Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping.

Friedreich ataxia and ataxia with selective vitamin E deficiency (AVED) share very similar clinical phenotypes. We have mapped the AVED locus to proximal 8q with only three large consanguinous Tunisian families, representing to our knowledge the first use of homozygosity mapping for primary linkage analysis. Subsequently, three additional families showed linkage with the same markers. A maximum lod score of 17.9 was obtained at theta = 0 for the haplotype D8S260-D8S510, consisting of the two closest markers. With only 6 families, the AVED locus is therefore mapped precisely as illustrated by the lod-1 confidence interval of 2.4 cM on either side of D8S260-D8S510. Isolation of a yeast artificial chromosome contig > 800 kilobases (kb) showed that D8S260 and D8S510 are less than 400 kb apart.

The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy.

Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.

Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia).

Schwartz-Jampel syndrome (SJS1) is a rare autosomal recessive disorder characterized by permanent myotonia (prolonged failure of muscle relaxation) and skeletal dysplasia, resulting in reduced stature, kyphoscoliosis, bowing of the diaphyses and irregular epiphyses. Electromyographic investigations reveal repetitive muscle discharges, which may originate from both neurogenic and myogenic alterations. We previously localized the SJS1 locus to chromosome 1p34-p36.1 and found no evidence of genetic heterogeneity. Here we describe mutations, including missense and splicing mutations, of the gene encoding perlecan (HSPG2) in three SJS1 families. In so doing, we have identified the first human mutations in HSPG2, which underscore the importance of perlecan not only in maintaining cartilage integrity but also in regulating muscle excitability.

Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35.

Amyotrophic lateral sclerosis (ALS) usually presents as a sporadic disorder of motor neurons. However, familial forms of ALS have been described--autosomal dominant forms (ALS1, ALS3), clinically indistinguishable from the sporadic form, and autosomal recessive forms with early onset and slower progression of symptoms (ALS2). To localize the gene for one of the autosomal recessive forms of ALS, we applied linkage analysis to a large inbred family from Tunisia. A lod score maximum of Zmax = 8.2 at theta = 0.00 was obtained with marker D2S72 located on chromosome 2q33-q35. The fine mapping of this region suggested that the ALS2 locus lies in the 8 cM segment flanked by D2S155 and D2S115.

Linkage of Tunisian autosomal recessive Duchenne-like muscular dystrophy to the pericentromeric region of chromosome 13q.

Autosomal recessive Duchenne-like muscular dystrophy (DLMD) is a severe dystrophic myopathy. The incidence is unknown because of its clinical similarity to Duchenne muscular dystrophy (DMD). Three highly inbred DLMD families from Tunisia were analysed for chromosomal linkage using 135 polymorphic microsatellite markers. A significant lod score of z = 9.15 at theta = 0.03 was found with the 13q12 locus D13S115. Two additional 13q12 markers, D13S143 and D13S120, also gave significant lod scores. Therefore, the primary DLMD defect gene lies in the pericentrometric region of chromosome 13q.

Safety and efficacy of colistin compared with imipenem in the treatment of ventilator-associated pneumonia: a matched case-control study.

OBJECTIVE: Our study aimed to determine the efficacy and safety of colistin in the treatment of ventilator-associated pneumonia (VAP) caused by pan-drug-resistant Pseudomonas aeruginosa or Acinetobacter baumanii. DESIGN: Pairwise, retrospective exposed-unexposed study. SETTING: Combined medical and surgical intensive care unit of Habib Bourguiba University Hospital (Sfax, Tunisia). PATIENTS: Sixty patients with VAP caused by pan-drug-resistant A. baumanii or P. aeruginosa matched to 60 controls with VAP caused by A. baumanii or P. aeruginosa susceptible to imipenem. All patients had normal renal function at the onset of antibiotic therapy. INTERVENTIONS: Case patients were treated by colistin intravenously and control patients were treated by imipenem intravenously. MEASUREMENTS AND RESULTS: Baseline characteristics were similar between the colistin and imipenem groups. The mean duration of antibiotic therapy for VAP was 9.5+/-3.8 days (range 5-22 days) with colistin and 8.9+/-2.8 days (range 5-20 days) with imipenem (p=0.32). A favorable clinical response to antibiotic therapy for VAP occurred in 45 patients (75%) in the colistin group and in 43 patients (71.7%) in the imipenem group (p=0.68). The time to resolution of infectious parameters after the initiation of antibiotic therapy was not statistically different between the two groups. During the antibiotic course, none of the patients in either group developed renal failure. CONCLUSIONS: We conclude that colistin can be a safe and effective option in the treatments of VAP caused by pan-drug-resistant P. aeruginosa or A. baumanii.

[Thrombotic microangiopathies. Incidence, pathogenesis, diagnosis, treatment and prognosis]. / Les microangiopathies thrombotiques. Incidence, physiopathologie, tableau clinique, prise en charge thérapeutique et pronostic.

INTRODUCTION: The objective of this work was to review current data about the pathophysiology, clinical features, and treatment of thrombotic microangiopathies. CURRENT KNOWLEDGE: Thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. In thrombotic thrombocytopenic purpura, systemic microvascular aggregation of platelets causes ischemia in the brain and other organs. In the hemolytic-uremic syndrome, platelet-fibrin thrombi occlude predominantly the renal circulation. Thrombotic microangiopathy is a rare disorder whose varied clinical manifestations result from the formation of platelet-rich thrombi within the microvasculature and consequent tissue ischemia. The clinical features are acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. This diagnosis is of considerable importance because of the possible fulminant clinical course. Some atypical forms may be unrecognized. Plasma exchange is the current reference treatment of thrombotic thrombocytopenic purpura. However, in the light of recent publications, either infusions of concentrates of purified enzyme or more intensive immunosuppressive therapy would be more specific.

[Prognostic factors of pneumococcal meningitis. Retrospective study of 31 cases]. / Facteurs de pronostic des méningites à pneumocoque. Etude rétrospective de 31 cas.

AIM: Our aim was to study the susceptibility of Streptococcus pneumoniae to antibiotics in patients with pneumococcal meningitis and to search for the prognosis factors in those patients. METHODS: We have studied retrospectively 31 cases of pneumococcal meningitis. Comparaisons were performed with univariate analysis. RESULTS: The mean age was 36.7 +/- 20.5 years (ranged: 9 and 78 years). The sex ratio was 3,4. The susceptibility of Streptococcus pneumoniae to penicillin G was affected in 10 cases (33% of isolated pneumococcus. The MIC to penicillin G was > or =2 in only one case. The hospital mortality was 26% (8/31). With univariate analysis, factors associated with death were: age > or =55 years (Ss p= 0,006, OR: 17.2 IC95%: 2.3-134), albuminorachie > or = 7 g/l (p = 0.002, OR: 22; IC95%: 1.9-2.51), shock (p = 0.031, OR: 6.7; IC95%: 1.05-42) and Glasgow Coma Score (GCS) < or =8 (p = 0.001, OR: 20; IC95%: 2.68-149). CONCLUSION: No susceptibility to penicillin G is not associated with a worse outcome in patients with pneumococcal meningitis. An age > or =55 years, albuminorachie > or =7 g/l shock and Glasgow Coma Score < or =8 at admission were determinant of the prognosis in our study.

[Traumatic unilateral renal artery thrombosis and protein C deficiency. A case report]. / Thrombose post-traumatique de l'artère rénale et déficit en protéine C. A propos d'un cas.

Post traumatic renal artery thrombosis is rarely described in the literature. This pathology can result from stretch injury to inelastic intima of the renal artery, or by the direct flow to the abdomen causing compression injury to the renal artery against the vertebral column. However, the association of this pathology with hematologic diseases (in particular protein C deficit) was never described. We report an observation of a 28-year-old man with an uneventful history who was admitted to the intensive care unit for traumatic head injury associated with post traumatic renal artery thrombosis requiring nephrectomy. The etiologic investigation of this thrombo-embolic complication reveals a protein C deficit. Our patient was improved under treatment. This original observation confirms that post traumatic renal artery thrombosis can be associated with hematologic diseases (in particular protein C deficit).

[Acute fatty liver of pregnancy. About 22 cases]. / Stéatose hépatique aiguë gravidique. A propos de 22 cas.

OBJECTIVE: To report the clinical experience, biochemical findings, complications and maternal outcome in patients with acute fatty liver of pregnancy (AFLP). PATIENTS AND METHODS: Retrospective study over a period of 11 years (1993-2003). The diagnosis of AFLP was confirmed by liver biopsy in 15 women. However, in 7 women a medical committee that took into account clinical symptoms, and laboratory findings assessed the diagnosis. RESULTS: Were included in this study, 22 women with a mean age of 30+/-5.4 years. Only 22.7% of cases were primigravid. The mean gestational age was 36+/-2.76 weeks (range 31-41 weeks). The fetus was a male infant in 75% of cases. Ten women were admitted in the hospital without jaundice. However 15 women had developed an icterus since their hospital admission or during ICU stay. The mean SAPS II on the ICU admission was of 24.86+/-11.2 points. Biological disturbances observed were mainly: liver cytolysis in 91% of cases, a trend to hypoglycaemia in 86%, a hypoprotidemia in 66.7% and CIVD in 32%. During their ICU stay, 19 women (86.4%) developed one or several organ failures associated to the hepatic failure and 18 women required blood transfusion. After an average stay of 7.5 days, evolution was marked by the death of seven patients (31.8%). Factors correlated with a poor prognosis were: the delay of medical consultation, the development of jaundice, the development of encephalopathy, respiratory or a circulatory failure. DISCUSSION AND CONCLUSION: AFLP is a rare but life-threatening complication. Furthermore AFLP shares features with other more common and less perilous illnesses. An early diagnosis and appropriate therapy of this pathology should improve the poor prognosis in our country.

[Thrombotic microangiopathies in the intensive care unit]. / Les microangiopathies thrombotiques en réanimation.

OBJECTIVES: To analyze the clinico-biological manifestations, identify the causes and evaluate the outcome of patients with severe thrombotic microangiopathies admitted in a Tunisian intensive care unit. METHODS: Retrospective study over a period of 10 years (1995-2004) in an intensive care unit. RESULTS: Were included in this study 9 cases with a mean age of 29.2+/-9 years (range 15-44 years). Fever was observed in 5 patients, neurological impairment in 5 and digestive manifestations in 6. Haemolytic anaemia, thrombocytopenia and acute renal failure were observed in 100% of the cases. In our study, the aetiologies of thrombotic microangiopathies were: complicated pregnancy in 6 cases, systemic lupus erythematosus in 1 case. In contrast, no aetiology was found in 2 patients. Plasma exchange was performed in 5 patients, while 4 patients received only plasma infusion. After an average stay of 18+/-12.5 days, evolution was marked by the death 3 patients. CONCLUSION: The incidence of severe thrombotic microangiopathies is rare in Tunisian ICU. The clinical manifestations are not specific. Despite the improvement in the outcome by exogenous plasma supply, thrombotic microangiopathies with severe organ dysfunctions leading to hospitalization in the intensive care unit are associated with a high mortality rate.

Prevalence of hospital-acquired infection in a Tunisian hospital.

In order to estimate the prevalence of hospital-acquired infection (HAI) and research factors associated with its occurrence, a one-day prevalence survey was conducted at the Habib Bourguiba University Hospital, Tunisia. We studied 280 patients who had been present in the same ward for at least 48 h, and who had occupied a hospital bed between 17 April 2002 (midnight) and 18 April 2002 (midnight). The overall prevalence of HAI was 17.9%. The most frequently infected sites were the lungs (32%), surgical wounds (28%) and the urinary tract (20%). Microbiological documentation was available in only 28% of HAIs, and the most frequently isolated organisms were Gram-negative rods (80.8%). Results of multiple logistic regression analysis indicated that HAI is linked to the medical category, the use of intravascular devices and antibiotic prophylaxis. This survey provided information on the prevalence of HAI in Tunisian hospitals, the breakdown of infections, and HAI predisposing factors.

[Celiac disease, cerebral venous thrombosis and protein S deficiency, a fortuitous association?]. / Maladie coeliaque, thrombose veineuse cérébrale et déficit en protéine S, une association fortuite?

INTRODUCTION: Celiac disease is a pathology which is rarely associated with thrombosis complications. Cerebral vascular thrombosis has never been described in patients with a celiac disease. OBSERVATION: We report an observation of a 21-year-old girl with a history of celiac disease who was hospitalized in the intensive care unit for convulsive status epilepticus secondary to a cerebral venous thrombosis. The etiologic investigation of this thrombo-embolic complication revealed protein S deficit. Our patient improved under symptomatic treatment. COMMENT: This original observation confirms that celiac disease can be associated with cerebral venous thrombosis.

[Evaluation of the antibiotics consumption in a Tunisian university hospital]. / Evaluation de la consommation des antibiotiques dans un hôpital universitaire tunisien.

PURPOSE: To estimate the consumption of antibiotics in our hospital and to determine the points at which will be targeted the recommendations of good practice of antibiotherapy. PATIENTS AND METHODS: Our study is a one day prevalence study where antibiotic's prescriptions are analyzed by a group of 6 doctors referents in antibiotherapy. RESULTS: During the study day, 443 patients were studied. Means age was 44.2 +/- 23.3 years (range: 1 and 102 years). 101 infections were diagnosed in 48 patients (10.8%). 192 patients (43.3%) received antibiotics. Antibiotherapy was curative in 44% of cases. The most prescribed antibiotics were gentamicin (85.2 DDD/1000 patients), metronidazole (79 DDD/1000 patients), and cefotaxime (73.9 DDD/1000 patients). According to the evaluation group, 30.7% of the antibiotic's prescription was considered unjustified. The antibioprophylaxis represents the category most often unjustified (49%). The molecules in which prescription was frequently considered unjustified are the ciprofloxacin (67%), the amoxicilline-clavulanate (40%) and the cefotaxime (40%). CONCLUSION: Our results suggest that an action of good practice should be targeted at the antibioprophylaxis and should concern especially molecules in which prescription was frequently unjustified.

Replicative potential and telomere length in human skeletal muscle: implications for satellite cell-mediated gene therapy.

In this study, we have evaluated the ability of human satellite cells isolated from subjects aged from 5 days to 86 years to proliferate in culture. Cells were cultivated until they became senescent. The number of cell divisions was calculated by counting the number of cells plated in culture compared to the number of cells removed following proliferation. Telomere length, which is known to decrease during each round of cell division, has been used to analyze the in vitro replicative capacity and in vivo replicative history of human satellite cells at isolation. The rate of telomere shortening in myonuclei of these muscle biopsies was also examined. Our results show that both proliferative capacity and telomere length of satellite cells decreases with age during the first two decades but that the myonuclei of human skeletal muscle are remarkably stable because telomere length in these myonuclei remains constant from birth to 86 years. The lack of shortening of mean terminal restriction fragments (TRF) in vivo confirms that skeletal muscle is a stable tissue with little nuclear turnover and therefore an ideal target for cell-mediated gene therapy. Moreover, our results show that it is important to consider donor age as a limiting factor to obtain an optimal number of cells.

Giant axonal neuropathy with inherited multisystem degeneration in a Tunisian kindred.

We describe a large kindred of 6 patients with a slowly progressive autosomal recessive form of giant axonal neuropathy (GAN). The propositus presented with progressive infantile onset of distal amyotrophy of 4 limbs, brisk reflexes, diffuse fasciculations, bulbar signs, and deep sensory loss in both lower limbs. The EMG and nerve biopsy showed typical hypertrophic neuritis. In 4 patients, there were giant axons filled with neurofilaments, with normal conduction velocity. In the youngest boy, the neurologic deficit was less severe, and the nerve biopsy revealed only a few unmyelinated axons filled with neurofilaments. These cases appear to represent a different genetic defect from other reported cases of GAN.

Clinical and genetic analysis of a Tunisian family with autosomal dominant cerebellar ataxia type 1 linked to the SCA2 locus.

Autosomal dominant cerebellar ataxias (ADCA) type 1 are a clinically and genetically heterogeneous group of neurodegenerative disorders. We report a large Tunisian ADCA type 1 family in which 17 patients (mean age at onset +/- SD = 35.6 +/- 15.3 years) were examined. There was mean anticipation of 10.3 +/- 15.4 years in this family; anticipation was greater in paternal (28 +/- 8.2 years) than in maternal (2.7 +/- 10.9 years) transmission. Linkage analysis performed with microsatellite markers linked to the spinal cerebellar ataxia 1 (SCA1) locus on chromosome 6p and the SCA2 locus on chromosome 12q excluded linkage to SCA1, but there was close linkage with marker D12S105 (Zmax = 2.51 at theta = 0.00). This result was confirmed by multipoint analysis, which generated a maximal lod score of 3.46 at this locus. Multipoint analysis and haplotype reconstruction reduced the interval containing the SCA2 locus to 6.4 cM, a narrowing of the 35-cM interval in a previously described Cuban SCA2 family with a clinical picture similar to that of our family, including a high frequency of postural and action tremor.

Linkage to chromosome 13q11-12 of an autosomal recessive cerebellar ataxia in a Tunisian family.

OBJECTIVE: To report the clinical findings and the genetic linkage mapping of an autosomal recessive cerebellar ataxia associated to peripheral neuropathy, showing an early onset cerebellar ataxia with retained tendon reflexes (EOCA) phenotype. BACKGROUND: EOCA is a clinical syndrome delimited by Harding distinguished from Friedreich's ataxia (FA) mainly by the preservation of tendon reflexes. Molecular genetic study of patients with EOCA has demonstrated genetic heterogeneity. A form of autosomal recessive spastic ataxia has been described in Charlevoix Saguenay area in Quebec (ARSACS); the gene responsible has been mapped to chromosome 13q. METHODS: Genetic linkage analysis was performed on 18 members of a large family including 8 of 9 members with EOCA. After exclusion of FA and ataxia with vitamin E deficiency loci as well as loci of autosomal dominant cerebellar ataxias, we performed a linkage analysis to markers of 13q11-12 region. RESULTS: The 9 affected members of this family showed stereotyped clinical features with cerebellar ataxia, pyramidal syndrome, and a variable degree of axonal peripheral neuropathy. Linkage was detected between the disease locus and the microsatellite marker D13S232. Surrounding markers to D13S232 confirmed the linkage and showed the homozygosity of the affected members. CONCLUSION: The family reported here showed the same locus as autosomal recessive spastic ataxia Charlevoix Saguenay disease.

Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14.

Miyoshi myopathy (MM) is a young-adult-onset, autosomal recessive distal muscular dystrophy initially affecting the plantar flexors. We analyzed 12 MM families, five with consanguineous marriage, for chromosomal linkage using polymorphic microsatellite DNA markers to map the MM gene. A significant lod score was obtained with the 2p12-14 locus D2S291 (Zmax = 15.3 at theta = 0). Two additional 2p12-14 markers, D2S286 (Z = 10.7 at theta = 0) and D2S292 (Z = 7.2 at theta = 0.05), also gave significant lod scores. These markers will be useful for diagnosis of symptomatic and presymptomatic patients, prenatal and carrier diagnosis of family members carrying MM, and ultimately identification of a gene responsible for MM.

Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families.

Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, the disease locus (FRDA) of which has been assigned to 9q13-q21.1 by genetic linkage analysis in affected families. We report two large inbred Tunisian families with FA manifestations that did not show the expected linkage. The disease locus could be excluded from a large (12 cMo) region around FRDA. This is the first report providing evidence for nonallelic genetic heterogeneity for the FA clinical phenotype. On subsequent analysis, all patients had very low levels of serum vitamin E whereas the parents and healthy sibs had normal vitamin E levels. This establishes that the selective vitamin E deficiency with normal fat absorption is an autosomal recessive trait, which is associated in the two families reported here with the FA phenotype.