STORAGE DISORDERS ENZYME DEFECTS CONSEQUENCES Accumulation of substrate

STORAGE DISORDERS

ENZYME DEFECTS & CONSEQUENCES • Accumulation of substrate - storage disorders • Metabolic block & decreased amount of end product -albinism • Failure to inactivate a tissue-damaging substrate - alpha 1 anti-trypsin deficiency

STORAGE DISORDERS • Inborn errors of metabolism – carbohydrate, lipid, protein

LYSOSOMAL STORAGE DISORDERS • most enzymes are within lysosomes IN THESE DISORDERS - Lysosomes are stuffed with incompletely digested macromolecules - Enlarge, accumulate substances, interfere with normal function - Reticulo-endothelial system – liver, spleen

LYSOSOMAL STORAGE DISORDERS • GLYCOGENOSIS Type 2—Pompe disease SPHINGOLIPIDOSES GM 1 gangliosidosis Type 1—infantile, generalized Type 2—juvenile GM 2 gangliosidosis Tay-Sachs disease Sandhoff disease GM 2 gangliosidosis variant AB

LYSOSOMAL STORAGE DISORDERS SULFATIDOSES • Metachromatic leukodystrophy • Multiple sulfatase deficiency • Krabbe disease • Fabry disease • Gaucher disease • Niemann-Pick disease: types A and B

LYSOSOMAL STORAGE DISORDERS • MUCOPOLYSACCHARIDOSES (MPSs) MPS I H (Hurler) MPS II (Hunter) • MUCOLIPIDOSES (MLs) I-cell disease (ML II) and pseudo-Hurler polydystrophy

Gaucher Disease • a cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase

Gaucher Disease • type I, or the chronic non-neuronopathic form. • the most common - 99% of cases, • storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain. • Splenic & skeletal involvements dominate this pattern of the disease. • It is found principally in Jews. • adults • Individuals with this disorder have reduced but detectable levels of glucocerebrosidase activity. • Longevity is shortened but not markedly

Gaucher Disease Type II, or acute neuronopathic infantile acute cerebral pattern. no predilection for Jews. there is virtually no detectable glucocerebrosidase activity in the tissues. • clinical picture is dominated by progressive central nervous system involvement, leading to death at an early age • Hepatosplenomegaly is also seen • •

Gaucher Disease • • third pattern, type III, intermediate between types I and II. systemic involvement characteristic of type I but have progressive central nervous system disease that usually begins in adolescence or early adulthood.

Morphology • Glucocerebrosides accumulate in massive amounts within phagocytic cells throughout the body in all forms. • The distended phagocytic cells, known as Gaucher cells, are found in the spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer's patches • have a fibrillary type of cytoplasm likened to crumpled tissue paper • Periodic acid–Schiff staining is usually intensely positive

Niemann-Pick disease types A and B • refers to two related disorders that are characterized by lysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase

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

Niemann-Pick disease • Sphingomyelin is a ubiquitous component of cellular membranes, • enzyme deficiency blocks degradation of lipid, • progressive accumulation within lysosomes, particularly within cells of the mononuclear phagocyte system. • Affected cells become enlarged, (90 μm) due to the distention of lysosomes with sphingomyelin and cholesterol. 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.

Glycogen Storage Disorders Glycogen storage disorders are classified according to which enzyme is lacking /not working normally & also which part of the body is affected Glycogen storage disorders mostly tend to affect liver and muscles. can affect kidney, heart, blood vessels, nervous system & bowel.

Glycogen Storage Disorders Type Ia (von Gierke's disease), type Ib, type Ic, type Id. Type II (Pompe's disease). Type III (Forbes-Cori disease). Type IV (Andersen's disease). Type V (Mc. Ardle's disease). Type VI (Hers' disease). Type VII (Tarui's disease). Type IX (liver phosphorylase kinase deficiency). Type XI (Fanconi-Bickel syndrome). Type 0 (Lewis' disease).

Hepatic type —von Gierke disease (type I) • Glucose-6 -phosphatase • Hepatomegaly —intracytoplasmic accumulations of glycogen and small amounts of lipid; intranuclear glycogen • Renomegaly —intracytoplasmic accumulations of glycogen in cortical tubular epithelial cells • Failure to thrive, stunted growth, • Hypoglycemia due to failure of glucose mobilization, often leading to convulsions

Myopathic type Mc. Ardle syndrome (type V) • Muscle phosphorylase • Skeletal muscle only —accumulations of glycogen predominant in subsarcolemmal location • Painful cramps associated with strenuous exercise; • myoglobinuria

Generalized glycogenosis —Pompe disease (type II) • Lysosomal glucosidase (acid maltase) • Mild hepatomegaly • Cardiomegaly • Skeletal muscle hypotonia, & cardiorespiratory failure within 2 years; • a milder adult form with only skeletal muscle involvement, presenting with chronic myopathy