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Clinical biochemistry lipid storage diseases
- 2. Introduction to lipids Lipid storage disorders Inheritance of lsd Pathophysiology Types of lsd Elaboration on lsd
- 3. Introduction-lipids ■ Fat like substances – important parts of membranes ■ It includes oils,fatty acids,waxes, steroids and other related compounds IMPORTANCE OF LIPIDS ■ Important constituents of cell membranes ■ Helps in absorption of fat soluble vitamins ■ Maintains membrane fluidity ■ Acts as thermal insulator and cellular metabolic regulators ■ Aids in hormone synthesis
- 4. LIPID STORAGE DISEASES ■ Lipid storage diseases or lipodosis are a group of inherited metabolic disorders in which harmful amount of fatty materials called lipids accumulate in some of the body cells and tissues. ■ People with these order - do not produce enzyme to metabolize lipid or produce enzymes that do not metabolize properly. ■ Overtime it causes permanent cellular and tissue damage ■ Especially in brain, peripheral nervous system,liver, spleen and bone marrow.
- 5. INHERITANCE OF LSD ■ Two means of inheritance - autosomal recessive and X- linked recessive AUTOSOMAL RECESSIVE ■ Occurs when both parents carry and pass on copy of faulty but none of the parents show symptoms X- LINKED RECESSIVE ■ Inheritance occurs when mother carries affected gene on the X- chromosome which determines the child’s gender and is passed to the son
- 6. PATHOPHYSIOLOGY ■ Glycosphingolipids are essential components of all cell membranes,inability to degrade these substances and their accumulation results in physiologic and morphologic alteration of specific tissues and organs which lead to characteristic clinical manifestation. ■ In particular,progressive lysosomal accumulation of sphingolipids in the cns can lead to a neurodegenerative course whereas storage in visceral cells can lead to organomegaly, skeletal abnormalities, bone marrow dysfunction, pulmonary infiltrationand other manifestations.
- 7. TYPES OF LIPID STORAGE DISEASES■ Gaucher’s disease ■ Niemann pick dis ■ Fabry’s dis ■ Farber’s dis ■ Krabbe dis ■ Tay Sach’s dis ■ Sandhoff dis ■ Metachromatic leukodystrophy
- 8. 1.GAUCHER’S DIS ■ Most common type of lsd CAUSE ■ Deficiency of enz glucocerebrosidase ■ Accumulation of glucocerebroside in spleen, liver, kidneys, lungs, brain and bone marrow
- 9. Types and symptoms Type 1 Non neuropathic Type2 Acute neuropathic Type3 Chronic neuropathic Age of onset adults infants juvenile Incidence 1 in 100000 1 in 100000 live births 1 in 50000 Clinical presentation Hepatosleenomeg aly Bone marrow suppression Bone abnormalities and fractures Hepatospleenome galy Seizure Dementia Ocular apraxia spasticity Hepatospeenomeg aly Seizure Dementia Ocular apraxia spasticity Enzyme Some activity Very little little
- 10. Diagnosis ■ Made via positive gaucher cells in a bone marrow aspirate ■ Contains monocytes and monocytoid cells which contain inclusions which are acid phosphatase positive and resemble the acid phosphatase positive inclusions in the Gaucher cells. ■ Enzyme beta glucocerebrosidase activity is assayed
- 11. Treatment ■ For type 1 and most type 3 enzyme replacement treatment is given
- 12. 2.NIEMANN PICK’S DIS CAUSE ■ It is of type A and B resulting from accumulation of fatty substance called Sphingomyelin ,due to deficiency of an enzyme called sphingomyelinase. ■ It results in accumulation of sphingomyelin in liver, spleen, bone marrow, lungs and in brain.
- 13. Types and symptoms Type A Type B Age of onset Infants are normal at birth, but at age of six, disease onsets. Pre teen years Symptoms Spleenomegaly Hepatomegaly Swollen lymph nodes Ataxia Spasticity Slurred speech Loss of muscle tone Anaemia Susceptible to infections Ataxia Pheripheral neoropathy Hepatoaspleenomegaly Pulmonary difficulty Brain
- 14. Treatment ■ There is currently no cure for the disease
- 15. 3.Fabry’s dis Cause ■ It is an x-linked disease ■ Caused by deficiency of alpha galactosidase A ■ Causes fat accumulation in the ANS , eyes, kidneys, and cardiovascular system ■ Onset is usually at childhood
- 16. Symptoms ■ Burning pain in arms and legs ■ Corneal clouding ■ Stroke or heart attack due to fatty storage in blood vessel walls ■ Cardiac and renal failure ■ Reduced sweating and gi tract motility reduced ■ Angiokeratoma ■ Early death is caused due to cardiac or renal complications
- 17. Treatment ■ Enzyme replacement therapy is given ■ Dialysis or renal transplant is done
- 18. 4.Farber’s dis CAUSE ■ Deficient enz is ceramidase ■ It results in accumulation of ceramide in joints , tissues, and cns SYMPTOMS ■ Dyspnea ■ Dysphagia ■ Vommiting ■ Arthritis ■ xanthoma ■ Joint contracture
- 19. Treatment ■ no specific treatment ■ Most children with the dis die by age 2
- 20. KRABBE DIS CAUSE ■ Caused by def of beta galactosidase ■ Results in accumulation of galactocerebrosides in white matter of cns and pns SYMPTOMS ■ Onset is usually before 6months ■ Hypertonia ■ Seizures ■ Spasticity ■ Irritability ■ Optic atrophy and blindness
- 21. Diagnosis ■ Characterized by grouping of cells into globoid bodies in whitematter of brain ■ There is also demyelination of nerves and degeneration and destruction of brain cells
- 22. Treatment ■ No specific treatment ■ But bone marrow transplantation is helpful
- 23. 5.Metachromatic leukodystrophy CAUSE ■ Def enz is arylsulphatase A resulting in accumulation of sulfatides in CNS and PNS SYMPTOMS ■ Developed normally at birth ■ Infant develops difficulty in walking and tendency to fall followed by intermittent pain in arms and legs ■ Other symp include loss of vision leading to blindness and developmental delays and dementia
- 24. Treatment ■ It is sympathomatic and supportive ■ Bone marrow transplantation may delay the dis progression
- 25. 6.GANGLIOSIDOSIS GANGLIOSIDOSIS GM1 GM2 -INFANTILE -TAYSACH’S DIS -ADULT TYPE -SANDHOFF DIS
- 26. 6A.GM1 GANGLIOSIDOSIS CAUSES ■ Caused due to def of enz beta galactosidase ■ Results in abnormal storage of acidic lipid materials particularly in nerve cells of cns and pns TYPES AND SYMPTOMS ■ 2 types based on age of onset TYPES SYMPTOMS Infantile Neurodegerative, seizure, hepatospleenomegaly, coarsing facial feature, skeletal irregularity, deafness and blindness Adult type Atrophy, dystonia, corneal clouding, angiakeratoma
- 27. 6B.GM2 GANGLIOSIDOSIS CAUSES Caused due to def of enz beta hexoaminidase TYPES 6B1.TAY SACCH’S DIS CAUSE ■ Due to def of enzbeta hexoaminidase A ■ Resulting in accumulation of gangliosides in nerve cells
- 28. Symptoms ■ Iniyially patient appears normal with sign and symp beginning at age of 6 months ■ Clinical features include ■ Rapid and progressive neuro degeneration ■ Cherry red spots in retina ■ Dementia ■ Deafness ■ Blindness ■ Seizure
- 29. Treatment ■ No specific treatment available ■ Symptomatic and supportive care ■ Anticonvulsants are given for seizures
- 30. 6B2.Sandhoff dis CAUSE ■ Due to def of enz beta hexoaminidase A and B ■ Results in accumulation of gangliosides and globosides in nerve cells SYMPTOMS ■ Neurodegeneration ■ Red spots in retina ■ Dementia ■ Deafness ■ Blindness ■ Hepatospleenomegaly ■ Seizures
- 31. Diagnosis ■ Made through clinical examination , biopsy, genetic testing, molecular testing of cells or tissues and enzyme assays ■ Urine analysis can identify stored material
- 32. Tabulation of LSD DISEASE DEFECTIVE ENZ MAJOR STORAGE COMPOUN D SYMPTOMS TREATMEN T NIEMANN PICK DIS Sphingomyelina se Sphingomyelins Hepatomegaly Sleenomegaly Mental retardation No cure FARBERS DIS Ceramidase Ceramide Painful and deformed joints Enzyme replacement therapy Dialysis or renal transplant GAUCHER S DIS Beta galactosidase Glucocerebrosid es Hepatomegaly Spleenomegal y Osteoporosis Mental retardation Enzyme replacement treatment
- 33. DISEASE DEFECTIVE ENZYME MAJIR STORAGE COMPOUN D SYMOTOMS TREATMEN T KRABBE DIS Beta galactosidase Glucocerebroside s Absence of myelin formation Hepatomegaly Spleenomegaly Mental retardation No specific treatment Bone transplantarion is helpful TAY SACCH’S DIS Hexo aminidase A Ganglioside GM2 Blindness Mental retarrdation Death with 2-3 years No specific treatment Symtomatic and supportive care Anticonvulsant for seizure FABRYS DIS Alpha galactosidase Ceramide trihexoside Renal failue Skin rash Pain in lower extremities Dialysis renal replacement Enz replacement
- 34. DISEASE DEFECTIVE ENZ MAJOR STORAGE COMPOUN D SYMPTOM S TREATMEN T SANDHOFF DIS Beta hexoaminidase A Gangliosides and globosides Neurodegener ation Red spot in retina Blindness Seizure Deafness hepatospleeno megaly No specific treatment METACHR OMATIC LEUKODYS TROPY Arylsuphatase Sulphanides Infants – Difficulty walking Progressive loss of vision Dementia Symptomatic and supportive Bone marrow transplantation
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