This document summarizes advances in understanding and treating Gaucher disease from the past to present and future prospects. It describes key findings such as the identification of the metabolic defect, development of diagnostic tests, characterization of the Gaucher cell, and establishment of enzyme replacement therapy as an effective treatment that improves outcomes. The summary also notes areas of ongoing research including potential new treatments like chaperone therapy, gene therapy and small molecule approaches, as well as emerging links between Gaucher disease and Parkinson's disease.
Gaucher disease is an inherited disorder that
affects many of the body's organs and tissues. The signs and symptoms of this
condition vary widely among affected individuals. Researchers have described
several types of Gaucher disease based on their characteristic features.
Type 1 Gaucher disease is the most common
form of this condition. Type 1 is also called non-neuronopathic Gaucher disease
because the brain and spinal cord (the central nervous system) are usually not
affected. The features of this condition range from mild to severe and may
appear anytime from childhood to adulthood. Major signs and symptoms include
enlargement of the liver and spleen (hepatosplenomegaly), a low number of red
blood cells (anemia), easy bruising caused by a decrease in blood platelets
(thrombocytopenia), lung disease, and bone abnormalities such as bone pain,
fractures, and arthritis.
Types 2 and 3 Gaucher disease are known as
neuronopathic forms of the disorder because they are characterized by problems
that affect the central nervous system. In addition to the signs and symptoms
described above, these conditions can cause abnormal eye movements, seizures,
and brain damage. Type 2 Gaucher disease usually causes life-threatening
medical problems beginning in infancy. Type 3 Gaucher disease also affects the
nervous system, but tends to progress more slowly than type 2.
The most severe type of Gaucher disease is
called the perinatal lethal form. This condition causes severe or
life-threatening complications starting before birth or in infancy. Features of
the perinatal lethal form can include extensive swelling caused by fluid
accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or
other skin abnormalities; hepatosplenomegaly; distinctive facial features; and
serious neurological problems. As its name indicates, most infants with the
perinatal lethal form of Gaucher disease survive for only a few days after
birth.
Another form of Gaucher disease is known as
the cardiovascular type because it primarily affects the heart, causing the
heart valves to harden (calcify). People with the cardiovascular form of
Gaucher disease may also have eye abnormalities, bone disease, and mild
enlargement of the spleen (splenomegaly).
Gaucher disease is an inherited disorder that
affects many of the body's organs and tissues. The signs and symptoms of this
condition vary widely among affected individuals. Researchers have described
several types of Gaucher disease based on their characteristic features.
Type 1 Gaucher disease is the most common
form of this condition. Type 1 is also called non-neuronopathic Gaucher disease
because the brain and spinal cord (the central nervous system) are usually not
affected. The features of this condition range from mild to severe and may
appear anytime from childhood to adulthood. Major signs and symptoms include
enlargement of the liver and spleen (hepatosplenomegaly), a low number of red
blood cells (anemia), easy bruising caused by a decrease in blood platelets
(thrombocytopenia), lung disease, and bone abnormalities such as bone pain,
fractures, and arthritis.
Types 2 and 3 Gaucher disease are known as
neuronopathic forms of the disorder because they are characterized by problems
that affect the central nervous system. In addition to the signs and symptoms
described above, these conditions can cause abnormal eye movements, seizures,
and brain damage. Type 2 Gaucher disease usually causes life-threatening
medical problems beginning in infancy. Type 3 Gaucher disease also affects the
nervous system, but tends to progress more slowly than type 2.
The most severe type of Gaucher disease is
called the perinatal lethal form. This condition causes severe or
life-threatening complications starting before birth or in infancy. Features of
the perinatal lethal form can include extensive swelling caused by fluid
accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or
other skin abnormalities; hepatosplenomegaly; distinctive facial features; and
serious neurological problems. As its name indicates, most infants with the
perinatal lethal form of Gaucher disease survive for only a few days after
birth.
Another form of Gaucher disease is known as
the cardiovascular type because it primarily affects the heart, causing the
heart valves to harden (calcify). People with the cardiovascular form of
Gaucher disease may also have eye abnormalities, bone disease, and mild
enlargement of the spleen (splenomegaly).
A lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine.
The most common lysosomal storage disease,
Incidence: approximately 1 in 40,000 for non-Jewish populations
Caused by a deficiency of the enzyme glucocerebrosidase
The glycolipid glucocerebroside accumulates in lysosomes of macrophages
Lipid-filled Gaucher cells displace normal cells in
Bone marrow
Spleen
Liver
Lungs
CNS
Skeletal disease is slow to respond to ERT and widely varies.
Some patients describe symptomatic improvement within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response.
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
Fabry disease runs in families. It can have lots of different symptoms, including pain in the hands and feet and a specific kind of rash.When you have Fabry disease, a certain type of fatty substance builds up in your body. It narrows your blood vessels, which can hurt your skin, kidneys, heart, brain, and nervous system.
A lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine.
The most common lysosomal storage disease,
Incidence: approximately 1 in 40,000 for non-Jewish populations
Caused by a deficiency of the enzyme glucocerebrosidase
The glycolipid glucocerebroside accumulates in lysosomes of macrophages
Lipid-filled Gaucher cells displace normal cells in
Bone marrow
Spleen
Liver
Lungs
CNS
Skeletal disease is slow to respond to ERT and widely varies.
Some patients describe symptomatic improvement within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response.
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
Fabry disease runs in families. It can have lots of different symptoms, including pain in the hands and feet and a specific kind of rash.When you have Fabry disease, a certain type of fatty substance builds up in your body. It narrows your blood vessels, which can hurt your skin, kidneys, heart, brain, and nervous system.
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1. Advances in Gaucher Disease:
The Past, Present and Future
Priya S. Kishnani,
Division Chief,
Medical Genetics,
Duke University Medical Center
MID-TERM SINGLE THEME CONFERENCE METABOLIC LIVER DISEASE
JAN 2012
2.
3. The Metabolic Defect In Gaucher Disease
Diagnostic Test : Measurement of leucocyte glucocerebrosidase activity
13. Neuropathology in Gaucher Disease
European, US and Israeli type of Gaucher disease
majority Type 1, rarely type 2 or type 3
Other area’s in the world such as Asia, Africa have
more neurologic Gaucher Disease
neuroprotective N370S mutation not observed or
rare
16. Cause Of Death In Type 1 Gaucher
Disease In Pre-ERT Era
• Bleeding
• Liver failure
• Infection
• Crippling bone disease
• Pulmonary hypertension
• Pulmonary failure
• Cancers
Risk markedly increased after splenectomy
RE Lee, Prog Clin Biol Res, 1981, 95, 177-215
27. Treatments For Gaucher Disease
• BMT - curative
• Ceredase – Early 1990s
• Cerezyme – The standard of care since 1994 for all
severities of Gaucher disease including life-threatening
forms
• Miglustat – Approved 2003 for patients who cannot
tolerate Cerezyme due to side-effects or needle phobia
• Velaglucerase alpha- Approved 2010
• In development– ERT (Protalix, carrot based product)
– Small molecule therapy (Eliglustat Tartrate)
– Chaperone therapy
28. Response to Enzyme Therapy
Pre-treatment
Age 8 Years, 8 Months
Post-treatment
Age 10 Years, 10 Months
29. Long Term Response To ERT In 1028
Type 1 GD Patients
•
•
•
•
•
•
•
•
•
Reverses anemia
Reverses bleeding tendency
Reverses hepato-splenomegaly
Virtually eliminated bone crises
Reverses marrow infiltration
Improves bone density
Reverses growth failure in children
Splenectomy is no longer performed
Improves quality of life indicators
Weinreb et al, ICGG, American J Med, 2002
30. Impact of ERT On Natural History of
Gaucher Disease
Causes of premature deaths in pre-ERT era :
• Bleeding
• Liver failure
• Infection
• Crippling bone disease
• Pulmonary hypertension
?
• Cancers – multiple myeloma ?
Problems eliminated by ERT
RE Lee, Prog Clin Biol Res, 1981, 95, 177-215
31. Platelet Response To ERT Stratified For
Severity Of Thrombocytopenia And Spleen Status
300
180
Without Spleen
With Spleen
Platelet Count (x10/mm)
160
260
60<120 x103/mm3
140
220
120
180
100
140
80
<60 x103/mm3
60
100
<120 x 103/mm3
60
40
20
20
0
6
12
24
0
6
12
24
Months on Enzyme Replacement Therapy
Long term response to ERT in 1028 patients: American Journal of Medicine, 2003
32. Hemoglobin Response To Long Term ERT Stratified
For Severity Of Anemia In 1028 Patients
Without Spleen
With Spleen
15
14
14
13
Hemoglobin (g/dL)
15
13
10-<12
12
11
11
10
10
9
10-<12
12
9
<10g/dl
<10g/dl
8
8
7
7
0
6
12
24
0
6
12
24
Months on Enzyme Replacement Therapy
Long term response to ERT in 1028 patients: American Journal of Medicine, 2003
33. Reduction Of Spleen Volume By ERT
0
Mean Spleen Percent Change (MN)
–10
–20
–30
–25.3
–36.2
–40
–50
– 49.5
–60
–54.4
–57.1
– 56.4
–70
6
12
24
36
Months on ERT
48
60
34. Cerezyme® (imiglucerase for injection)
Indications and Usage
Cerezyme® is indicated for long-term enzyme
replacement therapy (ERT) for pediatric and adult
patients with a confirmed diagnosis of type 1 Gaucher
disease that results in one or more of the following
conditions:
• Anemia
• Thrombocytopenia
• Bone disease
• Hepatomegaly or splenomegaly
Please see accompanying full prescribing information. For more information, visit
www.cerezyme.com or call Genzyme Medical Affairs at 1-800-745-4447.
36. Treatment Paradigms
SRT
Substrate inhibitor
UDP-Glucose +
Ceramide
ERT
GAUCHER
UDP-Glucose +
Ceramide
Glucosylceramide
Glucosylceramide
Glucose +
Ceramide
Glucose +
Ceramide
Modified from the Genetics of Development and Disease Branch / NIDDK / NIH
37. Chaperone therapy for mis-folded
proteins
• Mis-folded proteins are unstable
• May not meet ER Quality Control
• May never go to Lysosome
Golgi
Nucleus & ER
Enzyme is mis-folded
& unstable
Lysosome
38. Proposed Mechanism of Action for
Pharmacological Chaperones
Pharmacological
Chaperone
Endoplasmic
Reticulum
Golgi
Apparatus
Lysosome
Reduced ER Retention
Enhanced Trafficking
Substrate Clearance
Protein-Chaperone Complex
Misfolded Protein
Substrate Accumulation
40. Some advances in our understanding
• Gaucher disease and parkinsonism
41. Gaucher Disease (GD)
Parkinson Disease
(PD)
• Deficiency of enzyme,
glucocerebrosidase
accumulation of
glucosylceramides
• Loss of dopaminergic neurons
and the presence of Lewy
bodies, aggregates of proteins
including α-synuclein
• Variable age of onset
• Late onset,
common
• Complex multi-gene disorder
• Recessive, single gene disorder
• Multi-organ involvement
• Mainly affects substantia nigra
and brainstem
• Symptoms include enlarged
spleens and livers, low platelet
counts, bone and brain
involvement
• Symptoms include bradykinesia,
rigidity and tremor, and
frequently, dementia
42. GBA mutations are associated with parkinsonism
•
Rare group of patients have both Gaucher disease (GD) and
parkinsonism
•
Relatives of Gaucher probands have increased frequency of
parkinsonism
•
12% of brain bank samples with pathologically confirmed PD
had GBA mutations (Gaucher carrier frequency 0.6% in general population and
3.4% in Ashkenazi Jewish)
•
PD cohorts of different ethnicities have an increased frequency of
GBA mutations
•
Patients with other synucleinopathies also have GBA mutations
44. Brain samples show Lewy bodies, inclusions
characteristic of Parkinson disease and
related disorders.
H&E, 400X
-Synuclein antibody,
200X
45. ERT for Gaucher Disease in India
• Retrospective analysis of Gaucher patients receiving CHOderived recombinant macrophage-targeted
glucocerebrosidase ; Performed through 5 centers in India
• 25 of 52 patients diagnosed with Gaucher (17 Type I and 8
mild Type III) received treatment >6 months; Infusions given
every 15 days
• Indications for treatment included symptomatic anemia,
thrombocytopenia, organomegaly, bone disease, or mild
neurological impairment leading to impairment of quality of
life.
• 22 of the 25 children who survived were analyzed
Nagral A, Mewawalla P, Jagadeesh S, Kabra M, Phadke SR, Verma IC, Puri RD, Gupta N, Kishnani PS, Mistry PK.
Recombinant macrophage targeted enzyme replacement therapy for Gaucher disease in India. Indian Pediatr.
2011 Oct;48(10):779-84.
46. ERT for Gaucher Disease in India
After 6 months:
• Mean increase in hemoglobin 1.5 g/dL; Mean increase in platelets 32 x 10˄9/L
• Mean increase in weight 3 kg; Mean increase in height 7.1 cm
• Liver size decreased by mean range of 38.5% and spleen size decreased by mean
range of 34.8%
• All patient had improvement in bone pain
• In 2 patients, neurological symptoms improved; Remained static in all others
Nagral A, Mewawalla P, Jagadeesh S, Kabra M, Phadke SR, Verma IC, Puri RD, Gupta N, Kishnani PS, Mistry PK. Recombinant
macrophage targeted enzyme replacement therapy for Gaucher disease in India. Indian Pediatr. 2011 Oct;48(10):779-84.