Publications

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    ABSTRACT: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) were found to be a significant cause of late-onset autosomal dominant forms of Parkinson's disease (PD). To determine the motor characteristics of LRRK2-related disease, we conducted a longitudinal study of 58 G2019S LRRK2-associated PD patients and compared them with genetically undefined (GU) PD patients. Fifty-eight patients diagnosed with PD-related LRRK2 G2019S mutation were included in the study and compared with 54 sporadic PD patients with negative tests for LRRK2 G2019S, PINK1, SNCA, PRKN, and DJ1 mutations. Patients were assessed at baseline and after a follow-up period of 6 years. The Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Hoehn and Yahr, and the Schwab and England scores were determined. Logistic regression was used to examine associations of G2019S mutation status with motor phenotype and rate of motor decline. The LRRK2-associated PD patients had a mean age of onset of 56.25 ± 12.05 years and in most cases (58.6%) a postural instability gait difficulty (PIGD) phenotype. The mean annual decline in the MDS-UDRS III motor score and the Hoehn and Yahr staging was of 1.3% and 2%, respectively. The PIGD phenotype predicted a more rapid progression of motor impairment. The PD motor phenotype and motor scores were similar in the LRRK2-associated PD group and in the GU PD group, with no significant differences in the progression rate of motor impairment. Motor phenotype seems to be similar in LRRK2-related PD and idiopathic PD. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 12/2014; · 5.63 Impact Factor
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    European Journal of Neurology 10/2014; 21(11). · 3.85 Impact Factor
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    ABSTRACT: Background The frequency and type of central nervous system involvement in primary Sjögren’s syndrome (pSS) remains controversial. Brain magnetic resonance imaging (MRI) abnormalities in pSS are usually discrete hyperintense areas in the white matter. Tumefactive brain lesions have been rarely reported. Case report We describe a 31-year-old woman who exhibited transcortical motor aphasia, hemiparesis and partial motor seizures as the initial manifestation of pSS. Brain MRI revealed a large frontoparietal lesion extending into the corpus callosum. The patient had spontaneous recovery and developed sicca symptoms 6 months after onset. Primary SS was diagnosed on the basis of clinical features, abnormal Schirmer test findings, high levels of anti-La/SSB antibodies and positive salivary gland biopsy results. Conclusion The present case suggests that a pseudotumoral brain lesion can occur as an initial symptom of pSS.
    Journal of the neurological sciences 04/2014; · 2.32 Impact Factor
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    ABSTRACT: Introduction The association of chorea with a specific lesion on brain imaging is described as an atypical manifestation of chronic hyperglycemia. Case report Patient of 77 years, hospitalized for bilateral choreic movements predominant on the right with dystonic movements, appeared a month ago. At admission Hyperglycemia at 2.4 g/L, without ketosis, a type 2 diabetes (HbA1c 17.3%) on oral antidiabetic agents. CT scan shows hyperdensity of putamen and lenticular nucleus that eliminates an ischemic attack. Evolution after glycemic reequilibration and treatment by haloperidol is favorable, with regression of chorea. Discussion This is a rare syndrome, affecting more elderly, presenting a diabetes poorly controlled. There is hyperglycemia without ketosis and moderate hyperosmolarity. The symptoms usually regress after glycemic control and neuroleptic treatment (recurrence in 13% of cases). The appearance of this syndrome seems to be related to the achievement of the control system GABAergic of the basal ganglia leading to an excitation of the cerebral cortex, causing involuntary movements. The etiopathogenic hypotheses advanced are multiple: impaired striatal neurotransmission associated with metabolic disturbances of hyperglycemia, dysfunction of the hematoencephalic barrier and abnormalities of the cerebral vascularization. Conclusion Chorea secondary to nonketotic hyperglycemia is a rare complication and little known of type 2 diabetes. Transitional neuroleptic treatment and glycemic control make the symptoms regress in most cases with the disappearance of the lesion imaging.
    Apollo Medicine. 01/2014;
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    ABSTRACT: Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the α-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C>T and 205-1G>T), and one was novel (553+1T>A). Age of onset was 13.2 ± 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation, even in the absence of a serum vitamin E measurement.
    Brain 12/2013; · 10.23 Impact Factor
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    ABSTRACT: A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal dominant trait, which could not be ascribed to any known mutation. DNA from three affected members were subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically-matched controls. Subsequent genotyping was performed in a multi-ethnic case control series consisting of 2,928 patients and 2,676 control subjects from Canada, Norway, Taiwan, Tunisia and the United States.A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions.In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2, and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.
    Human Molecular Genetics 11/2013; · 6.68 Impact Factor
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    ABSTRACT: Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.
    Journal of Clinical Neuroscience 10/2013; · 1.32 Impact Factor
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    ABSTRACT: Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins. Published by Elsevier Ltd.
    Journal of Clinical Neuroscience 10/2013; · 1.32 Impact Factor
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    ABSTRACT: Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation.
    PLoS ONE 09/2013; 8(1):e53826. · 3.53 Impact Factor
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    ABSTRACT: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 Movement Disorder Society.
    Movement Disorders 08/2013; · 5.63 Impact Factor
  • Revue Neurologique 04/2013; 169:A44–A45. · 0.60 Impact Factor
  • Revue Neurologique 04/2013; 169:A42–A43. · 0.60 Impact Factor
  • Revue Neurologique 04/2013; 169:A75-A76. · 0.60 Impact Factor
  • E. Farhata, M. Kéfi, F. Hentati, R. Amouri
    Revue Neurologique 04/2013; 169:A16. · 0.60 Impact Factor
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    ABSTRACT: A variant in Syntaxin 6 (a soluble N-ethylmaleimide-sensitive factor attachment protein receptor STX6) (rs1411478) has been shown to be associated with progressive supranuclear palsy (PSP). Although Parkinson's disease (PD) and PSP are distinct neurodegenerative diseases, they share some clinical and genetic features. In this study, we evaluated STX6 genetic variability in PD susceptibility in ethnically matched case-control series from Canada, Norway, Taiwan and Tunisia and we evaluated the presence of pathogenic mutations within families. No pathogenic mutations were found in STX6. Similarly, statistical analysis of rs1411478 failed to identify differences in genotype or allelic frequencies between cases and controls. Our results do not support a role for STX6 in PD.
    Parkinsonism & Related Disorders 02/2013; · 4.13 Impact Factor
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    ABSTRACT: Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid β-glucosidase 1. β-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding β-glucosidase 2, GBA2. Two nonsense mutations (c.363C>A [p.Tyr121(∗)] and c.1018C>T [p.Arg340(∗)]) and a substitution (c.2618G>A [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans.
    The American Journal of Human Genetics 01/2013; · 11.20 Impact Factor
  • Fayçal Hentati, Emna Hentati, Rim Amouri
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    ABSTRACT: Giant axonal neuropathy (GAN) is a rare hereditary autosomal recessive neurodegenerative disease affecting both the peripheral and the central nervous system. Clinically it is characterized by an age of onset during the first decade, progressive and severe motor sensory neuropathy followed, in some patients, by the occurrence of various central nervous system signs such as cerebellar syndrome, upper motor neuron signs, or epilepsy. Although kinky hairs are reported in the majority of patients, it is not a constant finding. The prognosis is usually severe with death occurring during the second or third decade; nevertheless a less severe course is reported in some patients. The presence of a variable number of giant axons filled with neurofilaments in the nerve biopsy represents the pathological feature of the disease and it is usually associated to a variable degree with axonal loss and demyelization. Giant axons are also found in the central nervous system associated with Rosenthal fibers and a variable degree of involvement of white matter and neuronal loss. The disease is caused by mutation in the GAN gene encoding for gigaxonin, a member of BTB-Kelch. Up to now 37 mutations in the GAN gene have been reported. These mutations are scattered over the 11 exons of the gene without a clear genotype-phenotype correlation. These mutations resulting in gigaxonin deficiency lead to a slow down in ubiquitin-mediated protein degradation and possibly of other unidentified proteins. GAN represents a good model of a neurodegenerative disorder in which there is a primary defect of the ubiquitin proteasome system and its network with neurofilaments. The clarification of molecular mechanisms involved in GAN can help in understanding other frequent neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson disease.
    Handbook of Clinical Neurology 01/2013; 115:933-8.
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    The American Journal of Human Genetics 01/2013; · 11.20 Impact Factor
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    ABSTRACT: Ataxia with oculomotor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia caused by mutations in the SETX gene. It is a rare monogenic disease characterized by progressive cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and an elevated serum α-fetoprotein level. To date, >100 AOA2 patients have been described and 75 different mutations in the SETX gene have been identified. We report here the clinical and genetic findings of 13 AOA2 patients from 5 unrelated Tunisian consanguineous families. DNA was collected from probands and available family members, and the 24 SETX exons were screened by direct sequencing. Four different homozygous SETX gene mutations were identified. The missense mutation 915G>T [W305C] has been described previously in Algeria. The 3 other SETX mutations are novel, including a missense mutation c.7231C>T [R 2380 W], a nonsense mutation c.6475 C>T [R2098X], and a deletion c.7180-7183delAAAA [D2332fsX2343]. More extensive screening by molecular genetic analysis of SETX in patients with Friedreich ataxia-like phenotype may show that AOA2 is more common in Tunisia than previously thought.
    Diagnostic molecular pathology: the American journal of surgical pathology, part B 10/2012; · 2.28 Impact Factor
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    ABSTRACT: BACKGROUND: Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. We studied three families diagnosed with ARCA. METHODS: To determine the gene lesions responsible for their disorders, we performed high-density single-nucleotide polymorphism genotyping and exome sequencing. RESULTS: We identified a new mutation in the SACS gene and a known mutation in SPG11. Notably, we also identified a homozygous variant in APOB, a gene previously associated with ataxia. CONCLUSIONS: These findings demonstrate that exome sequencing is an efficient and direct diagnostic tool for identifying the causes of complex and genetically heterogeneous neurodegenerative diseases, early-stage disease or cases with limited clinical data.
    European Journal of Neurology 10/2012; · 3.85 Impact Factor

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