The lysosomal storage diseases currently number 45 and

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1 Recommendations on Diagnosis, Treatment, and Monitoring for Gaucher Disease Ana Maria Martins, MD, PhD, Eugenia Ribeiro Valadares, MD, PhD, Gilda Porta, MD, PhD, Janice Coelho, PhD, José Semionato Filho, MD, Mara Albonei Dudeque Pianovski, PhD, Marcelo Soares Kerstenetzky, MD, Maria de Fátima Pombo Montoril, MD, Paulo Cesar Aranda, MD, Ricardo Flores Pires, MD, Ronald Moura Vale Mota, MD, Teresa Cristina Bortolheiro, MD, and for Brazilian Study Group on Gaucher Disease and other Lysosomal Storage Diseases* The lysosomal storage diseases currently number 45 and have a cumulative incidence of 1 in 5000 live births. 1 Gaucher disease (GD) predominates among this group, having a frequency of 1 in in the United States of America. GD results from an autosomal recessive deficiency of the lysosomal enzyme acid beta-glucosidase (glucocerebrosidase), which is responsible for hydrolysis of glucocerebroside (glucosylceramide [GLC]) into glucose and ceramide. 2,3 Absent or reduced enzymatic activity leads to multisystemic accumulation of GLC in various tissues, principally in lysosomes of macrophages, consequently compromising the spleen, liver, bone marrow, bone mineral, and, less often, the lungs, skin, conjunctiva, kidneys, and heart. 3 Although several forms of GD manifest in the central nervous system, the cause of the neurologic manifestations have yet to be fully elucidated. 4-6 On microscopy, the macrophages with GLC inclusions take on the appearance of crumpled paper. These so-called Gaucher cells may be found in the tissues of the several affected organs. 7-9 Deposition of Gaucher cells within the liver and spleen lead to hepatomegaly and splenomegaly, respectively, and hypersplenism generally manifests as thrombocytopenia, anemia, and to a lesser degree, leucopenia. Infiltration of bone marrow by Gaucher cells leads to gradual alterations in the bone, which can lead to chronic bone pain, osteopenia, bone infarct, osteonecrosis, pathologic fractures, lytic lesions, and bone deformities. 10 Recommendations on the evaluation, monitoring, and treatment of GD have been made for adults and children In this publication, the Brazilian Study Group on GD and Other Lysosomal Storage Diseases provide updated recommendations for diagnosis, monitoring, and treatment of patients with GD, with special consideration given to Brazilian patients. 15 Clinical Presentation of Gaucher Disease As with most genetic diseases, the signs and symptoms of GD present along a continuum, ranging from the lethal neonatal form to the asymptomatic form. The disease is characterized by variable clinical expression and severity, even among siblings with the same genotype. 3,16 Currently, GD is classified into 3 clinical forms: nonneuropathic, acute neuropathic, and chronic neuropathic. Nonneuropathic GD (type 1) is the most frequent type, accounting for 95% of cases. Its incidence ranges from 1: to 1: in the general population, reaching 1:400 to 1:600 among Ashkenazi Jews According to the Brazilian GD Patient Association, more than 600 patients with GD patients were diagnosed in Brazil. Type 1 GD affects children and adults at any age and typical clinical manifestations include hepatomegaly, splenomegaly, anemia, thrombocytopenia, and bone disease. Cytopenia occur as a result of hypersplenism in most cases. In general, hemorrhagic manifestations are attributed to thrombocytopenia, although they may occur as a result of coagulation factor deficiency. 20 The clinical picture is also associated with asthenia, fatigue, postprandial gastric fullness, nutritional disturbances, and stunted growth. The accumulation of Gaucher cells in bone marrow leads to complications such as chronic pain, osteopenia, lytic lesion, fractures, and osteonecrosis. Bone crises stemming from ischemia of bone marrow are characterized by acute episodes of severe skeletal pain with fever, leukocytosis, and elevated erythrocyte sedimentation rate, radiographs show periosteal reaction without osteolysis. 3,21-23 Disease progression varies and survival may be normal depending on the severity of complications. 10,17,24,25 From the Centro de Referência em Erros Inatos (A.M.M), Universidade Federal de São Paulo, São Paulo, Brazil; Departamento de Propedêutica Complementar da Faculdade de Medicina (E.V.), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Unidade Hepatologia Pediátrica, Hospital de Clinicas Instituto da Criança (G.P.), Faculdade de Medicina da Universidade Federal de São Paul, São Paulo, Brazil; Departamento de Bioquímica ICBS (J.C.), Universidade Federal do Rio Grande do Sul e Serviço de Genética do Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Centro Geral Pediátrica (J.F.), Hospital da Fundação do Estado de Minas Gerais (FHEMIG), Minas Gerais, Brazil; Disciplina de Hematologia e Oncologia do Departamento Pediátrica (M.P.), Universidade Federal do Paraná, Paraná, Brazil; Serviço de Hepatologia Infantil do Hospital da Restauração (M.K.), Pernambuco, Brazil; Fundação de Hemoterapia e Hamatologia Central do Pará (M.M.), Pará, Brazil; Serviço de Hematologia do Hospital Evangélico de Londrina (P.A.), Paraná, Brazil; Clínica Dr. Ricardo Pires para Doenças Metabólicas (R.P.), Porto Alegre, Brazil; Serviço de Ortopedia Pediátrica, Hospital Socor Geral (R.M.), Minas Gerais, Brazil; Disciplina de Hematologia e Oncologia da Faculdade de Serviços Médicos da Santa Casa de São Paulo (T.B.), São Paulo, Brazil. BMI ERT GD GLC MRI Body mass index Enzymatic replacement therapy Gaucher disease Glucosylceramide Magnetic resonance imaging *The Brazilian Study Group on Gaucher Disease and other Lysosomal Storage Diseases is independent, and received financial support from Genzyme do Brasil for the holding of meetings by the group. The opinions or views expressed in this article are those of the authors and do not necessarily reflect the opinions or recommendations of Genzyme Brasil. Please see the Author Disclosures at the end of this article /$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved /j.jpeds S10

2 Vol. 155, No. 4, Suppl. 2 October 2009 Clinical manifestations presenting in the first or second decades of life are typically more aggressive and progress to greater severity than those manifesting at a later stage in life. The acute neuronopathic form (type 2) occurs in less than 1 in and generally affects infants at 4 to 5 months of age, compromising the brain, spleen, liver, and lungs. The neurologic picture is serious, with bulbar (stridor, convergent strabismus, swallowing difficulties) and pyramidal (opisthotonos, head retroflexion, spasticity, trismus) involvement and may present delayed neuropsychomotor development. Evolution is rapid, leading to death within the first 2 years of life, usually because of lung failure. 8,26-28 The incidence of the subacute neuronopathic (type 3) form is less than 1 in The distribution of type 3 GD is panethnic, but this form predominates in some geographic regions such as Northern Sweden. 29,30 Individuals with type 3 GD may experience early systemic affects similar to type 1, and the neurologic picture may manifest at any age, presenting convulsive crises, ataxia, supranuclear horizontal ocular palsy, or dementia. Patients with type 3 GD may have minimal neurologic involvement limited to alteration in ocular movement, and others evolve with ocular motor apraxia, discrete organomegaly, cornea opacity, and cardiac valve disease with progressive calcification. The latter group of patients often only survives to the second or third decades of life. Beyond the classic manifestations outlined, GD may also affect several additional organs: lungs (interstitial disease or pulmonary vasculopathy causing pulmonary hypertension) 31 ; gastrointestinal tract (diarrhea and poor absorption) 32 ; skin (brownish pigmentation on face and legs) 33 ; liver (enzymatic and bilirubin alterations may lead to chronic liver disease, cirrhosis, and portal hypertension) 34,35 ; heart (cardiac artery calcification and changes in contractility) 36,37 ; and kidneys (varied degrees of proteinuria with or without renal insufficiency). 38,39 Differential Diagnosis The differential diagnosis of GD must be made from other diseases presenting clinical manifestations similar to those observed in GD. For example, hepatosplenomegaly or pancytopenia may also occur in Niemann-Pick B, and infectious diseases such as hepatosplenic schistosomiasis and visceral leishmaniasis must also be considered in regions of prevalence. Leukemias and hemolytic anemias are also relevant for differential diagnosis in children, whereas in adults tricholeukemia and splenic marginal zone lymphoma should also be considered. Presentation of bone crises allows differential diagnosis of GD from osteomyelitis. In neuropathic forms of GD, diseases with hepatosplenomegaly and neurologic degeneration such as GM1 gangliosidosis and Niemann-Pick disease types A and C should be considered. 3,40 Comorbidities GD may also be associated with other diseases such as Parkinson s disease (mutations in the glucocerebrosidase gene or alterations in its region may represent risk factors for developing parkinsonism) 41,42 or neoplasias (multiple myeloma, chronic lymphocytic leukemia and lymphomas). 3,43-46 Recent recommendations for the management of the hematologic and oncohematologic aspects of GD suggests immunoglobulin profile determined at diagnosis and monitored every 2 years (patients < 50 years) or every year (patients > 50 years), because of the higher incidence of multiple myeloma in patients with GD. 47 It should be noted that a definitive link between GD and either Parkinson s disease or neoplasias has not been established. Laboratorial Diagnosis Enzymatic Activity Definitive diagnosis of GD requires confirmation by the acid beta-glucosidase enzyme assay in leukocytes or fibroblasts. Clinically suspect individuals with borderline enzymatic levels require confirmation by determining enzymatic activity in fibroblasts or performance of molecular analysis of the acid beta-glucosidase gene. Reference values may differ according to the analysis method and laboratory involved. Residual enzymatic activity does not correlate with disease severity. Enzymatic activity of leukocytes and fibroblasts in heterozygotes may predominate over that of normal individuals and homozygotes for GD. 3,48 Patients with GD present highly elevated concentrations of plasmatic chitotriosidase, an enzyme synthesized by activated macrophages. Although this may facilitate diagnosis, it should be noted that approximately 6% of the general population does not produce chitotriosidase because of the presence of null alleles in the gene of this enzyme. 49,50 Molecular Analysis The gene codifying acid beta-glucosidase is located in the long arm of chromosome 1 (1q2.1). To date, more than 300 mutations have been described. However, the most common mutations seen in approximately 90% of non-jewish patients are N370S, 84GG, L444P, and IVS N370S homozygotes generally present with a less severe phenotype, whereas L444P and D409H homozygosity confers neurologic involvement. 3,33 According to a study of 221 patients, the most common genotype identified in Brazil was N370S/ L444P. 51 Despite these general genotype-phenotype correlations, disease severity, and clinical outcomes cannot be predicted on the basis of genotype. Auxiliary Hematologic Tests Hematologic evaluations often reveal anemia, thrombocytopenia, and leucopenia but enables differentiation between chronic myeloid leukemia and lymphomas with expression in peripheral blood Bone marrow biopsy and aspirate shows infiltration by Gaucher cells (Figure). This method allows differentiation among lymphatic and leukemic infiltrations and infectious diseases and distinguishes the macrophages from other lysosomal storage diseases such as Niemann- Pick and sea-blue histiocytes S11

3 THE JOURNAL OF PEDIATRICS Vol. 155, No. 4, Suppl. 2 Figure. A, Gaucher cells in bone marrow. B, Leishman stain of bone marrow aspirate sample. Courtesy of Bortolheiro. Prolonged prothrombin and partial thromboplastin times occur in 40% of patients. Low fibrinogen levels have been associated with elevated D-dimer, indicating activation of the fibrinolytic system. 20 The hemorrhagic symptoms can be attributed to the quantitative and qualitative deficit of platelets, as well as alterations in plasma factors of coagulation. 55 Table I. Initial clinical and laboratorial assessment after GD diagnosis* Patient medical history including family history and physical examination Quality of life: functional health and well-being reported by patient (SF-36 health survey) Principle blood tests: Hemography with platelet count Biochemical marker: chitotriosidase Other selective tests: Iron, transferrin, ferritin, vitamin B 12 Prothrombin and partial thromboplastin time Aspartate amino transferase, alanine aminotransferase Alkaline phosphatase, calcium, phosphorus, albumin, total protein, direct and total bilirubin Mutation analysis Serum sample for antibodies Skeletal assessment: Radiography of the spine, long bones, and hips Bone densitometry of the spine and femur head Coronal magnetic resonance imaging (MRI), T 1 and T 2 of bilateral femur Assessment of visceral volume Volumetric ultrasonography of the liver and spleen, or with 3 measures (at largest axes) Splenic volume (MNR or computed tomography) Hepatic volume (MNR or computed tomography) Cardiac assessment in individuals aged more than 18 years: Thorax radiography Electrocardiography Echocardiography *Adapted with permission from Weinreb et al, Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol 2004;41: Copyright Elsevier Inc. 11 Basal sample and 1 subsequent sample 6 months after commencement of enzyme replacement therapy should be tested in cases of clinical indication, suspected immunologic adverse event or reduced enzyme replacement therapy efficacy. S12 Monitoring All patients with GD must undergo initial clinical and laboratory assessment (Table I) to determine the appropriate therapy. Before the advent of enzymatic replacement therapy, patients with symptomatic GD received only supportive treatment such as transfusion of hemocomponents, splenectomy, or analgesics. 56 Splenectomy has been associated with severe bone disease or significantly worsened lung or kidney disease in patients with GD. 31,38,39,57,58 There is a 10 times increased risk for osteonecrosis in patients who have undergone prior splenectomy. 58 Affected patients with kidney abnormality invariably have had before. 39 Splenectomy was recently identified as a risk factor for pulmonary hypertension even for patients without GD. 59 Treatment In the absence of treatment, the natural course of GD, even for type 1 presentation, is extremely unfavorable, evolving with frequent complications and high morbidity and mortality rates. Currently, 2 treatments are available for GD, enzymatic replacement therapy (ERT) and substrate reduction therapy. ERT with alglucerase (Ceredase; Genzyme Corporation, Cambridge, Massachusetts), acid beta-glucosidase isolated from human placentas, was originally approved in 1991 by the Food and Drug Administration in the United States of America for use in patients with type 1 GD. The modified form of the acid beta-glucosidase enzyme, imiglucerase (Cerezyme, Genzyme Corporation), is produced by recombinant DNA technology with mammalian Chinese hamster ovary cell culture and became available in ,60 ERT with imiglucerase is the current standard of care for the treatment of type 1 GD. 60 Substrate reduction therapy with miglustat (Zavesca; Actelion Pharmaceuticals, Allschwil, Switzerland) was recently approved in Brazil and is licensed in the European Union, the United States, and Israel. 61 Miglustat is an oral treatment indicated in patients with type 1 GD for whom ERT is not an option. 62 Indications for Treatment Diagnosis of GD must be confirmed by enzymatic or molecular tests (2 identified mutations). At least 2 of the following manifestations must be present in the nonneuropathic form for the patient to receive the treatment: hepatic, splenic (or prior splenectomy), cardiac, pulmonary, or renal compromise; anemia according to criteria described in Table II; number of platelets less than /mm 3 ; pain or bone Martins et al

4 October 2009 SUPPLEMENT Table II. Definition of anemia according to hemoglobin values Age Hemoglobin (g/dl) <6 months < to 24 months <9.5 2 to 12 years <10.5 >12 years females <11 >12 years males <12 Adapted with permission from Weinreb et al, Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher registry. Am J Med 2002;113: Copyright Elsevier Inc.. 22 crisis; active bone disease (marrow infiltration, osteopenia, bone infarct, osteonecrosis, fracture, lytic lesion, and Erlenmeyer s flask deformity); delayed growth, defined as height less than percentile 2.5 (low height) according to the National Center for Health Statistics Chart for 2000, 63 or delayed bone age, or body mass index (BMI = weight in kg/height 2 in meters) where a BMI < 5th percentile in children and adolescents (2-20 years) or BMI < 18.5 in adults over 20 years, are considered altered, 63 and impaired quality of life. All patients with chronic neuropathic form (type 3), those with history of brother or sister having neuropathic GD with identical genotype, or the L444P/L444P, D409H/D409H or L444P/D409H genotypes are also indicated for treatment. Patients with the acute neuropathic form (type 2) are not indicated for treatment. 29 Imiglucerase ERT with imiglucerase is the current standard of care for the treatment of GD and has been proven to improve the clinical manifestations of GD and enhance quality of life in patients with GD. 22,64-69 ERT with imiglucerase is recommended for all patients with type 1 and type 3 GD, regardless of age, who has symptoms with mild, moderate, or severe clinical manifestations. Each vial of imiglucerase contains 200 or 400 IU of the lyophilized enzyme for reconstitution in distilled water 5.1 or 10.2 ml, respectively, and subsequent dilution in physiological saline solution yields a final volume of 100 to 200 ml for intravenous infusion. Infusions are recommended every 2 weeks, with an infusion time of 1 to 2 hours. Infusion times of less than 1 hour are not recommended. Adverse reactions occur in less than 15% of patients and include malaise, pruritis, burning at infusion site, edema, anaphylactic reaction, urticaria/angioedema, thoracic discomfort, dyspnea, coughing, cyanosis, hypotension, nausea, vomiting, abdominal pain, diarrhea, cutaneous rash, fatigue, headache, tremors, dizziness, back pain, and tachycardia. 60 Each adverse event was reported in less than 1.5% of patients receiving imiglucerase, with the most frequently reported adverse events being self-limiting infusion-associated reactions that were managed by decreasing the infusion rate or pretreatment with antihistamines or antiinflammatory drugs. If no further adverse events occur, the speed of subsequent infusions may be increased after the first 30 minutes. 12 Significant events precluding the further use of imiglucerase, such as anaphylaxis, have been extremely rare. 60 Adverse reactions must be reported to the manufacturer s Pharmacovigilance department. Nonneuropathic form (Type 1). The dose of imiglucerase depends on GD type, patient age, organ involvement, severity, extent, and progression of the disease. The ideal dose for a patient is sufficient to maintain full or partial reversal of signs and symptoms of the disease (Gregory A. Grabowski, MD, personal communication). Some studies suggest that a dose-response effect of imiglucerase exists for several clinical manifestations, 67,70 which underscores previous recommendations that dosage must be individualized according to each patient s clinical scenario and progression. 13 In children, therapeutic intervention should occur as soon as possible and at the necessary dose to attain growth potential and avoid serious and irreversible manifestations of GD. 12,68,71-74 In nonneuropathic forms initial dosages should be individualized according to the high- and low-risk criteria illustrated in Tables III and IV. All patients, irrespective of age, should undergo clinical assessments every 6 months to receive appropriate dose adjustments. Initial doses should be maintained at the same level for at least 1 year in all patients in whom therapeutic goals are met. However, initial doses should be maintained for at least 24 months in patients with skeletal compromise. 72,73-76 Low-risk adult patients (Table IV) attaining all therapeutic goals may undergo dose reductions of 25% to 50% every 6 months after 1 year of treatment. Patients with bone disease are excluded from this permissible reduction in dosage. Reports in the literature state that maintenance doses of imiglucerase must not fall below 20 U/kg/2 weeks for adults and 30 U/kg/2 weeks for patients up to 18 years of age. 12,13,77,78 Dose adjustments should be individualized on the basis of regular monitoring of clinical manifestations and may be changed after attainment of the therapeutic goals illustrated in Table V. Some authors advocate the use of low doses up to 15 U/kg/ month administered either every 2 weeks or 3 times per week. However, therapeutic failure has been observed in some patients receiving such low-dose regimens of imiglucerase. 13,79-81 On opting for a given maintenance dose of imiglucerase for GD on the basis of clinical characteristics and disease severity, the patient population to which an individual patient belongs must be considered in determination of dose. A recent population study comparing data on patients with type 1 GD in Brazil with worldwide data suggests that the Brazilian patient group presented with more aggressive disease. 51 Therefore we recommend close monitoring of patients to safeguard against low doses leading to irreversible sequelae. High-risk adult patients (Table IV) attaining all therapeutic goals may have doses reduced to a lesser extent by 15% to 25% every 6 months after 1 year of treatment (except patients with bone compromise). The minimum dose for high-risk adults and children is 30 U/kg every 2 weeks because lower doses may lead to a worsening of the bone condition. 13 Patients experiencing therapeutic failure after a dose reduction or who were unable to maintain clinical improvement according to the measures outlined in Table V should have Recommendations on Diagnosis, Treatment, and Monitoring for Gaucher Disease S13

5 THE JOURNAL OF PEDIATRICS Vol. 155, No. 4, Suppl. 2 Table III. Children and adolescents (<18 years) with Gaucher disease: risk assessment and dose High risk (at least one of the following) Low risk (all of the following criteria) Initial dose 60 IU/kg every 2 weeks 30 IU/kg every 2 weeks Criteria Hemoglobin 2 g/dl below lower normal limit for sex and age Hemoglobin maximum of 2 g/dl below lower normal limit for sex and age Platelets #60 000/mm 3 or documented abnormal bleeding Platelets >60 000/mm 3 on 3 measurements Delayed growth Bone disease limited to osteopenia and marrow infiltration Active bone disease Hepatic volume <2.5 times normal value Alterations in hepatic function or volumetric increase >2.5 times Spleen volume <15 times normal value normal value Volumetric increase in spleen >15 times normal value Normal hepatic, cardiac, pulmonary and renal functions Pulmonary alterations Kidney disease Adapted with permission from Andersson et al, Individualization of long-term enzyme replacement therapy for Gaucher disease. Genet Med 2005;7: Copyright Walters Kluwer Health. 13 their dose increased to the minimum efficacious level previously observed. 13 Monitoring of bone disease in children is carried out with basic radiography, which has proved adequate. 23,82 However, magnetic resonance imaging (MRI) is recommended for more accurate assessment of bone disease in adults. 81 Detailed recommendations on the monitoring skeletal involvement in GD have been made by vom Dahl et al. 14 Chronic Neuropathic Form (Type 3). The initial recommended dose of imiglucerase for patients with type 3 GD is 120 U/kg/2 weeks. Adults with mild systemic disease and stable neurologic involvement may have maintenance doses adjusted gradually in 15% to 25% reductions every 6 months, depending on response, until 60 U/kg every 2 weeks is attained. 29,13 All patients at risk for development of neurologic disease (such as carriers of L444P/L444P, D409H/D409H or L444P/ D409H genotypes) must receive the minimum dose of 60 U/kg/2 weeks and continue to be carefully monitored every 6 months. Siblings of patients with the same genotype and neurologic involvement must be treated as if they exhibit neurologic disease. 83 Clinical and Laboratory Monitoring All patients with GD must be regularly monitored from a clinical and laboratory standpoint by multidisciplinary teams to assess course of the disease and effects of therapy (Table VI). Indications in Table VII are recommended for chronic neuropathic GD. Monitoring of bone disease in children and adults for initial assessment is carried out with x-ray examination 11,12,23,82 of the femora, spine, and any other symptomatic sites. Plain radiographs are useful to primarily visualize cortical thickness and mineral-phase lesions in more advanced GD and to measure bone age in children, but a far greater burden of marrow and bone disease can be demonstrated by imaging with MRI. In some countries the x-ray is broadly used because of its wide availability and low cost, but its sensitivity is not adequate to detect Gaucher marrow infiltration or early osteopenia. Therefore T 1 -weighted MRI is recommended to detect and quantify the extent of marrow infiltration; and T 2 -weighted MRI is recommended to identify focal lesions, active bone infarcts, osteonecrosis, and osteomyelitis, an important differential diagnosis in patients presenting a bone crisis. For more accurate assessment of bone disease in adults and children, it is desirable to conduct MRI studies at centers with radiologists experienced in evaluating patients with GD, mostly children. 84 The dual-energy x-ray absorptiometry of the lumbar spine and femoral neck is recommended for quantitative determination of bone density to detect osteopenia. 11,12,23,82 Conclusions GD is a clinically heterogeneous, progressive disease whose natural course can be extremely unfavorable, evolving with frequent complications and high morbidity and mortality rates. ERT with imiglucerase is the current standard of care for the treatment of GD. Miglustat is available to patients for whom ERT is not an option. Early implementation of Table IV. Adults ($18 years) with GD: risk assessment and dose High risk (at least one of the following) Low risk (all of the following criteria) Initial dose 60 IU/kg every 2 weeks 30 IU/kg every 2 weeks Criteria Symptomatic anemia or hemoglobin #8.0 g/dl Hemoglobin maximum of 2 g/dl below lower normal limit for sex and age Platelets #60 000/mm 3 or documented abnormal bleeding Platelets >60 000/mm 3 on 3 measurements Active bone disease Bone disease limited to osteopenia and marrow infiltration Alterations in hepatic function or volumetric increase > 2.5 times normal value Hepatic volume < 2.5 times normal value Volumetric increase in spleen > 15 times normal value Spleen volume < 15 times normal value Pulmonary alterations Normal hepatic, cardiac, pulmonary and renal functions Kidney disease Adapted with permission from Andersson et al, Individualization of long-term enzyme replacement therapy for Gaucher disease. Genet Med 2005;7: Copyright Walters Kluwer Health. 13 S14 Martins et al

6 October 2009 SUPPLEMENT Table V. Therapeutic goals in ERT 75 Pretreatment At 1 year At 2 years After 5 years Hemoglobin concentration Greater increase in more severe anemia Normal levels should be reached in most patients Platelet count Nonsplenectomized patients with thrombocytopenia >60 000/mm 3 Should increase 1.5- to 2-fold Increase should be maintained (may not reach normal values) <60 000/mm 3 Should increase 1.5-fold Increases should be progressive and continuous (may not reach normal values) Splenectomized patients with thrombocytopenia < /mm 3 Should increase in 6 months and normalize in 1 year Increases should be progressive and continuous (may not reach normal values) Hepatic volume* Should decrease by 20%-30% Should decrease by 30%-40% Spleen volume Should decrease by 30%-50% Should decrease by 50%-60% Bone disease Pain and bone crisis Reduction or remission in bone pain. Remission of bone crises Prevention of osteonecrosis Improvement in bone mineral density Normal levels should be maintained Adapted with permission from Pastores GM et al, Therapeutic goals in the treatment of Gaucher disease. Semin Hematol 2004;41(Suppl 5):4-14. Copyright Elsevier Inc. 75 *Hepatic volume reduction is greater in splenectomized subjects. Hepatic volume rarely normalizes when size at pretreatment is $2.5 times normal value. The higher the pretreatment spleen volume, the greater the reduction in splenic volume. adequate therapy after confirmation of diagnosis is necessary to prevent disease progression and onset of serious and irreversible complications. An appropriate disease management strategy includes an initial evaluation and ongoing monitoring for the individualization of therapy to achieve established therapeutic goals. We provide here updated recommendations on the evaluation, monitoring, and treatment of patients with GD, with specific reference to the Brazilian GD population. Selecting the correct dose of imiglucerase is vital to the success of the treatment. Doses should be individualized according to the clinical needs of the patient. Patients at high risk with type 1 GD should commence treatment on 60 U/kg every 2 weeks, whereas patients at low risk should be started on a dose of 30 U/kg. Regular monitoring of all clinical measures of relevance to GD must be performed to allow for dose adjustments in response to a patient s clinical progress and therapeutic response. Doses may be reduced in patients attaining therapeutic objectives after 1 year of treatment to 20 U/kg or 30 U/kg every 2 weeks in patients at low and high risk, respectively. However, patients with bone compromise should remain on the initial dose for a minimum of 2 years. The initial dose of imiglucerase in type 3 patients with GD is 120 U/kg every 2 weeks. In cases that respond well to treatment, the dose may be gradually reduced to 60 U/kg. Despite its high financial cost, ERT with imiglucerase remains an essential component of a successful disease management strategy because of its efficacy, which is recognized by governmental agencies funding this treatment. It is the duty of physicians to observe rigorous criteria when placing patients on imiglucerase, as well as in the provision of clinical and laboratorial monitoring. Doses must be individualized according to need and adjusted after close monitoring of clinical progress, allowing physicians to exercise their ability to preserve social resources. An effective disease management approach requires the comprehensive evaluation and monitoring of all clinical Table VI. Clinical-laboratorial monitoring of nonneuropathic patients with GD without and with imiglucerase therapy Patients without imiglucerase Therapeutic objectives met Therapeutic objectives unmet Annual months Quarterly Annual Annual Dose change or complication Anamnesis and physical examination X X X X SF-36 survey to adult and a QOL to children X X X X Complete hematologic evaluations X X X X Chitotriosidase X X X X Volumetric assessment of liver X X X X and spleen Skeletal assessment X X X X Blood tests, others Individualized monitoring required Pulmonary assessment Recommended every months in patients with above normal basal limits of pulmonary pressure Adapted with permission from Weinreb et al, Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol 2004;41: Copyright Elsevier Inc. 11 Recommendations on Diagnosis, Treatment, and Monitoring for Gaucher Disease S15

7 THE JOURNAL OF PEDIATRICS Vol. 155, No. 4, Suppl. 2 Table VII. Clinical-laboratory monitoring of patients with chronic neurologic GD* Patients not receiving imiglucerase Patients receiving imiglucerase Initial assessment Every 6 months Every 12 months Every 6 months Every 12 months Neurologic history Onset of symptoms X Stages of development Onset of retarded development X X X Neuropsychomotor development assessment X X X Cranial nerve assessment Extrinsic ocular motricity Rapid eye movement X X X Convergent strabismus X X X Slow object tracking X X X Speech Dysarthria X X X Eating Mastication difficulties X X X Deglutition difficulties X X X Stridor X X X Head posture Retroflexion X X X Motor assessment Myoclonus X X X Fine movements Pincer grasp (age # 2 years) X X X Finger tapping (age > 2 years) X X X Gross movements Weakness X X X Spasticity X X X Terminal and resting trembles X X X Extrapyramidal signs X X X Ataxia X X X Reflexes X X X Convulsions Type, frequency, and medications in use X X X Neurologic tests Electroencephalography X X X Audiometry X X X Brain stem auditory evoked potential X X X Adapted from ICGG Gaucher Registry. *This recommendation should be adapted to suit the needs of each patient, in accordance with their assisting doctor. Assessed only in patients younger than 18 years. relevant measures of GD. Initial and regular assessments as recommended here provide a rational basis for the individualization of adequate therapy to ensure the best possible outcomes for patients with GD. n Author Disclosures Ana Maria Martins, MD, PhD, travel expenses as part of continuous medical education and grants as Coordinator for the Fabry Registry in Brasil, since 2002 and Member of the International Board of Advisors for the Fabry Registry since Eugênia Ribeiro Valadares, MD, PhD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement. Gilda Porta, MD, PhD, José Semionato, Filho, MD, Mara Albonei Dudeque Pianovski, PhD, Maria de Fátima Pombo Montoril, MD, Paulo Cesar Aranda, MD, Ronald Moura Vale Mota, MD, Teresa Cristina Bortolheiro, MD, Janice Coelho, PhD, and Marcelo Soares Kerstenetzky, MD received travel expenses from Genzyme Brazil as part of continuous medical education. Ricardo Flores Pires, MD was a Genzyme S16 Associate Medical Director from October 2006 to May 2007 and before this period he had received travel expenses from Genzyme Brazil as part of continuous medical education. Reprint requests: Ana Maria Martins, Rua Joaquim Antunes, 620/72, CEP São Paulo, SP. anamartins.dped@epm.br. References 1. Meikle PJ, Hopwood JJ. Lysosomal storage disorders: emerging therapeutic options require early diagnosis. Eur J Pediatr 2003;162(Suppl 1):S Grabowski GA. Gaucher disease: lessons from a decade of therapy. J Pediatr 2004;144:S Beutler E, Grabowski G. Gaucher Disease. In: Scriver C, Sly W, Childs B, et al, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; p Nilsson O, Svennerholm L. Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J Neurochem 1982;39: Schiffmann R, Heyes MP, Aerts JM, Dambrosia JM, Patterson MC, DeGraba T, et al. Prospective study of neurological responses to Martins et al

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