Gaucher disease is caused by a deficiency of the enzyme glucocerebrosidase, leading to a buildup of glucocerebroside. There are three main types: type 1 is non-neuropathic and involves the spleen and bones; type 2 is infantile and causes acute neurological involvement; type 3 causes progressive neurological involvement beginning in teenage years. Symptoms include hepatosplenomegaly, bone pain, lung and kidney involvement. Treatment involves enzyme replacement therapy with recombinant enzymes or substrate reduction therapy with drugs like miglustat or eliglustat.

1. GAUCHER DISEASE – AN
OVERVIEW OF RECENT
ADVANCES.
Presenter – Dr. Urshlla Kaul
Moderator – Dr. Hoogar M.B

4. GAUCHER DISEASE :
TYPESTYPE – I : CHRONIC NON-NEURONOPATHIC FORM (ADULT)
BRAIN INVOLVEMENT SPARED
DOMINANT SPLENIC & SKELETAL INVOLVEMENT
LOW DETECTABLE LEVELS OF GLUCOCEREBROSIDASE
TYPE – II : ACUTE NEURONOPATHIC FORM (INFANTILE)
COMPLETE DEFICIENCY OF GLUCOCEREBROSIDASE
INFANTILE ACUTE CEREBRAL INVOLVEMENT
HEPATOSPLENOMEGALY – VARIABLE
TYPE – III : JUVENILE or INTERMEDIATE FORM
CHARACTERISTIC SYSTEMIC INVOLVEMENT
PROGRESSIVE CNS INVOLVEMENT BEGINS IN TEENAGE

6. CLINICAL FEATURES
HEPATOSPLENOMEGALY
GENERALISED LYMPHADENOPATHY
BONE MARROW INVOLVEMENT
TONSILS,THYMUS,PAYER PATCHES ENLARGED
LUNG INVOLVEMENT
CEREBRAL INVOLVEMENT

10. PATHOPHYSIOLOGY
CERAMIDEGLUCOSE
SENESCENT CELL MEMBRANES
CATABOLISM OF GLYCOLIPIDS
GLUCOCEREBROSIDES
ACCUMULATION OF GLUCOCEREBROSIDE
IN PHAGOCYTIC CELLS
GAUCHER CELL
GENE MUTATION
DEF’ GLUCOCEREBROSIDASE
GLUCOCEREBROSIDASE
CLEAVING

11. GAUCHER CELL :
• Distended (phagocytic cells) Gaucher cells are found in
Spleen, Liver, Bone marrow, Lymph nodes, Tonsils, Thymus,
Payers patches, alveolar septa & air spaces in Lung.
• It has a fibrillary type of cytoplasm (crumpled tissue paper).
• Gaucher cell is a large cell 100 micron in diameter bearing
one or more eccentrically placed nuclei. PAS staining is
positive
• EM finding: Fib cyto is elongated, distended lysosomes
containing stored lipid in stacks of bilayers.

12. GAUCHER CELL

13. BONE MARROW : PAS STAIN

18. FINDINGS IN ORGANS

19. SPLEEN
• Earliest sign of GD is Splenomegaly leading to Hypersplenism
(functional hyperactivity)
• Extent of enlargement depends on the mutation genotype.
(1226G / 84GG)
• Most common presenting – Bleeding manifestations ( Epistaxis,
Bruising & Prolonged Bleeding time)
• Mechanical obstruction due to massive Splenomegaly (Abd
discomfort, Pain ,Splenic Infarcts, nodules, subcapsular infarcts,
wedge shaped areas)
• Growth retardation in children – few cases

20. SPLEEN : GAUCHER’S DISEASE

22. LIVER:
•Hepatomegaly : Portal & Sinusoidal infiltration of
Gaucher cells along with Fibrosis, Inflammation
and/or Ischemia.
•Oesophageal varices in few cases.
•Liver failure/Portal hypertention uncommon.
•Hepatocytes not affected
•LFT normal / slightly abnormal(SGOT<SGPT may be
elevated).

23. BONE: Types of Orthopaedic
complications
•Nonspecific Bone pain episodic
•Pseudoosteomyelitis accompanied by with fever,
leukocytosis & Increased ESR.
•Pyogenic Osteomyelitis
•Chronic pain a/w stiffness of large joints.
•Aseptic necrosis of head of Femur
•Pathologic fractures.
•Spinal malalignment
•Growth & Stature reduction due to spinal deformity

24. BONE cont:
•WIDE metaphyseal-diaphyseal region (ERLENMEYER
FLASK) deformity – bilateral
•Epiphyses are unaffected.
•Bone density reduced diffuse or localized
•RARER:
• Compression /collapse of vertebral bodies
• Spinal cord /Nerve involvement.
• Ischemia /cortical necrosis due to intraosseous
pressure caused by the lipid laden cells.
•MECHANISM IS STILL UNEXPLAINED!!!

25. ERLENMEYER FLASK
DEFORMITY -

27. LUNGS:
•Findings are grouped in 3 categories:
•Interstitial infiltration of Gaucher cells.
•Capillary plugging leading to Pulmonary
Hypertention
•Alveolar consolidation reminiscent of Pneumonia
(type2GD)
•X-ray shows Miliary pattern/or reticular nodular
infiltrate

28. KIDNEY:
•Gaucher cells have been found in glomeruli, cortex,
medulla & interstitium without significant renal
complications.
•Kidney involvement in GD is uncommon .

29. HEART:
•Constrictive Pericarditis &Rheumatic aortic Valve
Disease
•Infiltration of myocardial interstitium by Gaucher
cells.
•Calcification of mitral/aortic valves & ascending
aorta

30. SKIN:
• ICHTHYOSES (Type-2 GD)
• Pterygium & Pingueculae in the conjuctiva

31. CNS:
•Type 2GD - Cranial nerve/extrapyramidal tract
involvement are common
•Classic triad (Trismus, Strabismus & Retroflexion)
•Type3- in the 1st
year of life children present with
(Spasticity, Hyperreflexia, positive Babinski sign &
Seizures

32. HAEMATOLOGICAL
MANIFESTATIONS:
•Anemia & Thrombocytopenia due to Hypersplenism &
infiltration of Gaucher cells in Bone marrow.
•Pancytopenia
•Iron def Anemia due to bleeding ASSO of GD with
Autoimmune disorders &Hematologic malignancies
•PT / APPT prolonged

33. IMMUNE SYSTEM
•Impaired chemotaxis of neutrophils
•T lymphocyte deficiencies in spleen and blood
including NKT cells.
•Hypergammaglobulinemia
•Monoclonal gammopathies
•Diffuse immunoglobulin elevation
•Change of IgM to IgG and IgA as disease progresses.
•Multiple myeloma
•Other concomitant malignancies
•Hodgkin’s, Acute leukemias, CLL, CML

34. OBGY
•Delay of puberty
•Heavy menstrual bleeding
•Spontaneous abortions
•Stillbirths, neonatal deaths
•Aggravation of thrombocytopenia and anemia
during pregnancy.

35. OTHER
•Hypocholesterolemia due to increased catabolism of
LDL and HDL.
•Serum level elevations of –
• Angiotensin converting enzyme (ACE)
• Chititriosidase
• Macophage colony stimulating factor
• Soluble CD 14
• Ferritin
• Transcobalamin II
• Beta hexosaminidase
• Lysozyme

36. MOLECULAR BASIS -
•Glucocerebrosidase gene is located on Chromosome 1 at
band q21.
•Just downstream the active gene is a highly homologous
pseudogene.
•More than 50 mutations in the active gene.
•Most common is Point mutation.
•Others are inserions, deletions, splicing, gene
conversion, crossing over between the functional gene
and pseudogene.

38. MUTATION 1226: A G
•Point mutation in exon 9
•Mild type of mutation
•75% Ashkenazi Jews and 36% non-Jews
•Late age of onset
•Protective against CNS involvement.

39. MUTATION 1448: T C
•Point mutation in exon 10
•Severe type of mutation
•Seen in all 3 types and Norbottnian variant
•Most common in type 2 and 3
•Gene conversion, unequal crossing over

40. MUTATION 84GG
•Extra guanine inserted into the cDNA at position 84
•Lethal type of mutation
•Second most common in Ashkenazi Jews

41. MUTATION IVS2 (+1)
•Splice site mutation where adenine is substituted by
guanine between exon 2 and intron 2.
•Lethal mutation

42. MUTATION 1604: G A
•Point mutation in exon 11
•Mild mutation, non neuronopathic

43. THERAPY
ENZYME REPLACEMENT THERAPY (ERT) WITH
RECOMBINANT ENZYMES – cerezyme, vpriv
BONE MARROW TRANSPLANTATION
GENE TRANSFER THERAPY
SUBSTRATE REPLACEMENT THERAPY (SRT) –
GLUCOSYLCERAMIDE SYNTHASE INHIBITORS.
MIGLUSTAT
ELIGLUSTAT

45. THANK YOU