Irith Hadas-Halpern

Gaucher's disease variant characterised by progressive calcification of heart valves and unique genotype

Gauchers disease is the most prevalent sphingolipid storage disease, characterised by substantial genetic and phenotypic variability. Cardiac manifestations are rare. We report 12 Arab Gauchers disease patients, 2-20 years of age, who presented with oculomotor apraxia but only slight classic signs of the disease. All but the youngest had calcifications of the aortic or mitral valves or both. All these patients were homozygous for the rare point mutation D409H (1342C). Valvular calcifications increased with age and showed progression during 2 years of follow-up. Two of the oldest patients underwent aortic valve replacement, and one sibling had died suddenly at age 16, before this study, Corneal opacities were another common feature. The potentially fatal course of this Gauchers disease variant, and the availability of a reliable PCR-based method for heterozygote detection, mean that population screening and genetic counselling in the geographic area at risk are important. Affected individuals should be closely monitored by echocardiography to gauge the need for valve replacement. The potential of enzyme replacement to prevent these cardiac complications cannot be ascertained at present, because of the high cost of therapy.

Replacement therapy with imiglucerase for type 1 Gaucher's disease

Gauchers disease, the most common sphingolipidosis, is caused by deficiency of the lysosomal enzyme glucocerebrosidase. Therapy with alglucerase (the placental enzyme) is safe and effective at various dosing regimens. We report the use of low-dose imiglucerase (the recombinant enzyme) at two dosing schedules: 15 u/kg once fortnightly or 2.5 u/kg thrice weekly. Mean reductions in spleen and liver volumes achieved (in all ten patients) by imiglucerase at 12 months were 36.4% and 14.5%, respectively; mean increase in haemoglobin and platelet counts were 13.4% and 25.7%. There were no serious side-effects. No significant differences were observed between the two schedules. Low-dose low-frequency imiglucerase may be an alternative cost-effective approach with satisfactory clinical response and uncompromised quality of life.

Low-dose enzyme replacement therapy for Gaucher's disease: Effects of age, sex, genotype, and clinical features on response to treatment☆

Although alglucerase therapy has become the treatment of choice for symptomatic patients with Gauchers disease, the low-dose/high-frequency regimen introduced as a means to reduce the high cost of treatment has raised major controversy. We evaluated the efficacy and safety of low-dose alglucerase in 29 patients with Gauchers disease who completed 6 to 28 months of therapy. All received intravenous alglucerase at a monthly dose of 30 units/kg, given usually in equal doses 3 times a week. All patients responded well to treatment. The hematological improvement and the reduction in organomegaly were satisfactory. No correlation was found between age, sex, genotype, previous splenectomy, or severity score index and the response to treatment. Patients with a greater degree of hepatomegaly tended to have a more pronounced decrease in liver size, although this reduction did not reach statistical significance. We confirmed that a low-dose/high-frequency regimen of alglucerase was as effective as a high-dose/low-frequency protocol in the treatment of Gauchers disease, even in the severely ill. Whenever cost is an issue, we recommend using this low-dose regimen.

Echocardiographic assessment of pulmonary hypertension in Gaucher's disease

BACKGROUND Enzyme therapy has been shown to decrease the signs and symptoms of Gauchers disease. A few patients, however, develop pulmonary hypertension on such treatment. We investigated the frequency of pulmonary hypertension in Gauchers disease. METHODS We studied 134 adults with type 1 Gauchers disease, including 73 patients on enzyme replacement, with echocardiography. We measured tricuspid incompetence (TI) with continuous-wave doppler. Pulmonary hypertension was indicated by a TI gradient of more than 30 mm Hg. FINDINGS Nine (7%) patients had pulmonary hypertension: all were treated and six had undergone splenectomy. Chest radiographs confirmed the presence of pulmonary hypertension in these patients as well as in most patients with TI gradients of 25-29 mm Hg. INTERPRETATION The confounding effects of disease severity and splenectomy in many treated patients precluded definitive conclusion of cause and effect. Nonetheless, we found an unexpectedly high rate of pulmonary hypertension and recommended routine echocardiographic monitoring of all treated and untreated patients with type 1 Gauchers disease. We also suggest consideration of treatment withdrawal if the TI gradient progresses to more than 30 mm Hg.

Accuracy of ultrasonography in assessing spleen and liver size in patients with Gaucher disease: comparison to computed tomographic measurements.

A comparison was made between volume measurements of spleen and liver by ultrasonography and by computed tomography, the two most common modes of assessment of organ size in patients with Gaucher disease, who require frequent follow‐up measurements. The two measurements showed a high degree of correlation within a broad range for both spleen and liver volumes. An algorithm for conversion of one measurement to the other was derived for both spleen and liver.

Withdrawal of enzyme replacement therapy in Gaucher's disease

Although enzyme replacement therapy is safe and effective in ameliorating the signs and symptoms of Gauchers disease, some patients have withdrawn from treatment. The purpose of this study was to evaluate the response to withdrawal and to discuss the implications for patients currently on unaltered therapy regimens since the advent of treatment. Fifteen patients, who had been treated with enzyme replacement for 5–56 months and then withdrew for 8–47 months, were assessed for changes in haematological parameters and in liver and spleen index volume. Despite non‐uniformity of duration of on and off periods, degree of organomegaly, anaemia and thrombocytopenia, most patients did not revert to respective baseline values in most parameters after withdrawal. None of the patients suffered exacerbation of bone involvement or had new or aggravated pulmonary hypertension. Adult patients with stable Gauchers disease may be withdrawn from therapy for circumscribed periods without forfeiting most gains accrued during enzyme therapy. Therefore, stopping and restarting may be considered in some patients. Alternatively, maintenance at reduced dosage and/or frequency may be appropriate in some adult patients who are stable or non‐responsive after the first years of enzyme therapy. This caveat does not apply to children.

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

Spontaneous intramural hematoma of the Esophagus

ABSTRACTSpontaneous intramural hematoma of the esophagus (SIHE) is a rare condition, usually presenting with severe acute chest pain. Vomiting, dysphagia, odynophagia, and hematemesis may appear later. We herein report a case of this disease in a patient treated with low doses of aspirin, and review the literature for possible etiologies for this condition. In addition, we compare the utility of the various diagnostic modalities in this uncommon condition.

Is there a correlation between degree of splenomegaly, symptoms and hypersplenism? A study of 218 patients with Gaucher disease

Despite the prevalence of splenomegaly as a sign in many disorders, there have been no studies that correlate the degree of organomegaly with the symptoms generally ascribed to splenic enlargement. The degree of splenomegaly was compared with five overt symptoms of mechanical displacement, i.e. chronic abdominal pain, abdominal discomfort, early satiety, pain while lying on the side, or attacks of acute (colicky) left upper quadrant pains. We have also employed splenomegaly as seen in Gaucher disease as a paradigm to determine whether there is a correlation between the degree of splenomegaly and the parameters of hypersplenism. Although there was a statistically significant correlation between degree of splenomegaly and blood counts, this proved to be clinically negligible. Surprisingly, there was also no correlation between degree of splenomegaly and any of symptoms investigated.

Low-dose high-frequency enzyme replacement therapy for very young children with severe Gaucher disease.

Summary Six children with a mean age of 4.6 years (range 2.5–7). suffering from severe Gaucher disease, were treated with low‐dose high‐frequency intravenous enzyme replacement (Ceredasea®. Genzyme. U.S.A.) for a period of 10–24 months. Although, in general, these patients were more severely affected than previously reported patients, the results of the treatment were as satisfactory as those obtained by using much higher doses at low frequency. In addition to regression of organomegaly and improvement of haematological abnormalities, we observed two unique clinical responses in three patients: two showed decreased tendency to bacterial infections, associated with improvement in neutro‐phil chemotaxis, and one patient, with type 3 Gaucher disease, showed some improvement in neurological findings. Several measures were taken to ameliorate the burden of the high‐frequency treatment. These included implantation of venous access devices, establishment of a home‐treatment programme and the application of effective local anaesthesia. Therefore the low‐dose high‐frequency protocol appears to be both an effective and feasible alternative to the costly high‐dose low‐frequency protocols even in very young children.