Nafisa Nawal Islam
Dept. of Genetic Engineering and Biotechnology
University of Dhaka
• Mechanism of Cholesterol Trafficking
• Signs and Symptoms
• Research Direction 2
Niemann–Pick disease refers to
- a fatal inherited metabolic disorder
- classified in a subgroup of lysosomal
storage disorders called sphingolipidoses
- involves dysfunctional metabolism of
- accumulation of harmful quantities of
lipids in the spleen, liver, lungs, bone
marrow, and brain.
• 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.
• 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
- no longer used.
Type A: Most (approx. 85%) cases being fatal by 18 months.
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.
This corresponds to a total incidence of approx. 1 in
100,000 for all types in a general population.
A Approximately 1 in
A and B 1 in 250,000 birth All other populations
C 1 in 150,000 birth
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:
NPC1 vs. NPC2 gene
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
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)
- Abnormal posturing of the limbs, trunk, head and face (dystonia)
- Enlargement of spleen and liver (hepatosplenomegaly)
* reduced appetite
* abdominal distension
- Jaundice (at/shortly after birth)
- Learning difficulties and gradual loss of intellectual ability (dementia)
- 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.
Vertical gazy palsy
0% 20% 40% 60% 80% 100%
Percentage of patients
Garver et al.
The most common Symptoms of NPC1 disease
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)
* 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
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
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
Anecdotally, organ transplant has been attempted with limited success.
Is there any Treatment?
Several other treatment strategies (under investigation in cell culture and
animal models of NPC), include:
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
Is there any Treatment?
• 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
• Loss of myelin in the CNS is considered to be a main pathogenic
• 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