Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population

Mucopolysaccharidosis type I (MPS I) was a group of rare autosomal recessive disorder caused by the deficiency of the lysosomal enzyme, alpha -L -iduronidase, and the resulting accumulation of undergraded dematan sulfate and heparan sulfate. MPS I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counseling and also impedes the selection and evaluation of patients undergoing therapy bone marrow transplantation

Mucopolysaccharidosis type I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients

<p>Abstract</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is an autosomal storage disease resulting from defective activity of the enzyme α-L-iduronidase (IDUA). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. MPS I has severe and milder phenotypic subtypes.</p> <p>Aim of study: This study was carried out on six newly collected MPS I patients recruited from many regions of Tunisia.</p> <p>Patients and methods: Mutational analysis of the IDUA gene in unrelated MPS I families was performed by sequencing the exons and intron-exon junctions of IDUA gene.</p> <p>Results</p> <p>Two novel IDUA mutations, p.L530fs (1587_1588 insGC) in exon 11 and p.F177S in exon 5 and two previously reported mutations p.P533R and p.Y581X were detected. The patient in family 1 who has the Hurler phenotype was homozygous for the previously described nonsense mutation p.Y581X.</p> <p>The patient in family 2 who also has the Hurler phenotype was homozygous for the novel missense mutation p.F177S. The three patients in families 3, 5 and 6 were homozygous for the p.P533R mutation. The patient in family 4 was homozygous for the novel small insertion 1587_1588 insGC. In addition, eighteen known and one unknown IDUA polymorphisms were identified.</p> <p>Conclusion</p> <p>The identification of these mutations should facilitate prenatal diagnosis and counseling for MPS I in Tunisia.</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of the enzyme of α-L-iduronidase (IDUA, EC 3.2.1.76). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. The clinical phenotype of MPS I ranges from the very severe in Hurler syndrome (MPS IH) to the relatively benign in Scheie syndrome (MPS IS), with an intermediate phenotype designated Hurler/Scheie (MPS IH/S) <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Isolation of complementary and genomic DNAs encoding human α -L- iduronidase <abbrgrp><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp> have enable the identification of mutations underlying the enzyme defect and resulting in MPS I clinical phenotype. More than 100 mutations have been reported in patients with the MPS I subtypes (Human Gene Mutation Database; <url>http://www.hgmd.org</url>). High prevalence of the common mutations p.W402X and p.Q70X has been described; both of them in the severe clinical forms <abbrgrp><abbr bid="B4">4</abbr><abbr bid="B5">5</abbr></abbrgrp>. A high prevalence of common mutation p.P533R has also been described in MPS I patients with various phenotypes <abbrgrp><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr></abbrgrp>. In addition, rare mutations including single base substitution, deletion, insertion and splicing site mutation have been identified <abbrgrp><abbr bid="B7">7</abbr></abbrgrp>, indicating a high degree of allelic heterogeneity in IDUA gene.</p> <p>Here, we described two novel IDUA mutations in MPS I Tunisian patients. These lesions were homoallelic in all the patients of the six families investigated as consanguineous marriages are still frequent in Tunisia <abbrgrp><abbr bid="B8">8</abbr></abbrgrp>.</p

Computer-Assisted Classification Patterns in Autoimmune Diagnostics: The AIDA Project

Antinuclear antibodies (ANAs) are significant biomarkers in the diagnosis of autoimmune diseases in humans, done by mean of Indirect ImmunoFluorescence (IIF)method, and performed by analyzing patterns and fluorescence intensity. This paper introduces the AIDA Project (autoimmunity: diagnosis assisted by computer) developed in the framework of an Italy-Tunisia cross-border cooperation and its preliminary results. A database of interpreted IIF images is being collected through the exchange of images and double reporting and a Gold Standard database, containing around 1000 double reported images, has been settled. The Gold Standard database is used for optimization of aCAD(Computer AidedDetection) solution and for the assessment of its added value, in order to be applied along with an Immunologist as a second Reader in detection of autoantibodies. This CAD system is able to identify on IIF images the fluorescence intensity and the fluorescence pattern. Preliminary results show that CAD, used as second Reader, appeared to perform better than Junior Immunologists and hence may significantly improve their efficacy; compared with two Junior Immunologists, the CAD system showed higher Intensity Accuracy (85,5% versus 66,0% and 66,0%), higher Patterns Accuracy (79,3% versus 48,0% and 66,2%), and higher Mean Class Accuracy (79,4% versus 56,7% and 64.2%)

Glycogen storage disease type I in Tunisia: An epidemiological analysis

International audienceObjective: Analysis of epidemiological data concerning GSD I in Tunisia. Subjects and methods: All the cases diagnosed as GSD I between 1992 and 2005 in a paediatric department recruiting all the metabolic diseases referred from the North of Tunisia were reviewed. Individual data (sex, socioeconomic and educational background, geographic origins, insurance coverage) were collected and pedigrees were reconstituted. Results: Twenty-two cases (9 boys and 13 girls from 20 homes) were identified. Fourteen belonged to 11 families originating from the North of Tunisia; ten of them are still alive. Both parents in 4 homes (21%) and one parent in 9 homes (47%) were illiterate. Most of the homes (60%) had a low income and 45% comprised at least 3 children. Only 7 homes (35%) had health insurance. Pedigrees indicated 44 infant deaths and at least 10 other cases fulfilling the clinical features of GSD I but not diagnosed. Conclusion: The paediatric prevalence of GSD I in the North of Tunisia can be estimated to 7.93 cases per one million inhabitants and its incidence to 1/100 000 births. However, it is likely to be more frequent because of underreporting or underdiagnosis leading to precocious deaths

Spectre mutationnel de la maladie de gaucher en Tunisie: forte fréquence des hétérozygotes composites N37OS/REC Ncil

European Neighbourhood Policy covering the Mediterranean Partner Countries[Article in French]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.EU-supported R&D programm

Diagnostic moléculaire de la maladie de Gaucher en Tunisie

Trabalho desenvolvido na sequência de projeto de colaboração Portugal-Tunisia iniciado no IBMC-UP.[ENG] Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid b-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.[FR] Résumé: La maladie de Gaucher est une maladie de surcharge lysosomale due à un déficit de l’enzyme β-glucosidase. Afin d’étudier le spectre mutationnel de cette affection en Tunisie, nous avons recherché les mutations récurrentes chez 30 patients. Le dépistage des mutations récurrentes par PCR/RFLP et séquençage direct a révélé que la mutation N370S est la plus fréquente (44 %, 22/50 allèles mutés), suivie par la mutation L444P qui présente une fréquence de l’ordre de 16 % (8/50 allèles mutés). L’allèle recombinant (RecNciI) a été retrouvé chez 14 % des cas étudiés. Les mutations non identifiées dans cette étude représentent 26 %. En outre, nos résultats ont montré que le génotype N370S/RecNciI est le plus fréquent dans les formes à révélation pédiatrique et il est associé à une atteinte viscérale sévère. La recherche de ces mutations en priorité fournit un outil de diagnostic moléculaire pour la majorité des patients, elle permet ainsi un dépistage des hétérozygotes indispensable pour le conseil génétique. Abstract: 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

Mutation spectrum of glycogen storage disease type Ia in Tunisia: implication for molecular diagnosis.

International audienceGlycogen storage disease type Ia (GSD Ia; OMIM 232200) is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the microsomal glucose-6-phosphatase (G6Pase). It is characterized by short stature, hepatomegaly, hypoglycaemia, hyperuricaemia, and lactic acidaemia. Various mutations have been reported in the G6Pase gene (G6PC). In order to determine the mutation spectrum in Tunisia, we performed mutation analysis in 22 Tunisian type I glycogen storage disease (GSD I) patients belonging to 18 unrelated families. All patients were clinically classified as GSD Ia. The R83C mutation was found to be the major cause of GSD Ia, accounting for 24 of 36 mutant alleles (66.6%), The R170Q mutation was the second most frequent mutation; it accounts for 10 of 36 mutant alleles (27.7%). The R83C and R170Q mutations could be rapidly detected by PCR/RFLP. Since the majority of Tunisian patients carried R83C and/or R170Q mutations, we propose direct screening of these mutations as a rapid, valuable and noninvasive tool for diagnosis of GSD Ia in Tunisian as well as in Northern African populations