In the name of GOD - PowerPoint Presentation

Slide1

In the name of GOD

Slide2

Gaucher disease

Slide3

Slide4

EPIDEMIOLOGY

O

ne

of the

most

common

lysosomal

storage diseases

.

1

in 75,000 births

worldwide

.

Type 1

GD

(non neuropathic)

is the

most prevalent

and occurs

with

greater

frequency in

the

Ashkenazi-Jewish

population

.

Types

2

(

acute

neuronopathic

)

and

3

(

subacute or

juvenile

neuronopathic

)

are

less common and occur in

all

ethnic types.

Slide5

PATHOGENESIS

D

eficiency

of a

lysosomal

enzyme

glucocerebrosidase

glucosylceramidase

or acid

beta-

glucosidase

).

A glycoprotein

enzyme whose major substrate is

glucocerebroside

, a component of the

cell

membrane.

In

the normal lysosome, the protein

saposin

C

is thought

to present

glucocerebroside

to GBA and thereby activate the enzyme

.

Slide6

PATHOGENESIS

D

eficiency

of GBA leads to accumulation of

glucocerebroside

in

the

lysosomes

of macrophages

.

The

deacylated

form of

glucosylceramide

,

glucosylsphingosine

,

is

elevated in

neuronopathic

disease(

role in the pathogenesis

of

neurodegeneration

) .

Slide7

PATHOGENESIS

Impaired recycling of cellular glycolipids.

Glucocerebroside

(

glucosylceramide

) that

are ordinarily degraded to glucose and lipid components accumulate within the

lysosomes

of cells.

Slide8

PATHOGENESIS

The

clinical manifestations

result

from the accumulation of the lipid-laden macrophages in

the

spleen

,

liver

,

bone marrow

,

bone,

and other tissues/organs

.

Gaucher

cells and neighboring

macrophages overexpress

and secrete

lysosomal

proteases

(

cathepsins

)

,

and

inflammatory

mediators

(IL-6,IL-8,IL-10,MIP,ect).

Slide9

PATHOGENESIS

Several

pathologic processes

within

bone

:

D

ecreased

mineral

density

M

arrow infiltration

Infarction

of

bone

A

bnormal

osteoclast

regulation

O

verproduction of cytokines

by activated macrophages

Slide10

PATHOGENESIS

Marrow

fibrosis

and

osteosclerosis

(

localized loss

of hematopoiesis).

Impaired

p

rimitive

hematopoiesis and proliferation of

mesenchymal

(

cytopenias

).

H

ypersplenism

Bone

marrow

infiltration

with Gaucher cells

I

mpaired

mesenchymal stem cells capacity to develop into osteoblasts

.

S

plenic

sequestration and

marrow failure.

(Thrombocytopenia)

Slide11

Gaucher cell

Slide12

GENETICS

A

utosomal

recessive

Mutations

in

the

glucocerebrosidase

gene located on chromosome 1q21

Slide13

Slide14

CLINICAL MANIFESTATIONS

GD1

Variable age of onset.

Some patients present between

12 and 24 months

of age,

O

thers

have

no clinical signs

until late adulthood.

Some

individuals with this genotype

remain asymptomatic

throughout

life

.

Slide15

CLINICAL MANIFESTATIONS

Type

1

(GD1)

:

V

isceral

involvement, bone disease, and bleeding

.

F

atigue

P

ubertal delay

Growth delay

Anemia

T

hrombocytopenia

,

H

epatosplenomegaly

Slide16

CLINICAL MANIFESTATIONS

Developmental

delay (type 2)

S

ubtle

cognitive

problems

(type 3)

Nonimmune

hydrops

(type 2)

C

ongenital

ichthyosis

(type 2)

Strabismus

or

supranuclear

gaze palsy (types 2 and 3)

Progressive

dementia

, ataxia, and myoclonus (type 3, rare)

Corneal

opacity (type 3C, rare)

Cardiovascular

calcification (type

3C

)

Slide17

CLINICAL MANIFESTATIONS

Visceral

disease

:

Splenomegaly

is the most

common

presenting

sign.

The

spleen can

be enlarged

as much as 5 to 75 times its normal size

.

Hepatomegaly

is

universal(less than spleen).

Hepatic

fibrosis typically occurs, but hepatic failure, cirrhosis, and portal

hypertension are

uncommon

,

except in

splenectomized

patients

.

Slide18

CLINICAL MANIFESTATIONS

Visceral

disease

:

Hepatosplenomegaly

may be

asymptomatic

or may be associated with early satiety,

abdominal complaints

(distension, discomfort, pain), and/or anemia and thrombocytopenia

.

Thrombocytopenia

may

result in bleeding and easy bruising

.

Splenic infarction

occurs rarely and can present as

acute abdominal pain.

Slide19

CLINICAL MANIFESTATIONS

Bone

marrow disease

Anemia

,

thrombocytopenia

,

or rarely

leukopenia

may be

present simultaneously.

The degree of anemia and thrombocytopenia

is related

to whether or not they have had

splenectomy

.

Thrombocytopenia

is common

in

nonsplenectomized

patients and occurs prior to anemia and leukopenia

.

Lymphopenia

is detected

more commonly

than neutropenia at presentation and may help differentiate GD1 from

hematologic malignancy .

Slide20

CLINICAL MANIFESTATIONS

Skeletal

disease

D

iffuse

bone

pain

O

steonecrosis (proximal

and

distal femur

, proximal tibia, and proximal

humerus

).

Osteolytic

lesions

P

athologic fractures

V

ertebral compression

fractures

F

ragility

fractures

Slide21

CLINICAL MANIFESTATIONS

Bone pain, bone crises, and severe radiologic

bone disease

were more common among

asplenic

patients

.

Bone crises were more common among

patients diagnosed

before age 10 years

than after age 10 years

.

Slide22

CLINICAL MANIFESTATIONS

Growth/development

Many

affected children grow poorly and have delayed puberty

.

50

percent of children with

GD may

have height ≤5 percentile for age and

sex.

Most

children with

severe growth deficiency

also

have

severe

visceral involvement

O

ther

causes of growth retardation should be evaluated

in otherwise

mildly-affected children .

Slide23

CLINICAL MANIFESTATIONS

Enzyme-replacement

therapy

started

before puberty

improved growth

and appeared

to normalize the onset of puberty

.

Slide24

CLINICAL MANIFESTATIONS

Pulmonary disease:

Interstitial

lung disease

(

less common

manifestation).

Hepatopulmonary

syndrome

(

hypoxemia on

standing)

results from

abnormal vascular shunting with the lung ( usually occurs in

splenectomized

patients ).

Slide25

CLINICAL MANIFESTATIONS

Neurologic disease:

Neurologic

manifestations, such as

peripheral polyneuropathy

, are

reported in

GD1 even though it is "

nonneuronopathic

"

.

A

ssociated

with

Parkinson

disease

.

Parkinson

is

earlier

in onset and

less dopamine-responsive

than non-

Gaucher

-associated Parkinson disease

.

Slide26

CLINICAL MANIFESTATIONS

M

ost

patients with GD never develop

Parkinson

disease

.

GBA

mutations

may only

increase the risk in individuals who are otherwise prone to developing Parkinson disease

.

Slide27

CLINICAL MANIFESTATIONS

Malignancy:

Increased

rates of

malignancies

, particularly hematologic (lymphoma,

leukemia,multiple

myeloma), have been reported

.

Some

patients have had

multiple malignancies

.

Slide28

GD2

A

cute

,

neuronopathic

form of GD.

Early onset

in the first year after birth

.

Visceral

involvement

is extensive and severe.

M

ay

present

with

congenital

ichthyosis

(

collodion

baby) .

F

irst

sign of CNS disease :

O

culomotor

dysfunction

(

strabismus,

saccade,bulbar

palsy or paresis )

.

S

evere

hypertonia, rigidity, arching (

opisthotonus

),swallowing

impairment, and seizures.

Slide29

GD3

S

ubacute

or chronic

neuronopathic

form

.

L

ater onset than

GD2

.

M

ay

have onset

before age two

years with very

slow

disease

progression.

The

distinction between type 2 and 3 is therefore often difficult.

Slide30

GD3a

Progressive

dementia

,

ataxia,

myoclonus

M

ild

hepatosplenomegaly

E

arlier

development of neurologic symptoms (

myoclonic

seizures, strabismus, and

supranuclear

gaze palsy

.)

Bone involvement is

variable.

Slide31

GD3b

E

xtensive

visceral and bone

involvement.

M

assive

hepatosplenomegaly

.

P

rogressive

skeletal abnormalities (

kyphoscoliosis

and barreled

chest).

S

upranuclear

gaze

palsy

M

yoclonic seizures

S

canning

(explosive)

speech

D

iminished intelligence

Slide32

GD3c

Cardiovascular form

Supranuclear

gaze

palsy

C

ardiovascular

calcification

V

isceral disease

Bone

disease

N

eurologic

involvement

can begin

late, and progression is variable.

Slide33

Perinatal-lethal form

A

perinatal-lethal form (lethal in utero or in the newborn period) can present

as

nonimmune

hydrops

.

GD

should be considered in the differential diagnosis of

pregnancy loss

accompanied by severe

hydrops

.

Slide34

LABORATORY FINDINGS

Gaucher

cells

(

Macrophages filled with lipid material

):

cardinal feature

Have a

wrinkled tissue

paper

Slide35

Gaucher disease

Slide36

CLINICAL MANIFESTATIONS

Common presenting features seen in all types :

Slide37

LABORATORY FINDINGS

Thrombocytopenia and anemia

Liver enzymes may be

mildly elevated

ACE may be increased

Acid phosphatase activity( the

tartrate-resistant

isoenzyme

): elevated

Hyperferritinemia

: common

Polyclonal

gammopathy

and monoclonal

gammopathy

Slide38

RADIOLOGIC FINDINGS

Imaging

studies can

suggest

the diagnosis of

Gaucher

disease.

Erlenmeyer flask deformity of the distal

femur:

Fibrous dysplasia

Niemann

-Pick disease

O

steopetrosis

H

eavy

metal

poisoning

Slide39

Erlenmeyer flask deformity

Slide40

DIAGNOSIS

R

educed

glucocerebrosidase

activity

in

peripheral

leukocytes.

Mutation

analysis

help predict

clinical manifestations and identify undiagnosed affected family

members

and

heterozygote.

Fractures ,

lytic

lesions,osteopenia,osteonecrosis

.

Marrow infiltration

on

MRI.

Slide41

DIAGNOSIS

An

ultramicro-fluorometric

assay

for diagnosis of GD from

dried blood spots

on filter paper has

been developed

and may facilitate diagnostic efforts in newborns and adults

.

Slide42

Bone marrow studies

The

diagnosis is made

when

Gaucher

cells are detected

in the bone marrow

of patients

who are being evaluated for splenomegaly, anemia, or thrombocytopenia

.

B

one

marrow studies are

not necessary

to make the

diagnosis

.

Slide43

Prenatal diagnosis

E

nzyme

analysis

by

CVS

or

amniocentesis

Obtaining

a

skin biopsy

from the

proband

and

assaying cultured

skin fibroblasts simultaneously with the prenatal sample is helpful in cases where there may

be significant

residual enzymatic activity

.

K

nowledge

of the

DNA mutations

in the

proband

or in

the heterozygous

parents allows the use of DNA mutation analysis together with enzyme analysis

for prenatal

diagnosis.

Mutation

analysis

is recommended as a confirmatory assay

.

P

reimplantation

genetic diagnosis

is also possible

.

Slide44

DDX

Leukemia

Lymphoma

I

nflammatory disease

N

iemann

-Pick

types A, B, or

C(

more severe/extensive liver disease and

neurologic findings

).

Slide45

DDX

Rickets

V

itamin

C

deficiency

C

opper deficiency

S

ickle

cell

disease

Paget disease

R

enal

disease or skeletal

abnormalities

Deficiency of

saposin

C

Severe

disease with or without

neuronopathic

manifestations but

glucocerebrosidase

activity

is normal

in vitro

Slide46

Thanks for your attention