Search

Introduction: Gaucher disease is an autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase which leads to an accumulation of glucosylceramide in the macrophages. Splenomegaly, hepatomegaly, cytopenias (anemia, thrombocytopenia) and bone disorders are the main symptoms. The diagnosis is often delayed, leading to unnecessary investigations and treatments, and delaying the specific treatment. The primary objective of our study was to establish, in patients who had a diagnostic delay of more than one year, the reported misdiagnoses before the final diagnosis. The secondary objectives were to investigate the risk factors associated with error and delayed diagnosis., Methods: Retrospective study including patients with Gaucher disease from the French Gaucher Disease Registry. Collection of data by a single investigator from a standardized form., Results: Among 83 patients with a known diagnostic delay, 13 patients (15 %) had one or two misdiagnoses. These included osteo-articular diagnoses (osteomyelitis, osteoarthritis, arthritis, osteochondritis, rheumatic fever, n=8), haematological diagnoses (gestational thrombocytopenia, immunological thrombocytopenia, n=4), infectious diagnoses (visceral leishmaniasis, mononucleosis, n=2) and hemochromatosis. The osteo-articular and infectious diagnoses concerned the child and the adolescent while the haematological diagnoses and the hemochromatosis concerned the adult. No factors were found associated with misdiagnoses. Patients with a diagnostic delay greater than one year were less likely to have hepatosplenomegaly as the first symptom., Conclusion: There is a risk of diagnostic error related to phenotypic heterogeneity and lack of specificity of Gaucher disease symptoms. This study helps to better identify the misdiagnoses associated with Gaucher disease., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Gaucher disease is a rare autosomal recessive genetic disease, caused by a deficiency of the lysosomal enzyme, glucocerebrosidase that leads to the accumulation of its substrate (glucosylceramide) in lysosomal macrophages. In the general population, its incidence varies between 0.4 and 5.8/100,000 inhabitants. Type 1 Gaucher disease is the most frequent and is characterized by its extreme heterogeneity including asymptomatic or more severe presentations. The most frequent symptoms are anemia, thrombocytopenia, splenomegaly, and/or hepatomegaly, and a potentially severe bone involvement. Type 2 and type 3 Gaucher diseases are associated with neurological involvement that can be severe. Diagnosis is confirmed by demonstrating a deficiency of glucocerebrosidase activity in leucocytes, and by the identification of biallelic pathogenic variants in GBA1 gene. Type 1 Gaucher disease is associated with a higher risk of Parkinson disease, some solid cancers, and hematologic diseases in particularly multiple myeloma. Specific treatment, such as enzyme replacement therapy or substrate reduction therapy is indicated in symptomatic type 1 Gaucher disease. Only enzyme replacement therapy is indicated in type 3 Gaucher disease. Treatment improves quality of life and prognosis. The rarity of Gaucher disease and its wide variability in clinical presentations lead to diagnosis delays. There is a strong need for a better knowledge of its symptoms among physicians, to reduce irreversible complications., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid β-glucosidase. In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in 30 Tunisian patients with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing had shown that N370S was the most frequent mutation (22/50 mutant alleles, 44%), followed by L444P mutation, which is found in 16% (8/50 mutant alleles). The recombinant allele (RecNciI) represented 14%. Our findings revealed that the genotype N370S/RecNciI was mosst frequent in patients with childhood onset and it was associated with severe visceral involvement. The screening of these three mutations provided a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allowed also genetic counselling for their family members., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Introduction: Gaucher's disease (GD) remains rare and cohort studies are essential to improve our knowledge of this disease., Methods: We performed a 10-year retrospective study of patients with GD followed-up in the Rennes University teaching hospital., Results: Among a population of 1,500,000 inhabitants, 12 patients with GD were identified. Eight were men, and four were women. Mean age at diagnosis was 32.3 years and the first symptoms appeared around 31 years old. Main symptoms were: splenomegaly (82%), hepatomegaly (64%), thrombocytopenia (73%), anemia (64%), deterioration of general status (45%), bone pain (27%). Parkinsonism was noted in two patients, polyclonal gammopathy in two others, and monoclonal gammopathy was evidenced in four patients, with chronic lymphocytic lymphoma in one of them. Enzymatic activity dosage confirmed the diagnosis of GD for eight patients. For the remaining four patients, diagnosis was obtained by identification of Gaucher's cells on tissue examination. Substitutive enzymotherapy (SE) was performed for seven patients, with great improvement of initial symptoms. For two of these seven patients, SE is changed for miglustat with persistent improvement of clinical status., Conclusion: Association between GD and Parkinsonism or between GD and gammopathy was confirmed in our study. Other cohort studies are needed to improve the knowledge of GD.

Gaucher disease is well-known in adult patients and must be regarded as a pediatric disease, two thirds of the patients manifesting before the age of 20. Three clinical forms have been defined based on the presence of neurological involvement. Gaucher disease type 1, without neurological signs, generally begins before the five years age with splenomegaly as the main symptom. The bone crises are more frequent than in adulthood. Gaucher disease type 2 or acute neuronopathic form begins between three and six months and do not have any treatment. Type 3 or chronic neuronopathic form appears like a type 1 with progressive horizontal saccade-initiation failure and developmental delay. Onset in childhood is predictive of a severe and progressive phenotype. The presence of neurological symptoms induces important consequences for treatment, prognosis and genetic counselling.

Gaucher disease management in France is facilitated by CETG (Comitee of Evaluation and Treatment of Gaucher disease). Four hundred and fifty-six patients are enrolled in 2006 in the French Gaucher registry of CETG. Two hundred and thirty patients had treatment. Eighty five % are type 1, 10.5% type 2 and 5.5% type 3. Only 1 patient had a saposin C deficiency. Information on CETG is available on www.cetl.net.

Gaucher disease is the most common lysosomal storage disorder, it results from the inherited deficiency of the enzyme glucocerebrosidase, the accumulation of its substrate causes many clinical manifestations. Since the discovery of GBA gene, more than 200 different mutations have been identified, but only handful mutations are recurrent (N370S, L444P and c.84insG). In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in ten unrelated Tunisian children with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing, has shown that N370S is the most frequent mutation (6/20 mutant alleles, 30%), followed by recombinant allele (RecNciI) which is found in five patients (5/20 mutant alleles, 25%), the L444P mutation represent 20% (4/20 mutant alleles). Our findings revealed that five among ten studied patients, were compound heterozygous N370S/RecNciI (50%). The screening of these mutations provides a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allows also genetic counselling for their family members.

A census is currently being carried out of the French cohort of Gaucher disease patients. This article describes its preliminary results, obtained by analysing the records of 101 patients for whom clinical and laboratory data were accessible while they were receiving enzyme therapy. At the time of diagnosis, all patients presented with splenomegaly, 70% had asthenia and one in three was already affected by major bone damage. After 1 year of enzyme therapy, splenomegaly had diminished by half and the different scores (asthenia, bone pain and abdominal pain, etc.) had markedly improved, as had the biochemical markers. As for the 6 patients affected by type 3 Gaucher disease and treated with enzyme therapy after the onset of neurological signs, a stabilisation or even some improvement of the disease was observed. In-depth study of the French cohort should make it possible to formulate consensus recommendations for the future, based on well-established data.

Unlabelled: Gaucher's disease is one of the rare lysosomial disease that could receive substitutive enzymatic treatment which may improve considerably the prognosis of certain forms. The purpose of this work is to study the epidemiology of the disease in Tunisia, to highlight the diagnostic and therapeutic difficulties and also to precise our subsequent needs for substitutive medication., Patients and Methods: We have conducted a retrospective survey of the hospital wards that were susceptible to take care of patients having Gaucher's disease. These wards are the paediatric, neonatology, internal medicine, haematology, neurology and cardiology wards., Results: In this study we have observed 27 cases of Gaucher's disease over a period of 18 years (1983-2001). The age at onset ranges from birth to 73 years of age, with an average age of 14.5 years. According to the age at onset and the clinical presentation, we classify our patients into: 20 cases of type 1 (74%), three cases of type 2 (12%), and three cases of type 3 (12%), and one case of unspecified type.Gaucher's disease type 1: The age at onset ranged from 10 months to 73 years with an average of 19 years. The main clinical signs that we have observed were splenomegaly, hepatomegaly, pallor, haemorrhagic appearance and also osteoporosis and bone pain observed in 40% of the cases. The diagnosis was based on histology showing the Gaucher's cells in various tissues while the diagnosis obtained by the dosage of glucocerebrosidase took place only in 50% of the cases. The treatment has always been symptomatic (analgesics, transfusion). A splenectomy was performed in 47% of the cases and none of the patients received a specific treatment. The follow-up period ranged from 1 month to 18 years with an average follow-up of 4 years. Among the 12 patients having a follow-up of at least 1 year, we have noticed an improvement after splenectomy in three cases, a stability in three cases and two worsening cases dealing mainly with bone problems. One patient aged 73 died from respiratory problem and three were lost to follow-up. Gaucher's disease type 2: We have observed three cases of Gaucher's disease type 2 diagnosed at 1 day, 45 days and 3 months of age. The visceral manifestations were serious and the neurological features included seizures, hypertony, ocular-nerve palsies and psychometric decline. The three patients died. Gaucher's disease type 3: Three patients were probably suffering from Gaucher's disease type 3 with visceral manifestations observed at the ages of 9 months, 1 year and 3 years, and also neurological signs observed at respective ages of 2.5 and 3 years. Two patients died and the remaining one was lost to follow-up., Conclusion: Gaucher's disease is not exceptional in Tunisia. Type 1 is by far the most common one. We have noticed some insufficiency in the diagnosis as the glucocerebrosidase enzymatic dosage was performed only in 50% of the cases as well as therapeutic insufficiency with no prescription of the specific treatment.

GENERAL CHARACTERISTICS: Gaucher's disease is a genetic disease of autosomal recessive transmission due to a deficit in a lysosomal enzyme: beta-glucocerebrosidase. The disease is characterised by deposits of glucosylceramide in the cells of the liver, spleen and bone marrow. Acute or chronic neurological forms (type 2 and 3) account for only 5% of patients suffering from Gaucher's disease and are less frequent than the non-neurological forms (type 1). CLINICAL AND BIOCHEMICAL MANIFESTATIONS: Gaucher's disease is associated with spleno- or hepato-megalia, asthenia, bone complications (Erlenmeyer flask deformity, osteopenia and osteonecrosis), as well as with haematological (thrombopenia, anaemia) or biochemical abnormalities (increase in angiotensin-converting enzyme, ferritin, tartrate-resistant acid phosphatase and chitotriosidase). Central nervous system involvement is only found in the type 2 and 3. Diagnosis relies on measurement of beta-glucocerebrosidase activity in the circulating leukocytes. REGARDING TREATMENT: Treatment with enzyme replacement (imiglucerase: recombinant enzyme preparation) improves the haematological abnormalities, hepatosplenomegalia and quality of life in a matter of a few months. Regression of the bone disorders is usually observed only after 3-4 years of treatment. Recently, gene therapy trials have successfully been started.

Gaucher disease is an uncommon autosomic recessive disorder. The disease is caused by a deficiency in the activity of the lysosomal enzyme glucocerebrosidase which is responsible for the degradation of glucosylceramide, résulting from the breakdown of red and white cell-membranes. In the absence of enzyme glucosylceramide accumulates in the lysosomes of macrophages. This accumulation leads to hepatomegaly, splenomegaly with subsequent haematologic abnormalities (leucopenia, anemia, thrombopenia) and bone manifestations. Three types of Gaucher disease are described: type 1 is the most common, type 2 and 3 are associated with neurologic symptoms. Macrophages are the likely cellular source of biochemical abnormalities: elevated blood level of ferritin, angiotensin converting enzyme, immunoglobulins and haemostasis abnormalities. Lysosomal perturbations lead to increased blood level of tartrate resistant acid phosphatase and chitotriosidase. Enzyme replacement therapy is available in France since 1991. In 2002, 136 patients are treated. The efficacy is overt on the asthenia, organomegaly and haematological manifestations. Bone pains disappear or decrease in intensity, however bone complications may be irreversible justifying treatment initiations before the appearance of lesions that may lead to serious functional impairment.

Gaucher disease, a condition transmitted by autosomal recessive inheritance, results from a genetic defect in beta-glucosidase, an enzyme which degrades sphingolipids. Deficiency in beta-glucosidase leads to accumulation of its substrate, glycosylceramide, in macrophages and, in the more severe cases, in neurons. Clinically, splenomegaly, hepatomegaly, bone destruction, cytopenia, and in some cases, central neurological lesions develop. Three phenotypes have been described according to the absence (type 1) or presence of neurological involvement (type 2: severe, type 3: intermediate severity). The disease occurs in patients of all ethnic origins but type 1 is particularly well known in Ashkenese Jews and type 3 is found in the Swedish province of Norrbottnie. About forty mutations of the beta-glucosidase gene have been identified. Four account for 80% of the known mutations (1226G, 1448C, 84GG, IVS2+1). Residual enzyme activity of mutant beta-glucosidase explains some of the phenotypic variations. The phenotype resulting from the 1226G mutation has sufficient enzyme activity for degradation of gangliosides in the brain, explaining the absence of neurological involvement in patients with this allele. Treatment is based on enzyme supplemention: blood parameters return to normal and the volume of the spleen and liver are greatly reduced after 6 months. In infants with very severe disease, bone marrow graft may be used.