Ayala Abrahamov

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.

Abnormal neutrophil chemotaxis in Gaucher disease

The tendency towards infection described in Gaucher disease patients has been attributed to their post‐splenectomy state. We noticed that certain patients with intact spleen have also suffered from recurrent pyogenic infections, thus an attempt to study their neutrophil functionhas been made. Nine of 29 patients studied expressed significant decrease in neutrophil chemotaxis directed towards zymosan activated serum or N‐formyl‐methionylleucyl‐phenylalanine. Random migration was significantly impaired in five of those nine patients. Adherence of neutrophils to nylon fibres and O2‐ production were intact. the patients with impaired chemotaxis were significantly affected by their disease (early onset of symptoms and severity score index > 10) and most of them had genotypes associated with severe disease (1448/1448 and 1226/84GG). No correlation was found with the spleen status. Three of the patients with impaired chemotaxis, and none of the patients with normal neutrophil function, suffered from recurrent pyogenic infections. It is suggested that the described neutrophil migration impairment may contribute to the tendency towards infection in certain patients with advanced Gaucher disease.

12 A practical approach to diagnosis and management of Gaucher's disease

The diagnosis of Gauchers disease is established by demonstration of reduced acid beta-glucosidase activity in peripheral blood leukocytes. Genotyping at the glucocerebrosidase gene locus can give additional prognostic information and facilitate carrier detection. However, extreme phenotypic diversity precludes reliable prediction of prognosis in individual patients. Histological diagnosis of Gauchers disease is unnecessary and can be misleading. A range of clinical, radiological and laboratory parameters are useful for staging disease activity which is central to achieving optimal timing to initiate enzyme therapy. Treatment should be individualized to obtain maximum therapeutic response. The recent introduction of chitotriosidase measurements has provided a valuable indicator of total cellular burden of storage cells. Serial measurements of chitotriosidase activity are useful for monitoring disease progression as well as response to therapy. A number of adjuvant therapies are available for use in conjunction with enzyme treatment. Special considerations apply to management of affected children.

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.

Abdominal ultrasound findings mimicking hematological malignancies in a study of 218 gaucher patients

Gaucher disease, the most prevalent sphingolipidosis, generally presents with splenomegaly, anemia, and thrombocytopenia. Hence, hematologists are often the specialists involved in diagnosis and management of these patients. We present ultrasonographic characteristics in a cohort of 218 consecutive Gaucher patients evaluated in our clinic during the past 5 years. Our data emphasize the high prevalence of lesions mimicking hematological malignancies in Gaucher disease. One fifth of 184 non‐splenectomized patients had intra‐splenic lesions, 6% of all patients had similar lesions in the liver, and 32% of 34 splenectomized patients (but none of the other patients) had marked retroperitoneal or peri‐portal lymphadenopathy.