Storage disorders

1. Storage disorders

2. OVERVIEW Lysosomal storage disorders Mucopolysaccharidoses Glycogen storage disorders Alkaptonuria

3. LYSOSOMAL STORAGE DISORDERS

4. LYSOSOMAL STORAGE DISOREDRS Lysosomes are key components of the “intracellular digestive tract.” They contain a battery of hydrolytic enzymes, which have two special properties. First, they function in the acidic milieu of the lysosomes. Second, these enzymes constitute a special category of secretory proteins that are destined not for the extracellular fluids but for intracellular organelles. This latter characteristic requires special processing within the Golgi apparatus, which is reviewed briefly.

6. LYSOSOMAL STORAGE DISOREDRS With an inherited deficiency of a functional lysosomal enzyme, catabolism of its substrate remains incomplete, leading to the accumulation of the partially degraded insoluble metabolite within the lysosomes. Stuffed with incompletely digested macromolecules, these organelles become large and numerous enough to interfere with normal cell functions, giving rise to the so-called lysosomal storage disorders

8. LYSOSOMAL STORAGE DISOREDRS

9. LYSOSOMAL STORAGE DISOREDRS

10. LYSOSOMAL STORAGE DISOREDRS

12. GM2gangliosidoses GM2gangliosidoses are a group of three lysosomal storage diseases caused by an inability to catabolize GM2gangliosides. Degradation of GM2gangliosides requires three polypeptides encoded by three distinct genes. The phenotypic effects of mutations affecting these genes are fairly similar, because they result from accumulation of GM2gangliosides. The underlying enzyme defect, however, is different for each.

13. GM2gangliosidoses TaySach’s disease Sandhoff disease GM2gangliosidosis variant AB

14. TaySach’s disease Tay-Sachs disease, the most common form of GM2gangliosidosis, results from mutations in the α-subunit locus on chromosome 15 that cause a severe deficiency of hexosaminidase A. This disease is especially prevalent among Jews, particularly among those of Eastern European (Ashkenazic) origin, in whom a carrier rate of 1 in 30 has been reported.

15. TaySach’s disease The hexosaminidase A is absent from virtually all the tissues GM2ganglioside accumulates in many tissues (e.g., heart, liver, spleen), involvement of neurons in the CNS and ANS and retina dominates the clinical picture. Histology- the neurons are ballooned with cytoplasmic vacuoles, each representing a markedly distended lysosome filled with gangliosides Stains for fat such as oil red O and Sudan black B are positive. Electron microscopy- several types of cytoplasmic inclusions can be visualized, the most prominent being whorled configurations within lysosomes composed of onion-skin layers of membranes

16. Tay Sach’s disease Progressive destruction of neurons, proliferation of microglia, and accumulation of complex lipids in phagocytes within the brain substance. The ganglion cells in the retina are similarly swollen with GM2ganglioside, particularly at the margins of the macula. A cherry-red spot thus appears in the macula, representing accentuation of the normal color of the macular choroid contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina

17. “Normal appearing” at birth Neurological defects Respiratory problems Pnemonia by 3yrs-usual cause of death Profound Psychomotor retardation Hypotonia Cherry red macula

21. Niemann-Pick disease types A and B 5 types - A,B,C,D,E Type A (infantile) and Type B (adult) are due to deficiency of sphingomyelinase, thus can’t break down sphingomyelin. Type C - defect in Esterification of Cholestrol. Type A severe variant is neuropathic form Types A and B more frequent in Ashkenazi Jews

22. Niemann-Pick disease types A and B Type A is a severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, and progressive wasting and early death within the first 3 years of life. In contrast, type B disease patients have organomegaly but generally no central nervous system involvement. They usually survive into adulthood.

23. Clinical features • Products accumulate in • Neurons in brain • Phagocytic cells in spleen • Liver • Bone marrow • Lungs • Lymph nodes • Hepatosplenomegaly

24. Niemann-Pick disease types A and B Rapid deterioration of CNS Skin is pigmented yellow-brown Lymph nodes are enlarged. Ocular manifestations: (cherry-red macula and corneal opacifications) are evident Few survive beyond 4 years of age

25. Niemann-Pick disease types A and B In the classic infantile type A variant, a missense mutation causes almost complete deficiency of sphingomyelinase. Sphingomyelin is a ubiquitous component of cellular (including organellar) membranes, and so the enzyme deficiency blocks degradation of the lipid, resulting in its progressive accumulation within lysosomes, particularly within cells of the mononuclear phagocyte system. Affected cells become enlarged, sometimes to 90 μm in diameter, due to the distention of lysosomes with sphingomyelin and cholesterol.

26. Niemann-Pick disease types A and B Innumerable small vacuoles of relatively uniform size are created, imparting foaminess to the cytoplasm. In frozen sections of fresh tissue, the vacuoles stain for fat. Electron microscopy confirms that the vacuoles are engorged secondary lysosomes that often contain membranous cytoplasmic bodies resembling concentric lamellated myelin figures, sometimes called “zebra” bodies.

28. Characteristic sea-blue histiocyte in a bone marrow smear

31. Gaucher disease Refers to a cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase. This disease is the most common lysosomal storage disorder. The affected gene encodes glucocerebrosidase, an enzyme that normally cleaves the glucose residue from ceramide. As a result of the enzyme defect, glucocerebroside accumulates principally in phagocytes but in some subtypes also in the central nervous system. Glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and erythrocytes.

32. Gaucher’s Disease • Most common. • Defeciency: acidβ-glucosidase. • Type I - 99% • Chronic Non-neuronopathic Form • Big Spleen • Accumulates In Bones • Type II • Infantile form • Lethal in 6 months • No predilection for Jews

34. Pale staining Gaucher cells have a faintly striated cytoplasm

36. Gaucher disease. Striations are well visualised in PAS after diastase digestion

37. Gaucher’s disease Prenatal diagnosis – aminocentesis , chrorionicvillus biopsy Gene therapy Enzyme replacement therapy

38. Mucopolysaccharidoses

39. Mucopolysaccharidoses Group of closely related syndromes that result from genetically determined deficiencies of lysosomal enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans). Chemically, mucopolysaccharides are long-chain complex carbohydrates that are linked with proteins to form proteoglycans. They are abundant in the ground substance of connective tissue.

40. Mucopolysaccharidoses The glycosaminoglycans that accumulate in MPSs are dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. The enzymes involved in the degradation of these molecules cleave terminal sugars from the polysaccharide chains disposed along a polypeptide or core protein. In the absence of enzymes, these chains accumulate within lysosomes in various tissues and organs of the body.

41. Mucopolysaccharidoses Classified numerically from MPS I to MPS VII each resulting from the deficiency of one specific enzyme. All except one are inherited as autosomal recessive traits; the exception, called Hunter syndrome, is an X-linked recessive trait. In general, MPSs are progressive disorders, characterized by coarse facial features, clouding of the cornea, joint stiffness, and mental retardation. Urinary excretion of the accumulated mucopolysaccharides is often increased.

42. Mucopolysaccharidoses Morphology. The accumulated mucopolysaccharides are generally found in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells, and fibroblasts throughout the body. Common sites of involvement are thus the spleen, liver, bone marrow, lymph nodes, blood vessels, and heart.

43. Mucopolysaccharidoses Microscopy Affected cells are distended and have apparent clearing of the cytoplasm to create so-called balloon cells. Under the electron microscope, the clear cytoplasm can be resolved as numerous minute vacuoles. These are swollen lysosomes containing a finely granular periodic acid–Schiff–positive material that can be identified biochemically as mucopolysaccharide. In addition, however, some of the lysosomes in neurons are replaced by lamellated zebra bodies similar to those seen in Niemann-Pick disease.

44. Mucopolysaccharidoses Hepatosplenomegaly, skeletal deformities, valvular lesions, and subendothelial arterial deposits, particularly in the coronary arteries, and lesions in the brain, are common threads that run through all of the MPSs. In many of the more protracted syndromes, coronary subendothelial lesions lead to myocardial ischemia. Thus, myocardial infarction and cardiac decompensation are important causes of death.

45. GLYCOGEN STORAGE DISORDERS

46. The glycogen storage diseases result from a hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen. Depending on the tissue or organ distribution of the specific enzyme in the normal state, glycogen storage in these disorders may be limited to a few tissues, may be more widespread while not affecting all tissues, or may be systemic in distribution.[

48. On the basis of specific enzyme deficiencies and the resultant clinical pictures, glycogenoses have traditionally been divided into a dozen or so syndromes designated by roman numerals, and the list continues to grow. • On the basis of pathophysiologyglycogenoses can be divided into three major subgroups • Hepatic forms • Myopathic forms • Glycogen storage diseases associated with (1) deficiency of α-glucosidase (acid maltase) (2) lack of branching enzyme

50. HEPATIC type