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Niemann Pick Disease (Nafisa Nawal Islam)

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October is the global awareness month of Niemann-Pick Disease (NPD), a fatal inherited metabolic disorder. Hence, I am sharing a presentation I made on NPD in 2013 in this month of 2016.

Published in: Health & Medicine
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Niemann Pick Disease (Nafisa Nawal Islam)

  1. 1. Nafisa Nawal Islam Dept. of Genetic Engineering and Biotechnology University of Dhaka Niemann-Pick Disease 1 Date: 05-Oct-2013 www.joyofjacob.blogspot.comwww.niemannpick.blogspot.com
  2. 2. Discussed topics • Introduction • History • Types • Prognosis • Incidence • Causes • Pathophysiology • Mechanism of Cholesterol Trafficking • Signs and Symptoms • Diagnosis • Treatment • Prevention • Research Direction 2
  3. 3. Niemann–Pick disease refers to - a fatal inherited metabolic disorder - classified in a subgroup of lysosomal storage disorders called sphingolipidoses - involves dysfunctional metabolism of sphingolipids - accumulation of harmful quantities of lipids in the spleen, liver, lungs, bone marrow, and brain. Introduction 3
  4. 4. • 1914 - Albert Niemann published the first description of Niemann–Pick disease, type A. • 1927 - Ludwig Pick described the pathology of the disease. • Early 1980s - The terms "Niemann–Pick type I" and "Niemann– Pick type II" were proposed to separate the high and low sphingomyelin forms of disease. • 1961 - Crocker proposed the classification of the disease that vary on the age of onset and severity. History 4
  5. 5. • Type A - Classic infantile form  Type B - Visceral juvenile form  Type C - Sub-acute/juvenile form - most common form of the disease - subtype with brain complications into C1 and C2  Type D (the "Nova Scotian type”) - caused by the mutation in same gene as Type C1 - was originally separated from Type C to delineate a group of patients sharing a common ancestry with otherwise identical disorders. - no longer used. Types 5
  6. 6. Prognosis  Type A: Most (approx. 85%) cases being fatal by 18 months. Rest-2/3 years  Type B: Children may live a comparatively long time, but may require supplemental oxygen because of lung impairment. • Type C: The life expectancy varies: some die in childhood, less severely affected ones can live into adulthood. 6
  7. 7. This corresponds to a total incidence of approx. 1 in 100,000 for all types in a general population. Niemann-Pick Disease type Incidence Among A Approximately 1 in 40,000 birth Ashkenazi Jews A and B 1 in 250,000 birth All other populations C 1 in 150,000 birth Incidence 7
  8. 8. Mutations in SMPD1 gene Mutations in NPC-1 genes Mutations in NPC-2 genes Causes 8
  9. 9. NPC1 NPC2 (or HE1 gene) Mutation in 95% of patients Rest 5% of patients Mapped at chromosome 18q11 chromosome 14q24.3 • Both genes encode cholesterol-binding protein, required for the transport of cholesterol. • Over 260 mutations have been identified in NPC1 • Mutations include: missense mutations small deletions point mutations NPC1 vs. NPC2 gene 9
  10. 10. • The disease has an autosomal recessive pattern of inheritance. • Both alleles of the gene must be mutated in such a way that function is impaired. • If both parents are carriers, there is a 25% chance for an affected child with each pregnancy. Is it Hereditary? ©www.medindia.net 10
  11. 11. retaining Source: http://disorders.eyes.arizona.edu/disorders/niemann-pick-disease-types-and-b 11
  12. 12. Source: http://disorders.eyes.arizona.edu/disorders/niemann-pick-disease-type-c2 12
  13. 13. In the classic infantile Type-A variant, a missense mutation Complete deficiency of sphingomyelinase Blocking the degradation of lipid Accumulation of sphingomyelin and cholesterol within lysosomes Enlargement of lysosomes and affected cells Creation of many small uniform-sized vacuoles, imparting a foamy appearance to the cytoplasm Pathophysiology 13
  14. 14. Mechanism of Cholesterol Trafficking • In normal cells, LDL-derived cholesterol enters cells via endocytosis by the LDL receptor • digested within the late endosomes and lysosomes. • bind to NPC1 located in the membranes. • transported to the ER & Golgi apparatus for recycling within the cell • ultimately to the plasma membrane (where the majority of cellular cholesterol resides). © www.treatable-id.org Figure: Cholesterol transport in normal and NP-C cells 14
  15. 15. Type A  Large abdomen within 3-6 months  Cherry red spot in the eye  Feeding difficulties (dysphagia)  Loss of early motor skills (ataxia)  Rapid decline in the child after 6 months Type B  Abdominal swelling may occur in early childhood  No brain and nervous system involvement  Some may develop repeated respiratory infections and breathing problems Signs and Symptoms (related to the organs in which they accumulate) 15
  16. 16. Type C - Abnormal posturing of the limbs, trunk, head and face (dystonia) - Enlargement of spleen and liver (hepatosplenomegaly) * reduced appetite * abdominal distension * pain * thrombocytopenia - Jaundice (at/shortly after birth) - Learning difficulties and gradual loss of intellectual ability (dementia) - Seizures - Irregular speech (dysarthria) - clumsiness and problem in walking - Sudden loss of muscle tone (cataplexy) associated with laughter - Impaired (upward and downward) movement of eyes - Enlargement of Bone marrow cavities - Thinning of cortical bone - Sleep related disorders, e.g. sleep inversion (sleepiness during the day and wakefulness at night) - Bipolar disorder, and depression, including hallucinations, delusions etc. 16
  17. 17. 17 87% 87% 83% 81% 80% 70% 52% 52% 52% 28% 42% 15%Hearing problems Psychiatric disorders Sleeping problems Epilepsy Respiratory dysfunction Dysarthria Gelsatic cataplexy Dysphagia Vertical gazy palsy Ataxia Learning difficulties Clumsiness 0% 20% 40% 60% 80% 100% Percentage of patients Garver et al. The most common Symptoms of NPC1 disease
  18. 18. Type A and B: * Measurement of ASM amount in WBC - by using a blood/bone marrow sample. - can detect patients, not carriers. * DNA tests (to determine if carriers have type A or type B) Type C: * Skin biopsy : scientists closely examine how the skin cells grow, keep track of how they move & store cholesterol. * DNA tests  Few centers offer tests for prenatal diagnosis.  Other tests might include: * Bone marrow aspiration * Liver biopsy * Slit-lamp eye exam 18 Diagnosis
  19. 19.  No effective treatment for Type A.  Bone marrow transplantation for Type B  A new treatment Miglustat (a glucosylceramide synthase inhibitor) has been approved for Type C.  Hydroxy-propyl-beta-cyclodextrin (HPbCD) as a potential treatment for NPC.  Individuals with Types C and D are frequently placed on a healthy, low- cholesterol diet and cholesterol lowering drugs.  Supportive care through nutrition, medication, physical therapy, occupational therapy and being followed by specialists can help relieve many symptoms, e.g. pain and seizures.  Parents may need to consider placement of a feeding/gastrostomy tube (g-tube)  Anecdotally, organ transplant has been attempted with limited success. Is there any Treatment? 19
  20. 20.  Several other treatment strategies (under investigation in cell culture and animal models of NPC), include:  Cholesterol mobilization  Neurosteroid (a special hormone that affects brain and other nerve cells) replacement  Curcumin (an anti-inflammatory & Ca-modulatory agent)  Pregnane X-receptor (identified as a potential target)  Future possible treatments may be –  Enzyme replacement therapy  Gene therapy 20 Is there any Treatment?
  21. 21. • DNA tests for Niemann-pick Type A & B  Identification of genetic defects in the DNA of many NPC patients  Carrier detection testing  Genetic testing and genetic counseling Prevention 21
  22. 22. • Loss of myelin in the CNS is considered to be a main pathogenic factor. • In animal models (carrying the underlying mutation for NPD), the expression of Myelin gene Regulatory Factor (MRF)* has been shown to be decreased. *MRF - an important transcription factor in the development and maintenance of myelin sheaths Research Direction 22
  23. 23. 23

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