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Download CLINICAL MANIFESTATIONS Visceral disease
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In the name of GOD EPIDEMIOLOGY 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. 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 . 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) . PATHOGENESIS Impaired recycling of cellular glycolipids. Glucocerebroside (glucosylceramide) that are ordinarily degraded to glucose and lipid components accumulate within the lysosomes of cells. PATHOGENESIS The clinical manifestations result from the accumulation of the lipidladen 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). PATHOGENESIS Several pathologic processes within bone: Decreased mineral density Marrow infiltration Infarction of bone Abnormal osteoclast regulation Overproduction of cytokines by activated macrophages 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) Gaucher cell GENETICS Autosomal recessive Mutations in the glucocerebrosidase gene located on chromosome 1q21 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. CLINICAL MANIFESTATIONS Type 1 (GD1) : Visceral involvement, bone disease, and bleeding . Fatigue Pubertal delay Growth delay Anemia Thrombocytopenia, Hepatosplenomegaly 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) 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 . 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. 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 . 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 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 . 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 mildlyaffected children . CLINICAL MANIFESTATIONS Enzyme-replacement therapy started before puberty improved growth and appeared to normalize the onset of puberty. 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 ). 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 nonGaucher-associated Parkinson disease . 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 . CLINICAL MANIFESTATIONS Malignancy: Increased rates of malignancies, particularly hematologic (lymphoma, leukemia,multiple myeloma), have been reported . Some patients have had multiple malignancies. 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. 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. GD3a Progressive dementia, ataxia, myoclonus Mild hepatosplenomegaly Earlier development of neurologic symptoms (myoclonic seizures, strabismus, and supranuclear gaze palsy.) Bone involvement is variable. 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 GD3c Cardiovascular form Supranuclear gaze palsy Cardiovascular calcification Visceral disease Bone disease Neurologic involvement can begin late, and progression is variable. 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. LABORATORY FINDINGS Gaucher cells (Macrophages filled with lipid material ): cardinal feature Have a wrinkled tissue paper Gaucher disease CLINICAL MANIFESTATIONS Common presenting features seen in all types : 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 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 Erlenmeyer flask deformity DIAGNOSIS 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. 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 . 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. 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 . DDX Leukemia Lymphoma Inflammatory disease Niemann-Pick types A, B, or C( more severe/extensive liver disease and neurologic findings). 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 Thanks for your attention
