A case of myelodysplastic syndrome is reported, in which the bone marrow contained many cells with the typical light microscopic morphology of Gaucher cells. In the absence of any evidence of inherited Gaucher's disease, these cells are considered to be pseudo-Gaucher cells, which have been described previously in association with other haematological diseases. This is the first report of their occurrence in myelodysplastic syndrome. (+info)
Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients.
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Type 1 Gaucher disease (GD), the most prevalent lysosomal storage disease, results from the deficient activity of acid beta-glucosidase. Molecular analysis of 12 unrelated Portuguese patients with type 1 GD identified three novel acid beta-glucosidase mutations (F109V, W184R and R395P), as well as three previously reported, but uncharacterized, lesions (R359Q, G377S and N396T). The type 1 probands were either heteroallelic for the well-characterized common lesion, N370S, and the F109V, W184R, R359Q or N396T lesions or homoallelic for the G377S or N396T mutations. Expression of the W184R, R359Q and R395P mutations revealed very low specific activities based on cross-reacting immunologic material (CRIM SAs of 0.0004, 0.016 and 0.045, respectively), consistent with their being found only in type 1 patients who had a neuroprotective N370S allele. In contrast, the F109V, G377S and N396T alleles had significant acid beta-glucosidase activity (CRIM specific activities of 0.15, 0.17, 0.14, respectively), in agreement with their being mild type 1 alleles. Thus, these studies identified additional acid beta-glucosidase mutations in the Portuguese population and demonstrated that the G377S and N396T mutations were neuroprotective, consistent with the mild clinical phenotypes of the type 1 patients who were homoallelic for the G377S and N396T lesions. (+info)
Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations.
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Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA). Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately .03), whereas the 84GG insertion (q approximately .003) occurs exclusively in the Ashkenazim. To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9.3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes. A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations. Of note, the presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a different conserved haplotype at these markers was identified on the 84GG chromosomes, which was unique to the AJ population. On the basis of the linkage disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less LD at the markers flanking the conserved haplotype than did the AJ N370S chromosomes. This finding is consistent with the presence of the N370S mutation in the non-Jewish European population prior to the founding of the AJ population. Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55.5 generations ago, respectively. The results of these studies are consistent with a significant bottleneck occurring in the AJ population during the first millennium, when the population became established in Europe. (+info)
Abnormal vertical optokinetic nystagmus in infants and children.
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AIMS: To determine if testing vertical optokinetic nystagmus (VOKN) has a role in the clinical assessment of infants and children. METHODS: A large field projection system was developed with which optokinetic nystagmus (OKN) could be stimulated in any direction. Gross abnormalities in the response were detected simply by observation. RESULTS: VOKN was tested in 144 children using this OKN projection system. 26 of these children had abnormal VOKN; 13 had a vertical saccade initiation failure "ocular motor apraxia" (in either direction, up/down, or in both) and 13 had absent VOKN (in either direction, up/down, or in both). Nine of the children with an up and/or down vertical saccade initiation failure (VSIF) had a neurometabolic disease (two had Niemann-Pick disease type C, five had Gaucher disease type III, one had Gaucher disease type II, and one had Gaucher disease type I). Five children with a VSIF had an abnormality identified by a magnetic resonance imaging (MRI) scan of the brain. In two of these children there was a focal lesion of the rostral midbrain. In 11 of the children with absent up and/or down VOKN an MRI scan revealed an abnormality. This involved the brainstem and/or the cerebellum in 10. Absent up and/or down VOKN was found in association with Joubert syndrome, Leigh disease, and cerebral palsy. CONCLUSION: VOKN testing has a useful role in detecting neurological abnormalities in infants and children. Detection of abnormal VOKN should indicate further investigations for a neurometabolic disease or an abnormality involving the cortex, brainstem, and/or cerebellum. Abnormal VOKN but normal horizontal OKN is highly suggestive of a rostral midbrain lesion. (+info)
Massive hepatic fibrosis in Gaucher's disease: clinico-pathological and radiological features.
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Hepatomegaly is frequent in patients with type 1 Gaucher's disease and is associated with infiltration of the liver with pathological macrophages. Most patients suffer no significant clinical consequences, but a few develop portal hypertension which may progress to parenchymal liver failure. We describe four patients with Gaucher's disease who have developed portal hypertension. We have reviewed their clinical histories and all available histological and radiological material. All had severe Gaucher's disease with multi-organ involvement, and had undergone splenectomy in childhood. Histologically, this advanced liver disease was characterized by a picture of extreme and advanced confluent fibrosis occupying the central region of the liver. This massive fibrosis is associated with characteristic radiological appearances. The liver histology in these cases is highly unusual and virtually unknown in other conditions. Our studies indicate that without specific treatment the liver disease is progressive and rapidly fatal. However, institution of enzyme replacement therapy with imiglucerase may have beneficial effects even when the condition is far advanced. (+info)
Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.
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Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although >100 mutations in the gene for human glucocerebrosidase have been described, most genotype-phenotype studies have focused upon screening for a few common mutations. In this study, we used several approaches-including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system (ARMS)-to genotype 128 patients with type 1 Gaucher disease (64 of Ashkenazi Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with type 3 Gaucher disease. More than 97% of the mutant alleles were identified. Fourteen novel mutations (A90T, N117D, T134I, Y135X, R170C, W184R, A190T, Y304X, A341T, D399Y, c.153-154insTACAGC, c.203-204insC, c.222-224delTAC, and c.1122-1123insTG) and many rare mutations were detected. Recombinant alleles were found in 19% of the patients. Although 93% of the mutant alleles in our Ashkenazi Jewish type 1 patients were N370S, c.84-85insG, IVS2+1G-->A or L444P, these four mutations accounted for only 49% of mutant alleles in the non-Jewish type 1 patients. Genotype-phenotype correlations were attempted. Homozygosity or heterozygosity for N370S resulted in type 1 Gaucher disease, whereas homozygosity for L444P was associated with type 3. Genotype L444P/recombinant allele resulted in type 2 Gaucher disease, and homozygosity for a recombinant allele was associated with perinatal lethal disease. The phenotypic consequences of other mutations, particularly R463C, were more inconsistent. Our results demonstrate a high rate of mutation detection, a large number of novel and rare mutations, and an accurate assessment of the prevalence of recombinant alleles. Although some genotype-phenotype correlations do exist, other genetic and environmental factors must also contribute to the phenotypes encountered, and we caution against relying solely upon genotype for prognostic or therapeutic judgements. (+info)
Delayed growth and puberty in patients with Gaucher disease type 1: natural history and effect of splenectomy and/or enzyme replacement therapy.
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BACKGROUND: Growth retardation in childhood was only recently recognized as a prominent feature of Gaucher disease type 1, but there are few data on both the pubertal development and the final outcome of growth and sexual maturation. OBJECTIVE: To investigate the natural pattern of growth and puberty in patients with Gaucher disease type 1 and the effect of splenectomy and enzyme replacement therapy. METHODS: We retrospectively analyzed growth and puberty in 57 patients with Gaucher disease type 1; 52 were followed since childhood and/or prepuberty and 42 have reached sexual maturity and final height. In the analysis we considered severity of disease, time of splenectomy, and start of enzyme replacement therapy. RESULTS: Deceleration of growth at age 3-5 years was observed in 30 of 57 patients followed since early childhood while untreated: height-SDS decreased from -0.34 +/- 0.42 at age 0-3 years to -1.93 +/- 0.95 (P < 0.01) at age 7-10 years and was more pronounced with severe disease. A high prevalence (59.6%) of delayed puberty, which was more frequent with severe disease, was observed in 47 patients followed before and throughout puberty. No primary endocrine pathology was found. All patients, untreated as well as treated, with growth and pubertal delay had a spontaneous catch-up, achieved full sexual maturation, and most (83.3%) reached a final height within the range of parental height-standard deviation score. Splenectomy (partial and/or total) performed in 20 patients while still growing had a beneficial effect on growth, which was temporary in some and did not affect puberty. ERT improved growth in 11 patients who started therapy before puberty, as evidenced by a progressive increase in the height-SDS, and seemed to normalize the onset of puberty. CONCLUSIONS: Growth retardation in childhood and delay of puberty are characteristic of Gaucher disease type 1 and are more frequent with severe disease. There is a spontaneous catch-up later in life and most patients reach a final height within their genetic growth potential. Enzyme replacement therapy apparently normalizes growth and possibly also the onset of puberty. (+info)
Report of the Spanish Gaucher's disease registry: clinical and genetic characteristics.
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BACKGROUND AND OBJECTIVES: Since 1993 the demographic, clinical, analytical, genetic and follow-up data of Spanish patients with Gaucher's disease (GD) have been collected in an anonymous national database. Some statistical analyses of these data are reported concerning the distribution, clinical and genetic characteristics of GD in Spain and the response to enzyme replacement therapy (ERT) is evaluated. DESIGN AND METHODS: We performed a cohort study in Spanish GD patients by national inquiry, submitted by mail to 75 Spanish hospitals (over 300 beds) directed to internal medicine, hematology and pediatric departments. The questionnaire included 30 questions (gender, height, weight, date of birth, date of diagnosis, abode and number of relatives affected, bone crises, neurologic symptoms, other symptoms, liver and spleen size, hemoglobin, leukocyte and platelet count, tartrate resistant acid phosphatase, ALT/AST, chitotrioxidase activity, total plasma cholesterol, triglycerides, high density lipoprotein cholesterol, enzymatic activity of acid -glycosides, mutation, X-ray examination, magnetic resonance imaging-MRI-evaluation, spleen removal, and orthopedic procedures (ERT, date of first infusion). Each case with a presumed diagnosis was considered an enrolled patient. Written informed consent was obtained from all patients. The cases without enzymatic or genetic diagnosis were studied in a reference laboratory (the same for all the samples). Clinical status was evaluated by Zimran's severity score index. The enzymatic activity of acid -glycosides was determined in cellular extracts of peripheral blood granulocytes by a fluorescent method using an artificial substrate (4-methyl-umbelliferyl -D-glycoside). Polymerase chain reaction (PCR) molecular analysis was performed in DNA samples to characterize the mutations (N370S, L444P, IVS2+1, 84GG, D409H, R463C and G377S) of the glycoside genes. Two groups were created according to age at diagnosis: children under 15 years and adults, in order to evaluate clinical, genetics and follow-up. Effectiveness of ERT was evaluated using objective parameters (hemoglobin, platelets, liver and spleen size, skeletal lesions), before and after therapy. In patients under ERT, quality of life (QOL) was assessed by a SF-36 modified inquiry, including 22 questions. Statistical analysis including descriptive and frequency distribution for each variable was performed, the ANOVA test was used to identify differences between groups. Paired t-tests (before and during therapy) were carried out. The degree of linear association among measured variables was estimated by Pearson's correlation. RESULTS: By December 1999 one hundred and fifty-five patients from 117 families had been included from 66 Spanish Hospitals; the inquiry was complete for 114 patients. Mean age at diagnosis: 24.0+/-16.9 years, M/F: 72/83. No symptoms were present at diagnosis in 19.3%; visceral disease was present in 95.6% and bone disease in 62.4%. Hemoglobin levels, leukocyte and platelet counts were below the normal range in 62.3% of cases. Higher acid phosphatase levels were observed in 99% of cases; biochemical liver dysfunction tests were found in 42.9%. The test for acid glycosidase showed a marked decrease in enzymatic activity. Morphologic documentation (spleen or liver tissue, bone marrow biopsy or aspirate) of GD was obtained in 71% of the patients. The most frequent mutations observed were N370S (46.3% of the alleles detected), and L444P (18.5%). In 18.7% of the cases the disease was stable or progressing slightly; in 23.8% the spleen had been removed between 1-14 years after diagnosis and 60.6% were under ERT. Children showed both greater liver enlargement and higher SSI (p = 0.0001). There was a correlation between SSI and clinical or analytical data in adults patients for spleen size (Z: 3.142; CI: 0. 173-0.637; p= 0.0017). In 35 patients on ERT, clinical and analytic data improved as did self-evaluated QOL (p< 0.0001). (A (+info)