Aya Abrahamov

Platelet function abnormalities in Gaucher disease patients

Bleeding manifestations are common in Gaucher disease patients. Although usually attributed to thrombocytopenia, some patients with relatively high platelet counts and normal coagulation tests have hemorrhagic phenomena. To investigate whether perturbed platelet function could explain these bleeding manifestations we performed platelet aggregation tests on 32 type I adult Gaucher patients who were not severely thrombocytopenic (platelet counts >50 × 109/L). Seven patients (22%) had abnormal platelet aggregation. In five, platelet aggregation was markedly reduced in response to collagen and ADP and virtually absent in response to epinephrine, whereas two patients had isolated severely impaired epinephrine‐induced aggregation. In one patient platelet aggregation markedly improved following one year of enzyme replacement therapy. Incubating normal platelets with high concentrations of glucocerebroside did not impair their ability to aggregate, suggesting that plasma glucocerebroside does not directly interfere with platelet function. Platelet dysfunction is a hithero unrecognised, relatively common cause of excessive bleeding in Gaucher patients. Am. J. Hematol. 61:103–106, 1999.

Survey of hematological aspects of Gaucher disease

Abstract Hematologists have classically been the treating physicians of patients with Gaucher disease, and today, despite both specific and symptomatic therapeutic advances, they remain at the forefront of specialists to whom patients with Gaucher disease present. It is therefore appropriate to review that has changed and what has remained the same in hematological signs and symptoms of the disease in the decade and a half since therapy has become available.

Gaucher's disease

Correspondence to: Dr Deborah Elstein (e-mail: zimran@md2.huji.ac.il) reduced enzyme activity with accumulation of glucosylceramide in the macrophages of the reticuloendothelial system. Three clinical subtypes of Gaucher’s disease have been described on the basis of the absence (type I) or presence (types II and III) of a neurological component (panel). All forms are panethnic. However, type I is more common, and is especially prevalent, among Ashkenazi Jews (predicted prevalence is about 1/850). More than 200 mutations have been identified in the -glucocerebrosidase gene, including point mutations, crossovers, and recombinations, but prediction of clinical course can only be broadly ascribed on the basis of genotyping. Gaucher’s disease

Gaucher disease: pediatric concerns.

Gaucher disease, the most prevalent lysosomal storage disorder, is inherited as an autosomal recessive condition. The gold standard for diagnosis is decreased acid β-glucosidase activity in the lymphocytes or fibroblasts; molecular analysis of mutations allows for some prognostication of disease severity. Prenatal diagnosis and carrier testing for at-risk families are currently available.There is tremendous phenotypic heterogeneity in the non-neuronopathic form (type I), ranging from clinically asymptomatic to massive hepatomegaly, hypersplenism, growth retardation in children and extensive involvement of bone and lungs. Presence on one allele of the most common mutation, N370S, which is the most prevalent among Ashkenazi Jews for whom there is a predilection for Gaucher disease, is protective of neurological involvement. Some mutations, such as 84GG and IVS2+1, are associated with more severe disease manifestations when appearing as compound heterozygotes with N370S, but when occurring in the homozygous state are not compatible with life. Other mutations, such as L444P, are associated with severe non-neurological disease when occurring as compound heterozygotes with N370S, but when occurring in the homozygous state may be predictive of neurological disease of either acute (type II) or subacute (type III) forms.In the past decade, enzyme replacement therapy has become available which has resulted in a reduction in liver and spleen volume and consequently improved anemia and thrombocytopenia in most patients. It has also engendered catch-up growth in many children, induced improvement in lung involvement secondary to Gaucher disease, and to some extent ameliorated episodes of bone pain. By virtue of treatment, many children who may have been severely affected no longer need to undergo splenectomy to treat hypersplenism, and therefore they are not at risk of bone involvement consequent to the loss of the preferred reservoir for lipid-laden ‘Gaucher cells’. However, enzyme treatment is ineffective in reversing neurological signs, requires a lifelong commitment to intravenous infusions, thereby reducing quality of life, and is relatively expensive for many national health schemes. Hence, alternative forms of treatment, such as substrate balance, are being explored. Symptomatic management, including orthopedic surgery, pain relief for bone pain and even splenectomy, still has importance for patients with Gaucher disease. In addition, there is the potential for bone marrow transplantation and, in the future, gene therapy to be curative, particularly for patients with the neuronopathic forms.

Booster-effect with velaglucerase alfa in patients with Gaucher disease switched from long-term imiglucerase therapy: early Access Program results from Jerusalem.

BACKGROUND Decreased spleen and liver volumes and increased hemoglobin levels and platelet counts usually occur with enzyme replacement therapy (ERT) in symptomatic patients with Gaucher disease. Because of decreased supply of imiglucerase, an FDA-approved Early Access Program (EAP) allowed use of a new, pre-licensed ERT, velaglucerase alfa. This report provides safety and efficacy findings in patients on EAP velaglucerase alfa who completed 6, 9, or 12 months as intravenous every-other-week ERT. METHOD EAP was approved by the Israeli Ministry of Health. All patients enrolled in the EAP were included for safety measures; only those with >6 month evaluations of hemoglobin, platelet counts, and liver and spleen volumes were included for efficacy. Descriptive statistics were employed. RESULTS Among 71 EAP patients, there were no drug-related serious adverse events or withdrawals; one patient (1.4%) with previous hypersensitivity to a different ERT had a drug-related allergic reaction. Of 44 patients with appropriate time-period evaluations, 8 patients were treatment-naïve and responded well to velaglucerase alfa. The 36 switch-over patients remained at imiglucerase low-doses; a majority of patients showed improvements in each efficacy parameter. CONCLUSION Switch-over from imiglucerase (10-224 months) was safe and in several patients velaglucerase alfa induced a booster-effect.

Growth failure due to protein loss in dermatitis

A 10-month-old infant is described who suffered from extensive atopic dermatitis, failure to thrive, hypoalbuminaemia and oedema. Large amounts of sticky exudate were lost through the skin and were shown to be rich in albumin. As renal and intestinal loss of protein was excluded, the patients condition was ascribed to the loss of albumin through the skin at a rate that outstripped the synthesis of this protein. Treatment with steroids resulted in dramatic clearing of his dermatitis, and subsequent rapid correction of his hypoalbuminaemia, oedema and anaemia.

The 1604A (R496H) mutation in Gaucher disease: genotype/phenotype correlation.

Gaucher disease is the most common sphingolipid storage disease but genotype only broadly predicts phenotype. The 1604G-->A (1604A;R496H) mutation has been described as having a low incidence among Ashkenazi Jews. The purpose of this study was to ascertain phenotypic expression and prevalence of this mutation among patients with Gaucher disease and among healthy Ashkenazi Jews. Patients in two Gaucher clinics (in the United States and Israel) and from an international Gaucher registry were assessed for frequency and phenotype expression; 200 healthy Ashkenazi Jews were screened as well. Molecular analysis was performed by standard methods. In the Gaucher clinic with mostly Jewish patients, the gene frequency was 1.68% compared with 0.38% in the international registry with mostly non-Jewish patients. Among Ashkenazi Jewish controls, no alleles with 1604A were identified. There was a marked overrepresentation of severe alleles in patients carrying the 1604A mutation, suggesting that many patients who are compound heterozygotes for 1604A are not diagnosed as having Gaucher disease because their disease is presumably so mild as to evade detection. In view of its rarity and mild expression, the inclusion of the 1604A mutation in the standard kit for screening for Gaucher disease is unnecessary.

Outcome of ten years’ echocardiographic follow-up in children with Gaucher disease

The non-neuronopathic form Gaucher disease, the most prevalent lysosomal storage disorder, is marked by tremendous phenotypic heterogeneity; cardio-pulmonary involvement is distinctly rare except in the most severely affected patients. With the advent of enzyme replacement therapy, most symptomatic patients will not suffer from lung disease. However, because of concern about pulmonary hypertension among adult patients exposed to enzyme replacement therapy, echocardiography has been recommended as an early warning system for routine follow-up of all patients, including children. The purpose of this study was to review the results of more than a decade of echocardiographic findings in children followed semi-annually in a large referral clinic in order to ascertain whether echocardiography as an early signal of pulmonary hypertension in children is appropriate. 330 echocardiographic examinations were performed in 71 children (276 patient follow-up years). Only four patients receiving enzyme therapy each had a single abnormal examination that upon repeat examination six months later reverted to within normal limits. There were no abnormal results among the untreated patients. Therefore, we feel comfortable with rescinding our recommendation with regard to routine echocardiographic examinations in children. At the present time we believe that a baseline examination to rule out abnormalities would be sufficient.

13,845 home therapy infusions with velaglucerase alfa exemplify safety of velaglucerase alfa and increased compliance to every-other-week intravenous enzyme replacement therapy for Gaucher disease.

BACKGROUND Lifelong intravenous (IV) enzyme replacement therapy (ERT) every other week for Gaucher disease is appreciated as decreasing quality of life in a palpable way. OBJECTIVE To review the Israeli experience with the home therapy option for IV velaglucerase alfa (Shire, Lexington MA USA) infusions every-other-week in the clinical trial context, in the early access program (EAP) during a shortage with the standard commercial ERT, and currently with the commercially available drug (VPRIV, Shire). RESULTS Among 24 patients participating in trials, 1654 infusions were at home; in the EAP and commercial setting, 12,191 infusions were performed at home for a total of 154 patients with 98.4% compliance. There were no incidents of serious adverse events. CONCLUSION This is the first review of experience of 174 patients and 13,845 intravenous infusions of velaglucerase alfa for Gaucher in the home setting, underscoring its safety.

Uncomplicated outcome after anesthesia for pediatric patients with Gaucher disease.

PurposeThe purpose of this retrospective review was to highlight clinical issues relating to anesthetic management in children who present with Gaucher disease-specific features that may impact on anesthetic management and surgical outcome. Previous reports have dealt primarily with neuronopathic forms where neurological dysfunction determined the mode of anesthesia. To date, no series of routine surgeries in pediatric patients with non-neuronopathic Gaucher disease has been published.MethodsAll surgeries performed in children with Gaucher disease in our institution during the period 1993-2003 were retrospectively analyzed.ResultsThere were 31 procedures under anesthesia in 15 pediatric patients. Twenty-seven of these (87%) involved either insertion or removal of a central venous catheter. There was no correlation between disease severity and the need for blood transfusion postoperatively [required in only eight cases (25.8%), including a total hip replacement]. No difficult intubations or other airway problems were recorded. Positioning of two patients, because of gibbus and prior to hip replacement, respectively, required special attention.ConclusionsWe record our experience in surgeries in children with mild, non-neuronopathic type I and severe neuronopathic type III Gaucher disease, who had relatively short surgeries under general anesthesia. Attention to hematological parameters in particular can minimize postoperative bleeding, the most serious complication.RésuméObjectifNotre revue rétrospective voulait souligner les aspects cliniques de ľanesthésie chez des enfants qui ont des caractéristiques spécifiques de la maladie de Gaucher pouvant influencer la conduite anesthésique et les suites chirurgicales. Les publications antérieures ont surtout porté sur les formes neuropathiques oú la dysfonction neurologique déterminait le mode ď anesthésie. Jusqu’à maintenant, aucune série n’a été publiée sur des interventions chirurgicales pédiatriques de routine dans des cas de maladie de Gaucher non neuropathique.MéthodeToutes les opérations réalisées dans notre institution de 1993 à 2003 chez des enfants atteints de la maladie de Gaucher ont été analysées rétrospectivement.RésultatsII y a eu 31 opérations sous anesthésie chez 15 enfants. Chez 27 (87 %) ďentre eux, on note ľinsertion ou le retrait ďun cathéter de la veine centrale. Il n’y avait pas de corrélation entre la sévérité de la maladie et les besoins de transfusion sanguine postopératoire, nécessaire dans huit cas seulement (25,8 %), y compris pour une arthroplastie totale de hanche. Aucune difficulté ďintubation ou ďautres problèmes liés aux voies aériennes n’ont été enregistrés. Ľinstallation de deux patients, à cause ďune gibbosité ou avant ľarthroplastie de la hanche, a nécessité une attention spéciale.ConclusionNous avons présenté des patients pédiatriques atteints ďune forme bénigne de la maladie de Gaucher, de type I non neuropathique et de type III neuropathique sévère, qui ont subi des opérations relativement courtes sous anesthésie générale. Une attention particulière aux paramètres hématologiques peut réduire les saignements postopératoires, complication la plus sérieuse.