azim58 - notes for Gaucher disease Pathogenesis, clinical manifestations, and diagnosis notes for Gaucher disease Pathogenesis, clinical manifestations, and diagnosis q GD is one of the few inherited metabolic disorders that can be treated by replacement of the deficient enzyme (enzyme replacement therapy). q Gaucher disease (GD) is the most common lysosomal storage disease. It occurs in approximately 1/75,000 births worldwide, but is more prevalent in individuals of Ashkenazi Jewish descent q There are approximately 20,000 individuals with GD in the United States, based upon a gene frequency study, two-thirds of whom are Ashkenazi Jews q Approximately 90 percent of patients have type 1 Gaucher disease (GD1), which is the nonneuronopathic form. This type is most common in the Ashkenazi Jewish population, in which the carrier frequency is approximately 1 in 12 q This subtype (type 2) is not prevalent, comprising about 1 percent of patients in the Gaucher Registry compared with 5 percent for type 3 disease, as a result of the very short lifespan of patients with type 2 GD. ?what are gaucher cells? q A mouse model of GD suggests that other cell types are affected, including thymic T cells, dendritic cells, and osteoblasts q decreased mineral density, marrow infiltration, and infarction of bone. q The increased bleeding tendency in patients with type 1 GD is related to thrombocytopenia, coagulation abnormalities, and defective platelet function q GD is an autosomal recessive disorder that is due to mutations in the glucocerebrosidase (GBA) gene located on chromosome 1q21 q More than 200 distinct GBA gene mutations are listed in the Human Gene Mutation Database (www.hgmd.cf.ac.uk). Three mutant alleles are particularly frequent in affected patients: N370S allele (non-Jewish Europeans and Ashkenazi Jews), L444P allele (Sweden), 84GG allele (homozygotes are potentially prenatally lethal) q Gaucher disease (GD) involves the visceral organs, bone marrow, and bone in all affected patients. Type 1: most common in Ashkenazi jews Type 3a: most common in Sweden q Splenomegaly is the most common presenting sign [35,41]. The spleen can be enlarged as much as 5 to 75 times its normal size (median 15.2 times [26]). q Hepatomegaly is universal, but the liver increases relatively less than the spleen. bone marrow disease skeletal disease q Bone pain, bone crises, and severe radiologic bone disease were more common among asplenic patients. q Many affected children grow poorly and have delayed puberty q Approximately 50 percent of children with GD have height =5th percentile for age and sex q in one series, all patients had spontaneous catch-up, and 83 percent achieved a final height within the range of what was expected based upon mid-parental height q Enzyme replacement therapy started before puberty improved growth and appeared to normalize the onset of puberty. definition of a gaucher cell q GCs are macrophage-like cells, expressing acid phosphatase, CD68, CD14, and HLA class II, but not CD11b, CD40, or dendritic cell markers. ^ from http://ajcp.ascpjournals.org/content/122/3/359.full.pdf q Neurologic manifestations, such as peripheral polyneuropathy, are reported in GD1 even though it is “nonneuronopathic� q Indeed, GBA mutations are the most frequent genetic associations with Parkinson disease in the general population q Type 3 (GD3) — Type 3 Gaucher disease (GD3) is the subacute or chronic neuronopathic form of GD (table 1). It has a later onset than GD2. q Macrophages filled with lipid material are known as Gaucher cells and are a cardinal feature of the disease. Gaucher cells have a characteristic histologic appearance of wrinkled tissue paper. Membrane-bound inclusions filled with glucocerebroside are seen with electron microscopy. Gaucher cells have the protein expression profile of the so-called alternatively activated macrophage, a phenotype associated with chronic inflammation and fibrosis q • The characteristic Erlenmeyer flask deformity of the distal femur caused by abnormal modeling of the metaphysis q • Fractures and lytic lesions were present on plain q • Marrow infiltration q • Bone infarction (The obstruction of the blood supply to an organ or region of tissue, typically by a thrombus or embolus, causing local death of the tissue.) and osteonecrosis were each present on MRI in 25 percent q • Osteopenia was present on dual energy X-ray absorptiometry (DEXA) in 42 percent ^ Osteopenia is a condition where bone mineral density is lower than normal diagnoses look for reduced glucocerebrosidase activity in peripheral leukocytes then do mutation analysis q The peripheral leukocyte assay uses an artificial substrate, 4-methylumbilliferyl-beta-glucoside q The diagnosis is often made when Gaucher cells are detected in the bone marrow of patients who are being evaluated for splenomegaly, anemia, or thrombocytopenia q • Gaucher disease (GD) is the most common lysosomal storage disease q • GD is an autosomal recessive disorder caused by mutations in the glucocerebrosidase (GBA) gene located on chromosome 1q21. More than 200 distinct mutations are reported. However three mutant alleles account for most cases: c.1226A>G (N370S), c.1448T>C (L444P), and c.84dupG (84GG). q Type 1 is distinguished from types 2 and 3 by the lack of characteristic involvement of the central nervous system. q • The diagnosis of GD is confirmed by the finding of reduced glucocerebrosidase activity in peripheral leukocytes. Diagnosis can also be confirmed by mutation analysis. (See 'Diagnosis' above.)