gaucher diseaseeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee.pptx

genetics

1. Gaucher disease Akram Hanafi Faculty of medicine, group 2 Semester 4 23/5/2023

2. Chief complaint A 37-year-old Caucasian woman with spherocytosis reported since childhood  hepatosplenomegaly from 3 years of age (resulting in an incorrect diagnosis of spherocytosis) and a severe sport-related fracture of the humerus with humeral head necrosis presented with swollen ankles, gradually increasing abdominal girth, sudden weight gain (3 kg in 6 days), and fatigue

3. Medical history No alcohol abuse, liver disease/hepatitis, blood coagulation abnormalities or prothrombotic diseases were reported. The first of the patient’s two pregnancies resulted in post-partum bleeding requiring a blood transfusion .

4. Family pedigree

5. Physical examination and lab Physical examination revealed paleness, hepatosplenomegaly and oedema in both legs, which was resolved with diuretics (a sign of portal hypertension). Blood examination showed leucopoenia (1,730/mm3), thrombocytopenia (92,000/mm3) and normocytic anaemia (haemoglobin [Hb] 7.8 g/dl, mean corpuscular volume [MCV] 90.1 fl ) with mildly increased ferritin (352 ng/ml) Further tests showed significantly elevated chitotriosidase activity (14,290 nmol/h/ml; normal value <100), low β- glucosidase activity (28 nmol/h/mg; normal range 200–500 ) .

6. Diagnosis Liver disease (but not Gaucher disease [GD]) was suspected and therefore a liver biopsy was performed. portal and lobular infiltration showed aggregated CD68-positive polygonal cells and granulated cytoplasm was observed, with no iron overload. GD was suspected at this point Further tests showed significantly elevated chitotriosidase activity (14,290 nmol/h/ml; normal value <100), low β- glucosidase activity (28 nmol/h/mg; normal range 200–500) and the identification of β- glucosidase (GBA) gene mutations, all of which led to a diagnosis of GD type 1

7. Plan, treatment and management Treatment with enzyme replacement therapy (ERT) led to improved laboratory parameters after 1 year. The patient is currently well and continues to receive ERT with no side effect. enzyme replacement therapy (ERT) with recombinant β- glucocerebrosidase remarkably improved the clinical outcome of Gaucher disease patients Substrate reduction therapy (SRT) with N- butyldeoxy - nojirimyci is approved for patients with mild Gaucher disease who are unable to receive ERT.

8. Etiology and pathogenesis Gaucher disease is caused by a defect in the  housekeeping gene  for  lysosomal glucocerebrosidase  enzyme (also known as beta-glucosidase) on the first  chromosome  (1q22). The  enzyme  is a 497- amino acid -long protein that catalyses the breakdown of glucocerebroside, a  cell membrane  component of  red  and  white blood cells . In Gaucher disease, the enzyme is unable to function correctly and glucocerebroside accumulates. The  macrophages  that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into 'Gaucher cells', which appear on  light microscopy  to resemble crumpled-up paper The three types of Gaucher's disease are  autosomal recessive . Both parents must be carriers for a child to be affected. If both parents are carriers, the chance of the disease is one in four, or 25%, with each pregnancy for an affected child

9. Epidemiology and incidence Type 1 (non-neuronopathic) Gaucher disease is the most prevalent lysosomal storage disorder as well as the most common Gaucher disease phenotype accounting for more than 90% of all Gaucher disease patients. It is an autosomal recessive disorder caused by mutations in GBA1 gene causing β-glucocerebrosidase deficiency. Type 1 Gaucher disease has a prevalence worldwide of 1 in 50,000 to 1 in 100,000, but it’s as high as approximately 1 in 480 to 1280 in individuals of Ashkenazi Jewish heritage

10. Recent information A recent study was a follow up with updated information about curative and approved therapies Mentions two specific ways to treat GD: recovery of enzyme activity to reduce abnormal accumulation, through enzyme replacement therapy (ERT), gene therapy (GT), genome editing (GE), allogeneic hematopoietic stem cell transplantation ( allo -HSCT) and chaperone therapy; reduction of glucocerebroside accumulation in lysosome, such as substrate reduction therapy (SRT )

11. References https://www.sciencedirect.com/science/article/abs/pii/S0014299922002849?via%3Dihub https://gaucherdiseaseplatform.org/case-studies/ https://www.gaucherdisease.org/gaucher-diagnosis-treatment/testing/