IN THE NAME OF GOD GAUACHER DISEASE Dr.mohammad raza alaei Pediatric Endocrinologist Shahid beheshty university GAUCHER DISEASE  Gaucher disease is the most common of the lysosomal storage  multisystemic lipidosis characterized by hematologic problems, organomegaly, and skeletal involvement, three clinical subtypes:  Type 1 or the adult, non-neuronopathic form  type 2, the infantile or acute neuronopathic form  type 3, the juvenile or chronic neuronopathic form  Non-neuronopathic Neuronopathic Type Type 1 Type 2 Type 3 Prevalence General Population: 1 in 40,000-60,000 <1 in 100,000 <1 in 100,000 Ashkenazi Jews: 1 in 850 CNS involvement None Severe Moderate to Severe Symptom Onset Any age First year of life Childhood  All are autosomal recessive traits  Type 1, accounts for 99% of cases  deficient activity of the Enzyme glucocerebrosidase ( acid β-glucosidase)  accumulation of glycolipid substrates, particularly glucosylceramide, in cells of the reticuloendothelial system.  This progressive deposition results in infiltration of the bone marrow, progressive hepatosplenomegaly, and skeletal CLINICAL MANIFESTATIONS variable age at onset in type 1, from early childhood to late adulthood, with most symptomatic patients presenting by adolescence.  25 percent of affected individuals may be asymptomatic  or splenomegaly discovered incidental   Severely affected individuals with Type 1 disease may die in the first or second decade. SPLENOMEGALY  The initial clinical manifestation is usually painless splenomegaly  Progressive macrophageal accumulation  splenomegaly is progressive  Huge spleen(60 -70 times NL size)  Irriversibl change due to infarction ,necrosis,fibrosis  Splenic nodules & infarction (30%) Splenic infarction:  localized mild pain to an acute abdomen with fever  Resolve within a few days to a week  HEPATOMEGALY  usually less than splenomegaly, but it maybe as large or larger than the spleen  particularly prominent in splenectomized patients  Abdominal distention,discomfort  LFT is NL ( may be slight elevation)  cirrhosis, esophageal varices or hepatic failure  Hepatic infarction may present as an acute abdominal catastrophe with a Budd-Chiari syndrome.  Cholelithiasis  Hepatocellular carcinoma HEMATOLOGICAL MANIFESTATION  Key manifestation of Gaucher disease  BM infilteration with Gaucher cells  leukopenia ,anemia, thrombocytopenia ,pancytopenia,coagulopathy  Hypersplenism  Pallor,fatigue, palpitation,dyspnea & regular transfusion Bleeding complication:  PLT & coagulation factor & qualitative PLT   After trauma & surgery Postpartum bleeding & heavy menstrual blood loss  Leukopenia   Impairment of nutrophil chemotaxis BONE MARROW INFILTRATION  First step of bone disease  Start in the lumbar spine then metaphyses & diaphyses of the femora  Bilaterally  Reduce fat content of BM  Increase osseous pressure(ischemia & infarction) BONE CRISES Manifestation of the osteonecrosic process  children > adult  severe pain,tenderness, redness and swelling,  fever, leukocytosis and elevation of ESR   mimicking acute osteomyelitis or the thrombotic crises of sickle cell disease. diagnosis is best confirmed by technetium radionuclide scan  Relieve pain by opioids  Pyogenic osteomyelitis is rare in Gaucher disease  surgical diagnostic procedures are not recommended for crises   Osteopenia  Pathologic fracture is common.  Osteosclerosis  osteonecrosis BONE REMODELING FAILURE  The most common skeletal feature is Erlenmeyer appearance  End of the Long bone usually distal part of femure & proximal of the tibia  In 80% of cases  Asymptomatic sign of the disease  Detectable on x - ray GROWTH RETARDATION ,PUBERTAL DELAY  GR is very common  Ultimatly grow to a NL Height  Pubertal delay due to anemia, hepatosplenomegaly and chronic disease, TREATMENT  enzyme replacement therapy, with recombinant acid β-glucosidase ,cerezyme(imiglucerase).  Gaucher disease was the first LSD for which this approach became available.  enzyme purified from human placenta :Ceredase (algucerase)  Cerezyme the standard of care ,is proven effective ,safe & well tolerated  Cerezyme vials: 200 & 400 U ,5 ml  Steady state cerezyme activity within 20 to 30 minutes  Clinically significant response in type 1 & 3  Is not likely to pass the BBB  Initial dose: Dosing & Dosage adjustment should always be individualized  In type 1:  There is still some controversy as to dose.  The dose generally employed is 60 U/kg every two weeks  30 U/kg every two weeks maybe just as effective  In type 3 :  120 U/kg every two weeks  Dosage adjustment:  Only be made after complete reassessment  No dose decrease until after achivement of all therapeutic goals  Children:  Increase if within 6 mo not all therapeutic goals  If bone crises continue ,the dose should be increased by at least 50 %  the dose should not be redused more frequenty than every 6 mo & should not be redused below 30 u / kg every two weeks  CEREZYME SIDE EFFECT  Local  Systemic  Antibody formation (IgG 15 %) THERAPEUTIC GOALS Hematology:  Hb> 12 g/dl for males & > 11 g/dl for females & children  PLT >30000  Viseral  Reduce liver volume:  By 20 – 30 % ( 1 – 2 yrs)  By 30 – 40 % ( 3 – 5 yrs)  Reduce spleen volume:  By 30 – 50 % ( 1 yr)  By 50 – 60 % ( 2 – 5 yrs)  Skeletal:  Reduce bone pain (1 – 2 yrs)  Provent bone crises (1 – 2 yrs)  Provent osteonecrosis & joint collaps (1 – 2 yrs)  Attain NL or ideal peak skeletal mass ( yr 2)  increase bone mineral density (3 – 5 yrs)  NL growth (yr 3)  NL onset of puberty   Pulmonary involvement:  Reverse hepatopulmonary sydrome  Ameliorate pulmonary HTN  Improve functional status  Prevent pulmonary disease  Improve or restore physical function  Reduce plasma biomarkers(chitotriosidase activity significantly( >15 % )  bone marrow transplantation curative but results in significant morbidity and mortality  appropriate candidates limited.   Alternative treatments, including the use of agents designed to decrease the synthesis of glucosylceramide by chemical inhibition of glucoslceramide synthase  Although enzyme replacement does not alter the neurologic progression of patients with Gaucher disease types 2 and 3, it has been used in selected patients as a palliative measure, particularly in type 3 patients with severe visceral involvement