N. Tebib

Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III

Glycogen storage disease type III (GSD III) is an autosomal recessive inborn error of metabolism caused by mutations in the glycogen debranching enzyme amylo-1,6-glucosidase gene, which is located on chromosome 1p21.2. GSD III is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. The spectrum of AGL gene mutations in GSD III patients depends on ethnic group. The most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands. Here, we present the molecular and biochemical analyses of 22 Tunisian GSD III patients. Molecular analysis revealed three novel mutations: nonsense (Tyr1148X) and two deletions (3033_3036del AATT and 3216_3217del GA) and five known mutations: three nonsense (R864X, W1327X and W255X), a missense (R524H) and an acceptor splice-site mutation (IVS32-12A>G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population.

Phenotypic continuum of type 2 Gaucher's disease: an intermediate phenotype between perinatal-lethal and classic type 2 Gaucher's disease.

The natural history and clinical presentation of the perinatal-lethal Gauchers disease, a severe variant of acute type 2 Gauchers disease, is quite different from classic type 2 Gauchers disease. Rare reported patients had an overlapping phenotype between these two forms confirming that phenotyping may be difficult. Here we report three patients with an intermediate phenotype. The first two patients showed at birth cholestatic jaundice, hepatosplenomegaly and hematological involvement consistent with hemophagocytosis in one patient, the death occurred from a severe liver involvement in one and lung disease in the second in the absence of neurological symptoms. The third patient displayed ichthyosis and facial dysmorphism but with neurological degeneration course and survival consistent with classic type 2 Gauchers disease.

Phenotypic spectrum of fucosidosis in Tunisia

SummaryFucosidosis (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 29u2009±u200910.3xa0months. 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 10xa0years, 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.

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

SummaryGlycogen 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.

Glycogen storage disease type I in Tunisia: An epidemiological analysis

SummaryObjective: 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.

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.

Neuromuscular Involvement in Glycogen Storage Disease Type III in Fifty Tunisian Patients: Phenotype and Natural History in Young Patients

Background Our aim was to describe the natural history of neuromuscular involvement (NMI) in glycogen storage disease type III (GSDIII). Methods We conducted a longitudinal study of 50 Tunisian patients, 9.87 years old in average. Results NMI was diagnosed at an average age of 2.66 years and was clinically overt in 85% of patients. Patients with clinical features were older (p = 0.001). Complaints were dominated by exercise intolerance (80%), noticed at 5.33 years in average. Physical signs, observed at 6.75 years in average, were dominated by muscle weakness (62%). Functional impairment was observed in 64% of patients, without any link with age (p = 0.255). Among 33 patients, 7 improved. Creatine kinase (CK) and aspartate aminotransferase (AST) levels were higher with age. Electrophysiological abnormalities, diagnosed in average at 6.5 years, were more frequent after the first decade (p = 0.0005). Myogenic pattern was predominant (42%). Nerve conduction velocities were slow in two patients. Lower caloric intake was associated with more frequent clinical and electrophysiological features. Higher protein intake was related to fewer complaints and physical anomalies. Conclusion Neuromuscular investigation is warranted even in asymptomatic patients, as early as the diagnosis of GSDIII is suspected. Muscle involvement can be disabling even in children. Favorable evolution is possible in case of optimal diet.

Biochemical and Clinical Profiles of 52 Tunisian Patients Affected by Zellweger Syndrome

BACKGROUNDnZellweger syndrome (ZS) is a peroxisome biogenesis disorder attributed to a mutation of the PEX genes family. The incidence of this disease in Africa and the Arab world remains unknown. This contribution is aimed at describing the clinical phenotype and biochemical features in Tunisian patients with ZS in order to improve the detection and management of this severe disorder.nnnMETHODSnA total of 52 patients diagnosed with ZS and 60 age- and sex-matched healthy controls were included in this study. Patients were recruited during the past 21 years, and the diagnosis of ZS was based on clinical and biochemical characteristics. Plasma very long chain fatty acids (VLCFA) were analyzed using capillary gas chromatography. The estimated incidence of ZS was calculated using the Hardy-Weinberg formula.nnnRESULTSnThe estimated incidence of ZS is 1/15,898 in Tunisia. Age at diagnosis varied between 3 days and 18 months. Severe neurological syndrome, polymalformative features, and hepatodigestive signs were observed in 100%, 67.9%, and 32% of patients, respectively. Values for plasma C26:0 and C26:0/C22:0 and C24:0/C22:0 ratios were noticeably higher in ZS patients than in controls. Distributions of values were completely different for C26:0 (0.10-0.37 vs. 0.001-0.009), C26:0/C22:0 ratio (0.11-1.29 vs. 0.003-0.090), and C24:0/C22:0 ratio (1.03-3.18 vs. 0.4-0.90) in ZS patients versus controls, respectively.nnnCONCLUSIONSnThis study highlights the high incidence of ZS in Tunisia and the possibility of simple and reliable biochemical diagnosis, thus permitting early genetic counseling for families at risk.

SFP PC-45 - Validité de la version en Arabe dialectal Tunisien de l’échelle de douleur San Salvadour

Objectifs traduire et adapter l’echelle DESS en arabe dialectal Tunisien et etudier sa validite Methodes La methode de traduction contre traduction a ete utilisee. La version traduite de l’echelle est pre-testee au pres d’un groupe heterogenede 30 personnes polyhandicapees (PPH). La limite d’acceptabilite du coefficient de Cronbach est de 0,7. Resultats La validite d’apparence de l’echelle est satisfaisante du fait qu’elle est bien acceptee (38/42 cotations), bien comprise (36/42 cotations) et souvent remplie en moins de 10 minutes (34/42 cotations). Des simplifications ont ete proposees dans l’enonce de 5 items. La bonne validite de construit discriminante est attestee par la diminution significative du score apres la prescription d’antalgiques pour les 10 patients ayant beneficie d’au moins 2 cotations (p=0,005). La validite de construit divergente est verifiee par l’absence de liaison significative entre les scores et d’autres parametres independants (epidemiologiques et cliniques). Le coefficient alpha de Cronbach a 0,82 temoigne d’une bonne coherence interne. Conclusion La version prefinale de l’echelle DESS traduite en arabe dialectal Tunisien est valide et utilisable a plus large echelle aupres des aidants de PPH Tunisiennes

SFP CO-33 - Les complications rénales de la glycogénose de type 1 (GSD1)

Objectifs rapporter les complications renales de la GSD1 et ses facteurs de risque Methodes Etude retrospective sur 10 ans des patients ayant une exploration renale. Resultats 38 patients âges de 8,6±5 ans (1,5 a 22 ans) et suivis depuis 7,4±4,5 ans ont ete etudies. L’atteinte tubulaire a interesse 23 patients qui ont tous une hypercalciurie. Elle est plus frequente en cas de d’acidose (12/14 versus 10/23 ; p=0,028), de lactacidemie plus elevee (5,9±3,4 versus 3,7±1,6 ; p=0,029) et d’une plus petite taille (−2,1 ±1,5 DS versus −0,87 ±1,5DS ; p=0,023). Les lithiases et/ou nephrocalcinose ont ete objectivees dans 7 cas (dont 5 ont regresse). L’atteinte glomerulaire (19/38) est plus frequente en cas d’hypertriglyceridemie (HTG) severe (p=0,042) et survient a un âge plus avance (11±5,2 ans versus 6,3 ±3,5 ans ; p=0,003). Il s’agit de microalbuminurie (15/31cas) necessitant le traitement par IEC dans 8 cas. La frequence des atteintes renales ne differe pas selon le type du regime (nutripompe ou amidon cru). Conclusions L’atteinte renale dans la GSD1 est frequente. L’atteinte tubulaire est precoce, liee a l’acidose lactique et peut etre depistee par la calciurie. L’atteinte glomerulaire est plus tardive et liee a l’HTG.