STORAGE DISORDER - a heterogeneous group of rare inherited disorders.pptx

Lysosomes are sub cellular organelles responsible for the physiologic turnover of cell constituents.
The lysosomes is commonly referred to as the cell’s recycling centers.

1. STORAGE DISORDER

2. INTRODUCTION Lysosomes are sub cellular organelles responsible for the physiologic turnover of cell constituents. The lysosomes is commonly referred to as the cell’s recycling centers .

3. They contain catabolic enzymes which require a low pH environment in order to function optimally. If one of these catabolic enzymes is defective, because of a mutation, large molecules accumulate within the cell, eventually killing it.

4. STORAGE DISORDER Lysosomal storage diseases describe a heterogeneous group of rare inherited disorders characterized by the accumulation of undigested or partially digested macromolecules resulting in cellular dysfunction and clinical abnormalities. Usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar containing proteins) or so called mucopolysaccharides.

5. TYPES Classically, lysosomal storage diseases encompassed only enzyme deficiencies of the lysosomal hydrolases. 40 types of LSD like Tay Sach Disease, Fabry Disease, Gaucher disease, Niemann Pick disease, Pompe’s disease etc. All are autosomal recessive disease except Hunter, Danon and Fabry disease which are X linked.

6. GAUCHER DISEASE This disease is a multisystem lipidosis characterized by hematological changes, organomegaly and skeletal involvement, manifested in the form of bone pains and multiple fractures. It is the most common genetic disorder among Ashkenazi Jews. It is the commonest Lysosomal storage disease.

7. DEFICIENCY It results from deficient activity of Lysosomal Hydrolase, β- Glucocerebrosidase which results in accumulation of undegraded glycolipid in the form of Glucosyl ceramide in the cells of reticuloendothelial system.

8. TYPES OF GAUCHERS DISEASE There are three clinical subtypes Type-1- (from early childhood- adulthood) • easy bruising due to thrombocytopenia, chronic fatigue due to anemia • hepatomegaly Progressive enlargement of spleen • Clinical bone involvement in the form of bone pains, or pathological fractures.

9. TYPES OF GAUCHERS DISEASE Type 2- • less common, • characterized by neurodegeneration, extreme visceral involvement • death within 2 years of life. Type 3- • It is intermediate in presentation to type 1 and 2. • Neurological involvement is there but occurs later in life with decreased severity as compared to Type 2.

10. MICROSCOPY Gaucher cells are plump macrophages that characteristically have the appearance in the cytoplasm of crumpled tissue paper due to accumulation of glucocerebroside.

11. Tay Sach Disease This is an inborn error of metabolism due to failure of degradation of gangliosides. • The enzyme hexosaminidase A is deficient which is composed of an α and β subunits. Mutation in α subunit. Autosomal recessive traits, with a predilection in the Ashkenazi Jewish population, where the carrier frequency is about 1/25.

12. VARIANTS OF TAY SACHS DISEASE Infantile TSD Birth: normal but develop Loss of motor skills Increased startle reaction Macular pallor and retinal cherry red spot Decreased eye contact Hyperacusis Progressive development of idiocy and blindness are diagnostic of this disease and they are due to wide spread injury to ganglion cells, in brain and retina.

13. Juvenile TSD extremely rare presents in children between 2 - 10 years who develop cognitive, motor, speech difficulties (dysarthria) swallowing difficulties (dysphagia) unsteadiness of gait (ataxia) and spasticity. Patients with Juvenile TSD usually die between 5–15 years.

14. Adult/Late Onset TSD. rare form of the disorder occurs in patients in their 20s and early 30s. It is characterized by unsteadiness of gait and progressive neurological deterioration. speech and swallowing difficulties unsteadiness of gait. spasticity, cognitive decline and psychiatric illness.

15. MICROSCOPY

16. Niemann Pick Disease Autosomal Recessive disorder Defect in sphingomyelinase enzyme. There are 2 types: A and B

17. TYPES OF NIEMANN PICK DISEASE Type A: Present within first 6 months. There is progressive mental retardation, spasticity. Massive hepatosplenomegaly. Failure to thrive. Children die within 2 years of life Type B: Late onset There is no involvement of brain but sphingomyelin is present in excessive amount in liver, spleen, and bone marrow.

18. COMPLICATIONS Cirrhosis, hepatic replacement by foam cells. Progressive pulmonary disease. Death occurs within 20 years of life.

19. MICROSCOPY

20. FABRY DISEASE Fabry disease is caused by mutations in the GLA gene that result in an absence of alpha-galactosidase A activity. Sign and Symptoms Pain: One of the first symptoms which often begins in childhood is a painful burning sensation in the hands and feet called acroparesthesia . The pain can be severe and worsen with exercise, stress, illness, and variations in temperature.

21. Stomach and Intestines Early gastrointestinal symptoms of Fabry disease include abdominal cramps, frequent bowel movements shortly after eating, diarrhea, and nausea. Eye Corneal and lenticular opacities.

22. Skin Condition A common skin condition associated with Fabry disease is a red, non-painful rash known as angiokeratoma . It usually appears in the area between the belly and the knees, but may also appear on other parts of the body such as the lips, tongue, hands, and toes.

23. MUCOPOLYSACCHARIDES MPSs result in accumulation of mucopolysaccharides in many tissues including liver, spleen, heart, blood vessels, brain, cornea, and joints. Affected patients in all forms have coarse facial features. Manifestations of Hurler syndrome include corneal clouding, coronary arterial and valvular deposits, and death in childhood. Hunter syndrome is associated with a milder clinical course

24. Glycogen Storage Diseases ( Glycogenoses ) H ereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen.

25. Glycogen Storage Diseases ( Glycogenoses ) In the most common hepatic form (von Gierke disease), liver cells store glycogen because of a lack of hepatic glucose-6-phosphatase. The liver is enlarged, and patients have hypoglycemia. There are several myopathic forms, including McArdle disease, in which lack of muscle phosphorylase gives rise to storage in skeletal muscles and cramps after exercise. In Pompe disease there is lack of lysosomal acid alpha-glucosidase, and all organs are affected, but heart involvement is predominant.

26. Most common lysosomal storage disorder Niemann pick Gaucher disease Fabry disease Tay sachs

27. NIEMMAN PICK DISEASE

28. Tay sach disease