GAUCHER DISEASE – AN OVERVIEW OF RECENT ADVANCES.

Presenter – Dr. Urshlla KaulModerator – Dr. Hoogar M.B

GAUCHER DISEASE : TYPES TYPE – 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

CLINICAL FEATURES HEPATOSPLENOMEGALY

GENERALISED LYMPHADENOPATHY

BONE MARROW INVOLVEMENT

TONSILS,THYMUS,PAYER PATCHES ENLARGED

LUNG INVOLVEMENT

CEREBRAL INVOLVEMENT

PATHOPHYSIOLOGY

CERAMIDEGLUCOSE

SENESCENT CELL MEMBRANES

CATABOLISM OF GLYCOLIPIDS

GLUCOCEREBROSIDES

ACCUMULATION OF GLUCOCEREBROSIDEIN PHAGOCYTIC CELLS

GAUCHER CELL

GENE MUTATION

DEF’ GLUCOCEREBROSIDASE

GLUCOCEREBROSIDASE

CLEAVING

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.

GAUCHER CELL

BONE MARROW : PAS STAIN

FINDINGS IN ORGANS

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

SPLEEN : GAUCHER’S DISEASE

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).

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

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!!!

ERLENMEYER FLASK DEFORMITY -

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

KIDNEY:

•Gaucher cells have been found in glomeruli, cortex, medulla & interstitium without significant renal complications.

•Kidney involvement in GD is uncommon .

HEART:

•Constrictive Pericarditis &Rheumatic aortic Valve Disease

• Infiltration of myocardial interstitium by Gaucher cells.

•Calcification of mitral/aortic valves & ascending aorta

SKIN:

• ICHTHYOSES (Type-2 GD)

• Pterygium & Pingueculae in the conjuctiva

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

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

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

OBGY

•Delay of puberty•Heavy menstrual bleeding•Spontaneous abortions•Stillbirths, neonatal deaths•Aggravation of thrombocytopenia and anemia

during pregnancy.

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

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.

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.

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

MUTATION 84GG

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

MUTATION IVS2 (+1)

•Splice site mutation where adenine is substituted by guanine between exon 2 and intron 2.• Lethal mutation

MUTATION 1604: G A

•Point mutation in exon 11 •Mild mutation, non neuronopathic

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

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