The mutational spectrum of hunter syndrome reveals correlation between biochemical and clinical profiles in Tunisian patients.

BACKGROUND: Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an X-linked recessive lysosomal storage disorder resulting from deficient activity of iduronate 2-sulfatase (IDS) and the progressive lysosomal accumulation of sulfated glycosaminoglycans (GAGs). METHODS: A diagnosis of MPS II or Hunter syndrome was performed based on the following approach after a clinical and paraclinical suspicion. Two biochemical and molecular tests were carried out separately and according to the availability of the biological material. RESULTS: All patients in this cohort presented the most common MPS II clinical features. Electrophoresis of GAGs on a cellulose acetate plate in the presence of a high concentration of heparane sulfate showed an abnormal dermatan sulfate band in the patients compared with that in a control case. Furthermore, leukocyte IDS activity ranged from 0.00 to 0.75 nmol/h/mg of leukocyte protein in patients. Five previously reported mutations were identified in this study patients: one splice site mutation, c.240 + 1G > A; two missense mutations, p.R88P and p.G94D; a large deletion of exon 1 to exon 7; and one nonsense mutation, p.Q396*. In addition, two novel alterations were identified in the MPS II patients: one frame shift mutation, p.D450Nfs*95 and one nonsense mutation, p.Q204*. Additionally, five known IDS polymorphisms were identified in the patients: c.419-16 delT, c.641C > T (p.T214M), c.438 C > T (p.T146T), c.709-87G > A, and c.1006 + 38 T > C. CONCLUSIONS: The high level of urine GAGs and the deficiency of iduronate 2-sulfatase activity was associated with the phenotype expression of Hunter syndrome. Molecular testing was useful for the patients' phenotypic classification and the detection of carriers.

Contribution of M470V variant to cystic fibrosis: First study in CF and normal Tunisian population.

PURPOSE: Determining the frequency of M470V polymorphism in cystic fibrosis and healthy cohort in Tunisia to establish the contribution of M470V polymorphism in cystic fibrosis variable presentation and course. Additionally, studying the origin of cystic fibrosis transmembrane conductance regulator gene in Tunisian population and its evolution among populations worldwide. PATIENTS AND METHODS: The genotyping of M470V marker was realized by PCR-RFLP technique in 34 unrelated patients and 50 healthy subjects. RESULTS: Statistical difference was found in the genotype and allelic distribution between CF and control groups. Exclusive association between F508del allele and M470 allele was noted. CONCLUSION: This study has contributed to better understanding involvement of the M470V polymorphism in the CF clinical expression in the Tunisian population and has confirmed the utility of this marker in the study of the origin and evolution of the CFTR locus in the human history.

[Molecular diagnosis of Gaucher disease in Tunisia]. / Diagnostic moléculaire de la maladie de Gaucher en Tunisie.

Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid ß-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.

A novel 22bp deletion in a Tunisian phenylketonuria family.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase. To date, more than 530 mutations in the PAH gene have been reported. In Tunisia, this disease seems to be the result of point mutations, few studies have been published about molecular defects of PKU in our country. In this study, we report a novel deletion in exon 6 of two brothers in a Tunisian family after DHPLC analysis and sequencing of the exon 6 of the PAH gene.

Homogénéité mutationnelle de la glycogénose de type Ia en Tunisie.

The glycogen storage disease type Ia (GSD Ia) is a rare inherited disorder, with autosomal recessive determinism. It is characterized by hepatomegaly, short stature and hypoglycemia with lactic acidemia. The confirmation of diagnosis is based on the enzymatic assay performed on liver biopsy. For Tunisians patients, this biochemical test is performed abroad. The aim of our study is the molecular characterization of GSD Ia in Tunisian patients and the development of a molecular diagnosis tool. Our study included 27 patients from 23 unrelated families, mutation analysis revealed that the R83C mutation is the most frequent (65%, 30/46 mutant alleles), followed by the R170Q mutation (30%, 14/46 mutant alleles). The homogeneity of mutation spectrum of GSD Ia in Tunisia allows the development of a cost effective and reliable tool for the confirmation of clinical diagnosis among suspected GSD Ia patients.

A novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree.

We identified in a large Tunisian pedigree a novel UBE3A frameshift mutation in exon 16 coding region, and we expect that the resulting UBE3A truncated protein in our patients is non-functional since the mutation implies the catalytic region of the enzyme. The family includes 14 affected patients born from four sisters. This mutation was found in all surviving affected individuals and their mothers pointing out the importance of genetic counseling possibility in Angelman syndrome (AS). All patients had severe mental retardation with epilepsy and microcephaly. Minor clinical expression variation was observed among the investigated patients. The severity of clinical expression is related to the detected molecular variation: deletion of 15 bp and insertion of 7 bp. These results are concordant with the gene expression observed in previously reported individuals with AS and truncated UBE3A protein.

[Congenital generalized lipodystrophy: a case report with neurological involvement]. / Lipodystrophie congénitale généralisée de type 1 avec atteinte neurologique.

Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by near complete absence of adipose tissue from birth. At least 2 genes located in 9q34 (AGPAT2) and 11q13 (Seipin) are implicated in type 1 and 2, respectively, and result in insulin resistance. We report here a novel case of CGL type 1 resulting from a novel homozygote mutation in the AGPAT2 gene. The clinical picture included pseudoathletic muscular hypertrophy, hypertrophic cardiomyopathy, enlarged liver, hypermetabolism rate, and hyperinsulinemia in a 1-year-old child from Libya. Peripheral hypertonia and reflex excitability revealed signal abnormalities in white matter on magnetic resonance imagery, which has not been described previously in the literature.

Factors predictive of prognosis of infantile spasms. A retrospective study in a low-income country.

PURPOSE: To describe the management of infants with epileptic spasms (ESs) in a low-income country and identify factors predictive of their prognosis. MATERIAL AND METHODS: We conducted a retrospective study in a university hospital in Tunis, Tunisia, over a period of 10 years. We included infants with recurrent ESs. RESULTS: Thirty-eight patients were included. The median age at onset of ESs was 5 months. Typical hypsarrhythmia was found in 21 patients (55%). Brain MRI was done in 32 patients (84%) and metabolic work-up in 34 patients (89%). ESs were categorized as symptomatic in 58% of the patients. Vigabatrin was prescribed as the first-line drug in almost half of the patients. At the last follow-up, 63% of the patients were seizure-free and 82% had a psychomotor delay. The presence of other types of seizures was associated with uncontrolled epilepsy at the last follow-up (P=0.020). The persistence of spasms after the first-line treatment was associated with abnormal final psychomotor development (P=0.047). CONCLUSIONS: Investigation practices and final outcomes of our patients were comparable to data from high-income countries. Treatment practices have been standardized to be in line with international guidelines.

Glycogen storage disease type I in Tunisia: an epidemiological analysis.

OBJECTIVE: 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.

Phenotypic spectrum of fucosidosis in Tunisia.

Fucosidosis (OMIM 230000) is a rare autosomal recessive lysosomal disorder due to deficient α-L-fucosidase activity(EC 3.2.1.51), leading to the accumulation of fucose-containing glycolipids and glycoproteins in various tissues. This study contained the largest ever Tunisian survey of fucosidosis patients, diagnosed during the period 1987-2007. The clinical pictures and outcomes of these patients are compared with literature data. Ten patients (8 boys and 2 girls) from six unrelated families were diagnosed at a mean age of 29 ± 10.3 months. Six of the patients were diagnosed as having the more severe phenotype. The other four cases presented the low progressive phenotype. This distinction was determined by the presence or absence of angiokeratoma and age of death. For all of the patients in our survey, early motor development was more severely delayed than described in the literature. Six patients presented psychomotor decline during the second year of life. Clinical features consist of variable mental retardation (all patients), progressive spastic quadriplegia (6/10 cases), coarse facies (9/10 cases), growth retardation (7/9 cases), visceromegaly (3 cases), angiokeratoma corporis diffusum (4 cases), recurrent bronchopneumonias (all cases), seizures (4 cases) and variable degrees of dysostosis multiplex (all cases). Portal cavernoma, never described in the literature, was observed in one patient. The outcomes were severe in this survey, probably owing to restricted health care; death occurred in 6 of the 10 patients before age 10 years, following recurrent pulmonary infections and neurological deterioration. No intrafamilial variability was noted in the multiplex families. The clinical presentation and outcomes of some of these patients were consistent with the continuous clinical spectrum of severity in fucosidosis attested by most clinical studies.

[Atypical presentation of Wegener disease in childhood]. / Présentation atypique de la maladie de Wegener de l'enfant.

The pediatric forms of Wegener granulomatosis (WG) are rare. The clinical picture and the profile have specificities compared to those of adults. We report a case of a girl aged of four years and a half who presented initially with a clinical picture of Henoch Schönlein purpura. Physical examination revealed additionally to purpura, scabby lesions on the buttocks. The histopathological examination of a skin biopsy disclosed histiocyte infiltration. There were no Ig A deposits on direct immunofluorescence study. One year later, the diagnosis of WG was suspected, when the patient developed a respiratory problem related to left pulmonary infarction. Screening for thromboembolic factors was positive for antiphosphilipid antibodies. Diagnosis of WG was confirmed by the histopathological study lung tissue and a significant titre of serum ANCA. Blood tests failed to provide evidence of renal involvement. Cyclophosphamide and prednisolone therapy was administrated. A relapse occurred one year later on the controlateral lung; but no biological marker of disease activity could be detected.

An uncommon complication of Listeria monocytogenes infection: Polyradiculoneuritis following Listeria meningoencephalitis.

Listeria monocytogenes, primarily a foodborne pathogen, is commonly responsible for disorders affecting the central nervous system and cranial nerves. We hereby present the first case to our knowledge of listeriosis linked to a peripheral neurological disorder causing acute upper limb weakness.

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

Glycogen 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.

[Mutation spectrum of Gaucher disease in Tunisia: high frequency of N370S/Rec NciI compound heterozygous]. / Spectre mutationnel de la maladie de Gaucher en Tunisie: forte fréquence des hétérozygotes composites N370S/Rec NciI.

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.

[Gaucher's disease in Tunisia (multicenter study)]. / La maladie de Gaucher en Tunisie (étude multicentrique).

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.

[Reference values of urinary orotic acid in a healthy Tunisian population]. / Valeurs de référence de l'oroticurie dans une population tunisienne saine.

BACKGROUND: Orotic acid (OA) is an intermediary metabolite of pyrimidine synthesis. An elevation of urinary orotic acid excretion has been described in congenital defect of the urea cycle enzymes and in primary orotic aciduria. Several techniques have been used to measure OA and many reference values are published without considering age and sex. POPULATION AND METHODS: The reference values of urinary OA excretion, expressed in mumol/mmol of creatinine, are reported in a healthy Tunisan population using a colorimetric method. The study included 20 men and 20 women (age = 31 +/- 11 years) and 30 children aged from 3 days to 8 years. RESULTS: There was a significant increase (P < 0.01) of urinary OA excretion in women (4.38 +/- 1.35) compared to men (3.26 +/- 0.80) and of children (5.03 +/- 1.14) compared to adults (3.82 +/- 1.24). Urinary OA excretion was significantly higher among children aged less than 1 year compared to older children. CONCLUSION: It is necessary for every laboratory practicing this kind of exploration to have its own norms which depend on both age and sex.

[Rosai-Dorfman disease: therapeutic issues in 2 cases]. / La maladie de Rosai - Dorfman : enjeux thérapeutiques à propos de 2 observations.

Rosai-Dorfman disease (RDD) is a benign lymphoproliferative disorder characterized by cervical lymph node enlargement with a consistent risk of airway compression and esthetic damage. Extranodal localizations are also described. There is no therapeutic consensus for pediatric forms of RDD. Through 2 pediatric cases with nodal involvement in 1 patient and a sinonasal and soft tissue localization in the other, we focus on the management problems of both nodal and extranodal RDD.