A novel large deletion in CCM1 gene in a Tunisian family.

Familial CCM is a rare entity associated with the mutation of three genes: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). We report here the first description of a Tunisian familial CCMs composed of six members. The father and two daughters were affected and symptomatic. The two other kindred were healthy. Surgical treatment was performed in only one affected patient. Molecular analysis of KRIT1, MGC4607 and PDCD10 genes identified a large KRIT1 deletion of the first ten exons. To the best of our knowledge, this large deletion has never been reported before.

Xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a form of general dermatosis characterised by photo-induced cutaneous-ocular impairment and by skin cancers. In addition to these signs, there may also be neurological involvement. This disease is related to a defect in genes within the nucleotide excision repair system for the first seven genetic groups (A-G), and to an abnormality in transcription groups for the eighth group (xeroderma pigmentosum variant - XPV). Cutaneous carcinomas are the most common types of cancer seen. They may begin in childhood. Multiple melanoma commonly occurs during the course of XP but given the frequency of spontaneous regression, the incidence is underestimated. The clinical appearance is characterised by polymorphous lesions with characteristic dyschromia and in most cases it is sufficient to establish the diagnosis. Investigation of unscheduled DNA synthesis (UDS) and cell survival following ultraviolet (UV) radiation were formerly considered the reference examination for laboratory diagnosis. However, these tests are now being replaced by new molecular biology techniques to screen for the genetic mutations characteristic of the disease. These techniques have proved extremely useful in identifying heterozygous patients and in antenatal diagnosis. Photoprotection is the key preventive measure: patients must avoid all exposure to the sun and to artificial sources of UV radiation. The therapeutic arsenal has recently been enriched by several modern therapeutic methods used to destroy cutaneous tumours such as imiquimod and photodynamic therapy (PDT). These approaches are valuable since they eliminate incipient tumours while sparing healthy skin. Surgery and cryosurgery are the most suitable methods for treating cutaneous tumours in children. Chemotherapy may be considered an alternative for the treatment of keratoacanthomas and squamous cell carcinomas (SCC). Cryosurgery may be combined with other therapeutic approaches to eliminate SCC of the lip. Management of these patients in reference centres, coupled with assistance from associations providing support for patients' families, has resulted in improved quality of therapy while slowing down disease progression.

Comorbidity in the Tunisian population.

Genetic diseases in the Tunisian population represent a real problem of public health as their spectrum encompasses more than 400 disorders. Their frequency and distribution in the country have been influenced by demographic, economic and social features especially consanguinity. In this article, we report on genetic disease association referred to as comorbidity and discuss factors influencing their expressivity. Seventy-five disease associations have been reported among Tunisian families. This comorbidity could be individual or familial. In 39 comorbid associations, consanguinity was noted. Twenty-one founder and 11 private mutations are the cause of 34 primary diseases and 13 of associated diseases. As the information dealing with this phenomenon is fragmented, we proposed to centralize it in this report in order to draw both clinicians' and researcher's attention on the occurrence of such disease associations in inbred populations as it makes genetic counseling and prenatal diagnosis challenging even when mutations are known.

Clinical and molecular investigation of Buschke-Fischer-Brauer in consanguineous Tunisian families.

BACKGROUND: Punctate palmoplantar keratoderma type I (PPPK-BFB), also called Buschke-Fischer-Brauer disease (MIM 148600) is a rare autosomal dominant disorder of keratinization, characterized by multiple hyperkeratotic lesions on the palms and soles. Recently, PPPK-BFB has been shown to be associated with mutations in the AAGAB gene in several families of European, African, Canadian and Asian origins. OBJECTIVE: To characterize the clinical and genetic features of PPPK-BFB in a broad group of Tunisian patients. METHODS: Epidemiological and clinical data were collected from 18 PPPK-BFB patients belonging to eight Tunisian families. We carried out mutational and structural analysis for families not previously investigated. RESULTS: Sequencing of the remaining families identified a total of three different mutations in AAGAB gene: one founder mutation (c.348_349delAG, p.R116Sfs*1) specific to the inbred Tunisian population, one recurrent mutation and (c.370C>T, p.R124*) one novel variant (c.430C>G, p.E144K). This novel mutation, involving a conserved amino acid, is predicted to be probably damaging to the p34 protein function. Assessment of the phenotypic presentation of this group of Tunisian patients was marked by variable severity and varying age at onset with a possible presence of anticipation noted in five out of eight families (62.5%). There is no apparent genotype-phenotype correlation. Despite the high degree of inbreeding, no homozygous individuals for AAGAB mutations were observed. Homozygous carriers in AAGAB gene are likely non-viable. CONCLUSION: This study contributes to further characterize PPPK-BFB in consanguineous families and to extend the mutational spectrum of AAGAB gene in the Tunisian population.

[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 human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.

A candidate gene for Branchio-Oto-Renal (BOR) syndrome was identified at chromosome 8q13.3 by positional cloning and shown to underlie the disease. This gene is a human homologue of the Drosophila eyes absent gene (eya), and was therefore called EYA1. A highly conserved 271-amino acid C-terminal region was also found in the products of two other human genes (EYA2 and EYA3), demonstrating the existence of a novel gene family. The expression pattern of the murine EYA1 orthologue, Eya1, suggests a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern is indicative of a role for Eya1 in the metanephric cells surrounding the 'just-divided' ureteric branches.

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.

[Biochemical and molecular diagnosis of primary hyperoxaluria type 1: Tunisian study about 15 cases]. / Diagnostic biochimique et moléculaire de l'hyperoxalurie primaire de type 1: étude tunisienne à propos de 15 cas.

BACKGROUND: The primary type 1 hyperoxaluria (HP1) is the most frequent and severe form of the primary hyperoxaluriae. It is related to an enzymatic deficit in alanine glyoxylate aminotransferase (AGT). It is a recessive autosomic disease. Rare in Europe, it is responsible for 13% of the end stage renal failure in the Tunisian child. AIM: The aim of this work is to evaluate the biological and molecular examinations contributing with the early diagnosis and the follow-up of the HP1 patients and to test their response to pyridoxin. PATIENTS AND METHODS: A prospective study of 15 children who have oxaluria lower than 500 µmol/l and normal renal function is carried out. The cristalluria study, oxaluria and the glycolate-glycerate urinary ratio were carried out on all the patients. The so-called mutation maghrebean T853 (Ile244 Thr) was detected by direct sequencing of the exon 7 gene AGXT. The response to pyridoxin was tested among 13 patients. RESULTS: The oxaluria concentration was greater or equal to 1000 µmol/l in nine cases (60%) and ranging between 600 and 1000 µmol/l in the remaining cases. The oxaluria flow was significantly high depending on the age. The glycolaturia was high among eight patients (57%). In 61,5% of the cases, the most frequent crystalline species was whewellite (C1). The "maghrebin" mutation was identified in nine patients at the heterozygous state, showing 25% allelic frequency. The response to pyridoxin was observed in the 13 tested cases. CONCLUSION: The HP1 is frequent in our country from where the need for an early diagnosis. The use of simple biochemical tools such as the study of the cristalluria, the morphological analysis of stones and the oxaluria allow to direct the diagnosis towards a HP1, confirmed by the glycolaturia determination. The molecular biology is required in the atypical forms.

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.

Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family.

Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is classified into eight groups. Among them, XP group A (XP-A) is characterized by the presence of neurological abnormalities in addition to cutaneous symptoms. In the present study, we report a particular family with XP-A in which some members showed an atypical clinical presentation, i.e. unexplained neurological abnormalities with discrete skin manifestations. Molecular investigation allowed identification of a novel XPA mutation and complete phenotype-genotype correlation for this new phenotypic expression of XP-A.

High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis.

Xeroderma pigmentosum (XP, OMIM 278700-278780) is a group of autosomal recessive diseases characterized by hypersensitivity to UV rays. There are seven complementation groups of XP (XPA to XPG) and XPV. Among them, the XP group C (XP-C) is the most prevalent type in Western Europe and in the United States. We report here on the clinical and genetic investigation of XP-C patients in 14 Tunisian families. As the XPC V548A fs X572 mutation has been identified in Algerian and Moroccan populations, Tunisian patients were first screened for this mutation by a direct sequencing of exon 9 of the XPC gene. All patients with a severe clinical form had this mutation, thus showing the homogeneity of the mutational spectrum of XPC in Tunisia. A potential founder effect was searched and confirmed by haplotype analysis. Taking into account the similarity of the genetic background, we propose a direct screening of this mutation as a rapid and cost-effective tool for the diagnosis of XP-C in North Africa.

Histological characterization of Darier's disease in Tunisian families.

BACKGROUND: Darier's disease (OMIM 124200) is an autosomal-dominant skin disorder characterized by warty papules and plaques in seborreheic areas, palmo-plantar pits and distinctive nail abnormalities. The disease has complete penetrance in adults and variable expressivity. It is caused by mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca(2+) ATPase type 2 isoform (SERCA2). OBJECTIVE: We report histological investigations of six unrelated Tunisian families including 15 affected individuals with Darier's disease mutations. RESULTS: The typical histological features of Darier's disease have been observed in the 15 patients. Variable histological features have been observed among Tunisian patients ranging from mild to moderate lesions of Darier's disease. A significant correlation has been observed between the clinical presentation of the Darier's disease (mild or moderate) and the intensity of the histological features. Isolated acral form of Darier's disease was seen in one case. Two distinct original associations have been observed: Darier's disease/pemphigus vulgaris in one patient and Darier's disease/ichtyosis in the other patient. CONCLUSION: Our findings confirmed the clinical heterogeneity of Darier's disease on the basis of histological study. The intensity of the histological features could be closely correlated to the severity of Darier's disease clinical presentation.

[Darier's disease: an evaluation of its neuropsychiatric component]. / Les manifestations neuropsychiatriques de la maladie de Darier : résultat préliminaire d'une étude epidémioclinique et génétique de huit familles.

BACKGROUND: Darrier's disease is a rare genodermatosis with a dominant autosomic penetrating variable transmission. The association between Darier's disease and neuropsychiatric disorders has been reported since 1996. Moreover, associations with mental retardation, schizophrenia, mood disorders and suicide have been reported. The discovery in 1999 of the ATP2A2 gene of Darier's disease, localised on chromosome 12, allowed significant advances notably in understanding the pathogenicity of these symptoms. MATERIAL AND METHODS: In this article, we present the preliminary results of a clinical and genetic study of eight Tunisian families, involving dermatologists, psychiatrists and geneticians. Eight patients with Darier's disease and their first degree relatives were included in the study after they had given their written consent. Thirty-five subjects were examined, 23 of them had Darier's disease. All patients were submitted to a complete clinical examination; notably dermatological screening, genetic inquiry and blood tests for haplotype analysis. Only 13 of them underwent a psychiatric examination. RESULTS: The psychiatric examination was carried out only in 13 patients with Darier's disease, who revealed neuropsychiatric symptoms with a frequency of 61.1% (8/13). Two patients presented mild mental retardation; six patients had mood disorders, three of them belonged to the same family (two had recurrent depression, four belonged to the bipolar spectrum [2 bipolar disorder type 2, 2 cyclothymia]). The coexpression of the two distinct phenotypes (Darier's disease and bipolar disease), within the same three members' of the family of our study, suggests the existence of a genetic linkage between the two diseases, as has been reported in the literature.

[Mitochondrial DNA: properties and applications]. / ADN mitochondrial: propriétés et applications.

Mitochondria are the intracellular organelle responsible for the production of cellular energy. They play an important role in the regulation of cellular metabolism, apoptosis and oxydative stress control. Mitochondrial DNA (mtDNA) has many special features such as a high copy number in cell, maternal inheritance, and a high mutation rate which have made it attractive to scientists from many fields. In anthropological genetics, mtDNA is useful to trace geographic distribution of genetic variation, for the investigation of expansions, migrations and other pattern of gene flow. mtDNA is widely applicated in forensic science. It is a powerful implement to identify human remains. mtDNA is characterized by the high rate of polymorphisms and mutations. Some of which are increasingly recognized as an important cause of human pathology such as oxidative phosphorylation (OXPHOS) disorders, maternally inherited diabetes and deafness (MIDD), Type 2 diabetes mellitus, neurodegenerative disorders, heart failure and cancer.

Supernumerary nipples in association with Hailey-Hailey disease in a Tunisian family.

Supernumerary nipples (SNs) or polythelia are developmental abnormalities of breast tissue. They are located along the embryonic mammary lines. Polythelia usually occurs as a sporadic abnormality, although familial aggregation has been occasionally reported. Hailey-Hailey disease is a rare autosomal genodermatosis characterized by disturbed keratinocyte adhesion. These cutaneous disorders have been described in correlation with many other abnormalities. We report here the association of Hailey-Hailey disease and supernumerary nipples in a Northern Tunisian family. To our knowledge, this is the first report of such a clinical association.

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.