1. In the name of GOD

2. Gaucher disease

4. EPIDEMIOLOGY 1 in 75,000 births worldwide.
One 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.

5. PATHOGENESIS
Deficiency 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 .

6. PATHOGENESIS
Deficiency 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) .

7. PATHOGENESIS Impaired recycling of cellular glycolipids.
Glucocerebroside (glucosylceramide) that are ordinarily degraded to glucose and lipid components accumulate within the lysosomes of cells.

8. 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).

9. PATHOGENESIS Several pathologic processes within bone:
Decreased mineral density
Marrow infiltration
Infarction of bone
Abnormal osteoclast regulation
Overproduction of cytokines by activated macrophages

10. PATHOGENESIS
Marrow fibrosis and osteosclerosis ( localized loss of hematopoiesis).
Impaired primitive hematopoiesis and proliferation of mesenchymal (cytopenias ).
Hypersplenism
Bone marrow infiltration with Gaucher cells
Impaired mesenchymal stem cells capacity to develop into osteoblasts .
Splenic sequestration and marrow failure. (Thrombocytopenia)

11. Gaucher cell

12. GENETICS Autosomal recessive
Mutations in the glucocerebrosidase gene located on chromosome 1q21

14. CLINICAL MANIFESTATIONS
GD1
Variable age of onset.
Some patients present between 12 and 24 months of age,
Others have no clinical signs until late adulthood.
Some individuals with this genotype remain asymptomatic throughout life.

15. CLINICAL MANIFESTATIONS
Type 1 (GD1) :
Visceral involvement, bone disease, and bleeding .
Fatigue
Pubertal delay
Growth delay
Anemia
Thrombocytopenia,
Hepatosplenomegaly

16. CLINICAL MANIFESTATIONS
Developmental delay (type 2)
Subtle cognitive problems (type 3)
Nonimmune hydrops (type 2)
Congenital 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)

17. 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 .

18. 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.

19. 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 .

20. CLINICAL MANIFESTATIONS
Skeletal disease
Diffuse bone pain
Osteonecrosis (proximal and distal femur, proximal tibia, and proximal humerus).
Osteolytic lesions
Pathologic fractures
Vertebral compression fractures
Fragility fractures

21. 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 .

22. 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
Other causes of growth retardation should be evaluated in otherwise mildly- affected children .

23. CLINICAL MANIFESTATIONS
Enzyme-replacement therapy started before puberty improved growth and appeared to normalize the onset of puberty.

24. 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 ).

25. CLINICAL MANIFESTATIONS
Neurologic disease:
Neurologic manifestations, such as peripheral polyneuropathy, are reported in GD1 even though it is "nonneuronopathic" .
Associated with Parkinson disease.
Parkinson is earlier in onset and less dopamine-responsive than non- Gaucher-associated Parkinson disease .

26. CLINICAL MANIFESTATIONS
Most patients with GD never develop Parkinson disease .
GBA mutations may only increase the risk in individuals who are otherwise prone to developing Parkinson disease .

27. CLINICAL MANIFESTATIONS
Malignancy:
Increased rates of malignancies, particularly hematologic (lymphoma, leukemia,multiple myeloma), have been reported .
Some patients have had multiple malignancies.

28. GD2 Acute, neuronopathic form of GD.
Early onset in the first year after birth .
Visceral involvement is extensive and severe.
May present with congenital ichthyosis( collodion baby) .
First sign of CNS disease : Oculomotor dysfunction( strabismus, saccade,bulbar palsy or paresis ).
Severe hypertonia, rigidity, arching (opisthotonus),swallowing impairment, and seizures.

29. GD3 Subacute or chronic neuronopathic form . Later onset than GD2.
May have onset before age two years with very slow disease progression.
The distinction between type 2 and 3 is therefore often difficult.

30. GD3a Progressive dementia, ataxia, myoclonus Mild hepatosplenomegaly
Earlier development of neurologic symptoms (myoclonic seizures, strabismus, and supranuclear gaze palsy.)
Bone involvement is variable.

31. GD3b Extensive visceral and bone involvement.
Massive hepatosplenomegaly.
Progressive skeletal abnormalities ( kyphoscoliosis and barreled chest).
Supranuclear gaze palsy
Myoclonic seizures
Scanning (explosive) speech
Diminished intelligence

32. GD3c Cardiovascular form Supranuclear gaze palsy
Cardiovascular calcification
Visceral disease
Bone disease
Neurologic involvement can begin late, and progression is variable.

33. 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.

34. LABORATORY FINDINGS
Gaucher cells (Macrophages filled with lipid material ): cardinal feature
Have a wrinkled tissue paper

35. Gaucher disease

36. CLINICAL MANIFESTATIONS
Common presenting features seen in all types :

37. 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

38. RADIOLOGIC FINDINGS
Imaging studies can suggest the diagnosis of Gaucher disease.
Erlenmeyer flask deformity of the distal femur:
Fibrous dysplasia
Niemann-Pick disease
Osteopetrosis
Heavy metal poisoning

39. Erlenmeyer flask deformity

40. DIAGNOSIS Fractures ,lytic lesions,osteopenia,osteonecrosis.
Reduced 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.

41. 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 .

42. 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 .
Bone marrow studies are not necessary to make the diagnosis.

43. Prenatal diagnosis Enzyme 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.
Knowledge 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.
Preimplantation genetic diagnosis is also possible .

44. DDX Leukemia Lymphoma Inflammatory disease
Niemann-Pick types A, B, or C( more severe/extensive liver disease and neurologic findings).

45. DDX Rickets Vitamin C deficiency Copper deficiency Sickle cell disease
Paget disease
Renal disease or skeletal abnormalities
Deficiency of saposin C
Severe disease with or without neuronopathic manifestations but glucocerebrosidase activity is normal in vitro

46. Thanks for your attention