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.

1. Nafisa Nawal Islam
Dept. of Genetic Engineering and Biotechnology
University of Dhaka
Niemann-Pick Disease
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Date: 05-Oct-2013
www.joyofjacob.blogspot.comwww.niemannpick.blogspot.com

2. Discussed topics
• Introduction
• History
• Types
• Prognosis
• Incidence
• Causes
• Pathophysiology
• Mechanism of Cholesterol Trafficking
• Signs and Symptoms
• Diagnosis
• Treatment
• Prevention
• Research Direction 2

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
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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
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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
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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.
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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
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8. Mutations in
SMPD1 gene
Mutations in
NPC-1 genes
Mutations in
NPC-2 genes
Causes
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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
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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. retaining
Source: http://disorders.eyes.arizona.edu/disorders/niemann-pick-disease-types-and-b
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12. Source: http://disorders.eyes.arizona.edu/disorders/niemann-pick-disease-type-c2
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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
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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
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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)
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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.
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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. 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.  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?
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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
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Is there any Treatment?

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
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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
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