic glycogenosis is X-linked hepatic phosphorylase kinase deficiency.
Cirrhosis: Types 3, 4 and 9
Muscle glycogenoses: Types 2,5 and 7
Involving liver and muscle: Types 3 and 9
Those with renal dysfunction: Types 1 and 11
Those with neurological involvement: 2,3,4
