storage disORDERS

1. 25/2/16 storage disORDERS Dr KsheeraCariappa Assistant Professor

2. What are they???? • Group of disorders  genetic defects in the metabolism of carbohydrates, lipids & proteins resulting in intracellular accumulation of their intermediate metabolites (inborn errors of metabolism)

3. Classification • Depending on the biochemical composition of the accumulated material within the cells they are classified as • Glycogen storage diseases / Glycogenoses • Mucopolysaccharidoses • Gangliosidoses • Sulfatidoses

5. GLYCOGEN STORAGE DISEASES

6. Introduction • Glycogen is a branched-chain polymer of glucose and serves as a dynamic but limited reservoir of glucose, mainly in skeletal muscle and liver. • There are a number of different enzymes involved in glycogen synthesis, utilization and breakdown within the body.

7. Continued… • Glycogen storage disorders (GSD) are a group of inherited inborn errors of metabolism due to deficiency or dysfunction of enzymes. • confined to just liver and muscle • But some cause more generalised pathology and affect tissues such as the kidney, heart and bowel. • The classification of glycogen storage disorders is based on the enzyme deficiency and the affected tissue.

9. Epidiomology • The overall GSD incidence is estimated at 1 case per 20,000-43,000 live births. • Type I is the most common (25% of all GSD).

10. Inheritance patterns • Autosomal recessive (I, II, III, IV, V, VII, some IX). • Both parents are carriers. • Chance of sibling being affected is 1 in 4. • X-linked (some IX, VI)

11. Types • There are eleven (11) distinct diseases that are commonly considered to be glycogen storage diseases • Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs as type 0.

13. Type I, Von Gierke's disease Autosomal recessive Affected enzyme: glucose-6-phosphatase Affected tissue: Liver and kidney Clinical features: At birth: failure to thrive & stunted growth • Large quantities of glycogen are formed and stored in hepatocytes, renal and intestinal mucosa cells. • The liver and kidneys become enlarged.

14. hypoglycemia • Abnormalities of lipids hyperlipoproteinaemia & ketosis may lead to xanthoma formation. • Uric acid is often elevated and may cause clinical gout. Galactose, fructose, and glycerol are metabolised to lactate. The elevated blood lactate levels cause metabolic acidosis. • Bleeding manifestations due to platelet defects

16. Treatment • Blood loss may require oral iron. • Raised uric acid levels may require allopurinol. • Treatment of hyperuricaemia and pyelonephritis protect renal function. • Liver transplantation for primary disease or for hepatocellular carcinoma seems effective.

17. Type II, Pompe's disease Cause: • The deficiency of the lysosomal enzyme alpha-1,4-glucosidase (acid maltase) leads to the accumulation of glycogen in many tissues. Clinical feature: • The clinical spectrum is continuous and broad, with presentation in infants, children and adults. • In the infantile form, accumulation of glycogen in cardiac muscle leads to cardiomegaly & cardiac failure.

18. Accumulation may also occur in the liver, which results in hepatomegaly and elevation of hepatic enzymes. • Glycogen accumulation in muscle and peripheral nerves causes hypotonia and weakness. • Glycogen deposition in blood vessels may result in intracranial aneurysms.

20. Diagnosis Muscle biopsy shows a severe vacuolar myopathy with accumulation of both intralysosomal and free glycogen in both the infantile and childhood variants 

21. Treatment: • Enzyme replacement therapy (Alglucosidasealfa) • Diet therapy may provide temporary improvement but does not alter the disease course: a high-protein, low-carbohydrate diet may be beneficial. • Physiotherapy and occupational therapy may be required.

22. Type III, Cori disease • Affected enzyme: Glycogen debranching enzyme. Deposition of abnormal glycogen structure. • Affected tissues: Liver and muscle. • Clinical features: • About 15% affect liver only. Hypoglycaemia, poor growth, hepatomegaly, moderate progressive myopathy. • Symptoms can regress with age. • A few cases of liver cirrhosis and hepatocellular carcinoma have been reported.

23. Continued… • Treatment: As with type I, also protein supplements for muscle disorder.

24. Type IV, Andersen's disease, Amylopectinosis • Affected enzyme: Glycogen branching enzyme. Abnormally structured glycogen forms. • Affected tissues: Many, including liver. Rare variant affects peripheral nerves. • Clinical features: • Hepatomegaly, failure to thrive, cirrhosis, splenomegaly, jaundice, hypotonia, waddling gait, lumbar lordosis.

25. Continued… • Treatment: Liver transplant. • Prognosis: Mostly death by age 4 due to cirrhosis and portal hypertension.

26. Type V, McArdle's disease Cause: Myophosphorylase deficiency Affected tissue: Muscle Clinical features • Clinical findings may be absent on physical examination. Muscle strength and reflexes may be normal • Painful muscle cramps after exercise • In later adult life, persistent proximal weakness and muscle wasting may be present.

27. The fatal infantile form presents with hypotonia and reduced reflexes. • Ischaemic forearm test: traditional test but is painful and non-ischaemic exercise tests are now preferred.

28. Treatment • No specific treatment exists. • Avoid strenuous (anaerobic or sustained) exercise, including lifting or pushing. • A carbohydrate rich diet benefits patients.

29. Type VI, Hers disease • Affected enzyme: Liver phosphorylase. • Affected tissues: Liver, rare cardiac form. • Clinical features: • Most common variant is X-linked therefore usually affects only males. • Hepatomegaly, hypoglycaemia, growth retardation, hyperlipidaemia.

30. Continued… • Treatment: Cardiac transplantation for rare cardiac form. May need frequent feeding to avoid hypoglycaemia. • Prognosis: Usually normal life span.

31. Type VII, Tarui disease Cause: Phosphofructokinase (PFK) deficiency Affected tissue: Muscle Clinical features: • Exercise intolerance, muscle cramping, exertionalmyopathy, compensated haemolysis and myoglobinuria. Note : Symptoms can be similar to McArdle's Glycogen Storage Diseasebut more severe.

32. Treatment: No specific treatment exists. There is evidence that a high protein diet may improve muscle function and slow progression of the disease. Vigorous exercise should be avoided as it causes myoglobinuria.

33. Type XI, Fanconi-Bickel syndrome • Affected enzyme: Glucose transporter GLUT2[solute carrier family 2 ,facilitated glucose transporter] • Clinical features: Similar features to Von Gierke's disease, e.g. hypoglycaemia.

34. Type 0, Lewis disease • Affected enzyme: Hepatic glycogen synthase. • Affected tissues: Liver. • Clinical features • Seizures can occur. • Fatigue and muscle cramps after exertion. • Mild growth retardation in some cases.

35. Investigation Blood tests: • Blood glucose: hypoglycaemia is likely • Liver function tests: monitoring for hepatic failure • Anion gap calculation: if glucose low, this may indicate lactic acidaemia • Urate

36. Creatinine clearance • Creatine kinase • Full blood count

37. Urine tests: • Myoglobinuria after exercise found in 50% of people with McArdle'sand Tauri’s disease.

38. Imaging • Abdominal ultrasound scan: hepatomegaly • Echocardiography: to look for cardiac involvement in certain types of GSD

39. Biopsy • Of liver. • Muscle or other tissues gives definitive diagnosis.

40. Differential Diagnosis • In GSD affecting muscle, exclude the muscular dystrophies (including Duchenne's) and secondary disorders of muscle including polymyositis.

41. MUCOPOLYSACCHARIDOSES

42. Mucopolysaccharidoses are a group of six inherited syndromes numbered from MPS I to MPS VI. • Each of these results from deficiency of specific lysosomal enzyme involved in the degradation of mucopolysaccharides or glycosaminoglycans, and are, therefore, a form of lysosomal storage diseases. • Mucopolysaccharides which accumulate are: chondroitinsulphate, dermatansulphate, heparansulphate and keratansulphate.

43. All these syndromes are autosomal recessive disorders except MPS II (Hunter’s syndrome) which has X-linked recessive transmission. • Syndrome of MPS manifests in infancy or early childhood and involves multiple organs and tissues, chiefly connective tissues, liver, spleen, bone marrow, lymph nodes, kidneys, heart and brain.

44. The mucopolysaccharides accumulate in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells and fibroblasts. • The material is finely granular and PAS-positive by light microscopy. • By electron microscopy, it appears in the swollen lysosomes and can be identified biochemically as mucopolysaccharide.

45. Hurler Syndrome • Mucopolysaccharidoses I (MPS I) • Autosomal recessive (chromosome 4) 1/100,000 births • Accumulate dermatan and heparin sulphate

46. Clinical features: Progressive deterioration • Large liver and spleen • Dwarfism • Hearing loss • Macroglossia • Mental retardation • Cloudy corneas • Limited joint movement • Respiratory abnormalities

47. Hunter Syndrome Mucopolysaccharidosis II Deficiency of iduronate-2-sulfatase • Dermatan and heparin sulfate • X-linked recessive (rare disease, >200 mutations) • Airway obstruction • Skeletal deformities • Cardiomyopathy • Neurological decline • Death 2nd decade

48. GANGLIOSIDOSES

49. Gangliosidoses • Two groups 1. GM 1 Gangliosidoses • Cause • Due to deficiency of enzyme beta galactosidase • Resulting in abnormal storage of acidic lipid materials particularly in nerve cells of central and peripheral nervous system.

50. Types a) Infantile • Neurodegeration • Seizures • Hepatosplenomegally • Coarsning of fascial features • Skeletal irregularites • Distended abdomen • Deafness • Blindness