meriem Tazir - Academia.edu (original) (raw)
Papers by meriem Tazir
SUMMARY This paper describes a genetic study of the chronic spinal muscular atrophies of late inf... more SUMMARY This paper describes a genetic study of the chronic spinal muscular atrophies of late infancy and early childhood in Algeria. There were 50 index patients occurring in 44 kindreds and fourteen secondary cases. Genetic and nosological studies indicated that 52 ~o of the patients constitute a genetically homogeneous subgroup with an age of onset between 3 and 24 months and an autosomal recessive mode of transmission. They also indicated that a large subgroup of index patients (48~) had a late age of onset, between 3 and 14 years. Such a large number of late presenting cases has not been reported in previous series. The majority of these cases are probably due to an autosomal recessive gene. A small proportion may represent new dominant mutations or nongenetic phenocopies. A possible sex influence on disease manifestations is discussed. A trend toward later male onset has been noted, and the degree of disability is more marked in males at or after the age of 10. Finally, some e...
Movement Disorders Clinical Practice, 2021
Revue Neurologique, 2018
S131 sévère débutant tôt dans l'enfance, avec un syndrome dysmorphique important des pieds et des... more S131 sévère débutant tôt dans l'enfance, avec un syndrome dysmorphique important des pieds et des mains et plus tardivement une atteinte des muscles proximaux et respiratoires. Conclusion Il est important de rechercher chez les patients CMT avec mutation GDAP1 une atteinte du larynx et une dysfonction respiratoire car leur prise en charge précoce améliore le pronostic vital. Informations complémentaires Pas de conflits d'intérêt. Mots clés Début dans l'enfance ; GDAP1 ; CMT
Revue Neurologique, 2015
Introduction L’ataxie avec apraxie oculomotrice de type 1 (AOA1) est caracterisee par une ataxie ... more Introduction L’ataxie avec apraxie oculomotrice de type 1 (AOA1) est caracterisee par une ataxie cerebelleuse autosomique recessive d’apparition precoce avec atteinte cognitive, hypoalbuminemie, hypercholesterolemie et neuropathie. Objectifs Nos analyses visaient a explorer le gene de l’aprataxine (APTX) afin d’identifier des mutations chez nos patients, poser un diagnostic moleculaire et relever les particularites phenotypiques propres a notre population. Methodes Nous avons procede au criblage du gene APTX chez les patients ayant une ataxie autosomique a transmission recessive, d’apparition precoce et pour lesquels les formes les plus frequentes (ataxie de Friedreich et ataxie avec deficit isole en vitamine E) avaient ete prealablement exclues. Le criblage du gene a ete realise par PCR et sequencage direct du gene et de ses sequences flanquantes. Resultats Nous avons identifie 6 patients (issus de 5 familles) portant des mutations homozygotes dans le gene APTX . Cinq patients (4 familles) portaient la mutation la plus frequemment decrite (c.837G>A ; p.Trp279 * ). Un patient portait une mutation abolissant un site d’epissage de l’exon 7 du gene (c.875-1G>A). Les patients presentaient des tableaux cliniques evocateurs, avec notamment une ataxie cerebelleuse a debut precoce debutant durant la premiere decade, une apraxie oculomotrice et une atteinte cognitive. Discussion Deux de nos patients souffraient d’un deficit cognitif, trait que l’on croyait exclusif aux patients AOA1 japonais, mais qui a ensuite ete rapporte parmi une cohorte de patients italiens, ce qui elargit pour la seconde fois cette description a des patients non japonais. Une atrophie cerebelleuse est constante chez les patients AOA1 et etait egalement presente chez nos patients ayant beneficie d’une IRM cerebrale. Conclusion Les patients algeriens atteints d’AOA1 presentent un phenotype similaire au tableau classique decrit dans la litterature, avec toutefois la presence de signes rarement decrits en dehors de la population japonaise.
Journal of the Neurological Sciences, 2014
Journal of Interferon & Cytokine Research, 2014
Alzheimer's disease (AD) ... more Alzheimer's disease (AD) is a neurodegenerative disease leading to a progressive and irreversible loss of mental functions. It is characterized by 3 stages according to the evolution and the severity of the symptoms. This disease is associated with an immune disorder, which appears with significant rise in the inflammatory cytokines and increased production of free radicals such as nitric oxide (NO). Our study aims to investigate interferon (IFN)-γ and tumor necrosis factor-α (TNF-α) involvement in NO production, in vivo and ex vivo, in peripheral blood mononuclear cells from Algerian patients (n=25), according to the different stages of the disease (mild Alzheimer's, moderate Alzheimer's, and severe Alzheimer's) in comparison to mild cognitive impairment (MCI) patients. Interestingly, we observed that in vivo IFN-γ and TNF-α levels assessed in patients with AD in mild and severe stages, respectively, are higher than those observed in patients with moderate stage and MCI. Our in vivo and ex vivo results show that NO production is related to the increased levels of IFN-γ and TNF-α, in mild and severe stages of AD. Remarkably, significant IFN-γ level is only detected in mild stage of AD. Our study suggests that NO production is IFN-γ dependent both in MCI and mild Alzheimer's patients. Further, high levels of NO are associated with an elevation of TNF-α levels in severe stage of AD. Collectively, our data indicate that the proinflammatory cytokine production seems, in part, to be involved in neurological deleterious effects observed during the development of AD through NO pathway.
Archives of Medical Research, 2014
Background and Aims. There is growing evidence that increased blood concentration of total homocy... more Background and Aims. There is growing evidence that increased blood concentration of total homocysteine (tHcy) may be a risk factor for Alzheimer's disease (AD). The present study was conducted to evaluate the association of serum tHcy and other biochemical risk factors with AD. Methods. This is a case-control study including 41 individuals diagnosed with AD and 46 nondemented controls. Serum levels of all studied biochemical parameters were performed. Results. Univariate logistic regression showed a significant increase of tHcy (p 5 0.008), urea (p 5 0.036) and a significant decrease of vitamin B12 (p 5 0.012) in AD group vs. controls. Using multivariate logistic regression, tHcy (p 5 0.007, OR 5 1.376) appeared as an independent risk factor predictor of AD. There was a significant positive correlation between tHcy and creatinine (p !0.0001). A negative correlation was found between tHcy and vitamin B12 (p !0.0001). Conclusions. Our findings support that hyperhomocysteinemia is a risk factor for AD in an Algerian population and is also associated with vitamin B12 deficiency. Ó 2014 IMSS. Published by Elsevier Inc.
Neuromuscular Disorders, 2009
Neuromuscular Disorders, 2000
Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a perip... more Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a peripheral neuropathy and features of central nervous system involvement. We describe four patients belonging to a consanguineous Algerian family with late onset (6±10 years) slowly progressive autosomal recessive giant axonal neuropathy. The propositus presented with a Charcot±Marie±Tooth 2-like phenotype with foot deformity, distal amyotrophy of lower limbs, are¯exia and distal lower limb hypoesthesia. Central nervous system involvement occurred 10 years later with mild cerebellar dysarthria and nystagmus in the propositus and 16 years after onset, a spastic paraplegia in the oldest patient. The two youngest patients (13 and 8 years old) do not present any signs of central nervous involvement. Magnetic resonance imaging showed cerebellar atrophy in the two older. Nerve biopsy showed moderate axonal loss with several giant axons ®lled with neuro®laments. Genetic study established a linkage to chromosome 16q locus. This clinical presentation differs from the classical form of giant axonal neuropathy.
Neurology, 2010
... site principal investigator and research team leader), Alexandra Dürr, MD, PhD (Paris, site c... more ... site principal investigator and research team leader), Alexandra Dürr, MD, PhD (Paris, site coinvestigator), Ebba Lohmann, MD (Paris, site coinvestigator), Marie Vidailhet, MD (Paris, site coinvestigator), Anne-Marie Bonnet, MD, (Paris, site coinvestigator), Michel Borg (Nice, site ...
Neurology, 2006
Background: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral mo... more Background: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin. Objective: To identify mutations in the SH3TC2 gene. Methods: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis. Results: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (Յ34 m/s) were not correlated with disease duration. The functional disability score was Յ3, indicating that the patients could walk without help. Unexpectedly, typical giant axons were observed on biopsies from a large Algerian family. Conclusions: Charcot-Marie-Tooth type 4C (CMT4C) is less severe than other autosomal recessive (AR) CMT. Intrafamilial variability is important, making phenotype-genotype correlations difficult, but spine deformities are clearly a hallmark of CMT4C. In the presence of scoliosis, a neurologic examination is recommended. Giant axons on biopsies are also suggestive of CMT4C. For genetic analysis, the R954X mutation should be looked for before systematic sequencing of exon 11.
Neurology, 2008
Objective: Mutations in various genes of the neuromuscular junction cause congenital myasthenic s... more Objective: Mutations in various genes of the neuromuscular junction cause congenital myasthenic syndrome (CMS). A single truncating mutation (1293insG) in the acetylcholine receptor epsilon subunit gene (CHRNE) was most often identified in CMS families originating from North Africa and was possibly a founder mutation. Methods: Twenty-three families were studied with an early onset form of CMS and originating from Tunisia, Algeria, Morocco, and Libya. Screening for the mutation 1293insG was performed by direct sequencing. Haplotype analysis was done with 9 (CA)n repeat microsatellite markers and 6 SNPs flanking 1293insG on chromosome 17p13-p12. Dating was calculated using the ESTIAGE method for rare genetic diseases. Results: The 1293insG mutation was identified in 14 families (about 60% of the initial 23). The expression of the CMS in affected members of these families was relatively homogeneous, without fetal involvement or being life-threatening, with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. Haplotype analysis revealed a common conserved haplotype encompassing a distance of 63 kb. The estimated age of the founder event was at least 700 years. Conclusions: These results strongly support the hypothesis that 1293insG derives from an ancient single founder event in the North African population. Identification of founder mutations in isolated or inbred populations may have important implications in the context of molecular diagnosis and genetic counseling of patients and families by detection of heterozygous carriers.
Acta Neuropathologica, 2007
We report two sporadic patients of CMT disease in diVerent consanguineous families. The electroph... more We report two sporadic patients of CMT disease in diVerent consanguineous families. The electrophysiological examination led to the diagnosis of a severe demyelinating neuropathy. The nerve biopsies exhibited numerous outfoldings of the myelin sheaths and onion-bulb proliferations. The consanguinity and the histological Wndings pointed to a diagnosis of CMT 4B. However, the detection of abnormal and regular widenings between the major dense lines of the myelin lamellae by electron microscopy led us to search for a P0 gene mutation. Two heterozygous mutations of this gene were identiWed: S63F and N131Y. DiVerent aspects of uncompacted myelin lamellae have been described in some cases of P0 mutations and a few now appear to be quite speciWc to it. More than 30 genes are implicated in CMT and as mutation search is time-and money-consuming, we believe that in some selected patients ultrastructural examination of nerves, among other criteria, helps orientate the molecular diagnosis of CMT.
Nature Genetics, 2004
Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We ha... more Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination. We previously identified a 16-cM interval on chromosome 9q34 associated with an autosomal recessive adolescent-onset cerebellar ataxia segregating in two families 1,2 , one with additional oculomotor apraxia 1 and the second with associated elevated serum AFP, immunoglobulins and creatine kinase levels but no oculomotor apraxia 2,3. We identified nine additional families with ataxia linked to 9q34 by homozygosity mapping (Supplementary Methods online). As most affected individuals had both oculomotor apraxia and elevated AFP levels we assumed that they were affected by the same disorder, which we named AOA2 (OMIM 606002). We identified distal and proximal recombinations in families with two affected individuals (Fig. 1a), localizing the defective gene underlying AOA2 to a 1.1-Mb interval containing 13 genes (Fig. 1b) and
Brain
The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involve... more The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous vari...
SUMMARY This paper describes a genetic study of the chronic spinal muscular atrophies of late inf... more SUMMARY This paper describes a genetic study of the chronic spinal muscular atrophies of late infancy and early childhood in Algeria. There were 50 index patients occurring in 44 kindreds and fourteen secondary cases. Genetic and nosological studies indicated that 52 ~o of the patients constitute a genetically homogeneous subgroup with an age of onset between 3 and 24 months and an autosomal recessive mode of transmission. They also indicated that a large subgroup of index patients (48~) had a late age of onset, between 3 and 14 years. Such a large number of late presenting cases has not been reported in previous series. The majority of these cases are probably due to an autosomal recessive gene. A small proportion may represent new dominant mutations or nongenetic phenocopies. A possible sex influence on disease manifestations is discussed. A trend toward later male onset has been noted, and the degree of disability is more marked in males at or after the age of 10. Finally, some e...
Movement Disorders Clinical Practice, 2021
Revue Neurologique, 2018
S131 sévère débutant tôt dans l'enfance, avec un syndrome dysmorphique important des pieds et des... more S131 sévère débutant tôt dans l'enfance, avec un syndrome dysmorphique important des pieds et des mains et plus tardivement une atteinte des muscles proximaux et respiratoires. Conclusion Il est important de rechercher chez les patients CMT avec mutation GDAP1 une atteinte du larynx et une dysfonction respiratoire car leur prise en charge précoce améliore le pronostic vital. Informations complémentaires Pas de conflits d'intérêt. Mots clés Début dans l'enfance ; GDAP1 ; CMT
Revue Neurologique, 2015
Introduction L’ataxie avec apraxie oculomotrice de type 1 (AOA1) est caracterisee par une ataxie ... more Introduction L’ataxie avec apraxie oculomotrice de type 1 (AOA1) est caracterisee par une ataxie cerebelleuse autosomique recessive d’apparition precoce avec atteinte cognitive, hypoalbuminemie, hypercholesterolemie et neuropathie. Objectifs Nos analyses visaient a explorer le gene de l’aprataxine (APTX) afin d’identifier des mutations chez nos patients, poser un diagnostic moleculaire et relever les particularites phenotypiques propres a notre population. Methodes Nous avons procede au criblage du gene APTX chez les patients ayant une ataxie autosomique a transmission recessive, d’apparition precoce et pour lesquels les formes les plus frequentes (ataxie de Friedreich et ataxie avec deficit isole en vitamine E) avaient ete prealablement exclues. Le criblage du gene a ete realise par PCR et sequencage direct du gene et de ses sequences flanquantes. Resultats Nous avons identifie 6 patients (issus de 5 familles) portant des mutations homozygotes dans le gene APTX . Cinq patients (4 familles) portaient la mutation la plus frequemment decrite (c.837G>A ; p.Trp279 * ). Un patient portait une mutation abolissant un site d’epissage de l’exon 7 du gene (c.875-1G>A). Les patients presentaient des tableaux cliniques evocateurs, avec notamment une ataxie cerebelleuse a debut precoce debutant durant la premiere decade, une apraxie oculomotrice et une atteinte cognitive. Discussion Deux de nos patients souffraient d’un deficit cognitif, trait que l’on croyait exclusif aux patients AOA1 japonais, mais qui a ensuite ete rapporte parmi une cohorte de patients italiens, ce qui elargit pour la seconde fois cette description a des patients non japonais. Une atrophie cerebelleuse est constante chez les patients AOA1 et etait egalement presente chez nos patients ayant beneficie d’une IRM cerebrale. Conclusion Les patients algeriens atteints d’AOA1 presentent un phenotype similaire au tableau classique decrit dans la litterature, avec toutefois la presence de signes rarement decrits en dehors de la population japonaise.
Journal of the Neurological Sciences, 2014
Journal of Interferon & Cytokine Research, 2014
Alzheimer's disease (AD) ... more Alzheimer's disease (AD) is a neurodegenerative disease leading to a progressive and irreversible loss of mental functions. It is characterized by 3 stages according to the evolution and the severity of the symptoms. This disease is associated with an immune disorder, which appears with significant rise in the inflammatory cytokines and increased production of free radicals such as nitric oxide (NO). Our study aims to investigate interferon (IFN)-γ and tumor necrosis factor-α (TNF-α) involvement in NO production, in vivo and ex vivo, in peripheral blood mononuclear cells from Algerian patients (n=25), according to the different stages of the disease (mild Alzheimer's, moderate Alzheimer's, and severe Alzheimer's) in comparison to mild cognitive impairment (MCI) patients. Interestingly, we observed that in vivo IFN-γ and TNF-α levels assessed in patients with AD in mild and severe stages, respectively, are higher than those observed in patients with moderate stage and MCI. Our in vivo and ex vivo results show that NO production is related to the increased levels of IFN-γ and TNF-α, in mild and severe stages of AD. Remarkably, significant IFN-γ level is only detected in mild stage of AD. Our study suggests that NO production is IFN-γ dependent both in MCI and mild Alzheimer's patients. Further, high levels of NO are associated with an elevation of TNF-α levels in severe stage of AD. Collectively, our data indicate that the proinflammatory cytokine production seems, in part, to be involved in neurological deleterious effects observed during the development of AD through NO pathway.
Archives of Medical Research, 2014
Background and Aims. There is growing evidence that increased blood concentration of total homocy... more Background and Aims. There is growing evidence that increased blood concentration of total homocysteine (tHcy) may be a risk factor for Alzheimer's disease (AD). The present study was conducted to evaluate the association of serum tHcy and other biochemical risk factors with AD. Methods. This is a case-control study including 41 individuals diagnosed with AD and 46 nondemented controls. Serum levels of all studied biochemical parameters were performed. Results. Univariate logistic regression showed a significant increase of tHcy (p 5 0.008), urea (p 5 0.036) and a significant decrease of vitamin B12 (p 5 0.012) in AD group vs. controls. Using multivariate logistic regression, tHcy (p 5 0.007, OR 5 1.376) appeared as an independent risk factor predictor of AD. There was a significant positive correlation between tHcy and creatinine (p !0.0001). A negative correlation was found between tHcy and vitamin B12 (p !0.0001). Conclusions. Our findings support that hyperhomocysteinemia is a risk factor for AD in an Algerian population and is also associated with vitamin B12 deficiency. Ó 2014 IMSS. Published by Elsevier Inc.
Neuromuscular Disorders, 2009
Neuromuscular Disorders, 2000
Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a perip... more Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a peripheral neuropathy and features of central nervous system involvement. We describe four patients belonging to a consanguineous Algerian family with late onset (6±10 years) slowly progressive autosomal recessive giant axonal neuropathy. The propositus presented with a Charcot±Marie±Tooth 2-like phenotype with foot deformity, distal amyotrophy of lower limbs, are¯exia and distal lower limb hypoesthesia. Central nervous system involvement occurred 10 years later with mild cerebellar dysarthria and nystagmus in the propositus and 16 years after onset, a spastic paraplegia in the oldest patient. The two youngest patients (13 and 8 years old) do not present any signs of central nervous involvement. Magnetic resonance imaging showed cerebellar atrophy in the two older. Nerve biopsy showed moderate axonal loss with several giant axons ®lled with neuro®laments. Genetic study established a linkage to chromosome 16q locus. This clinical presentation differs from the classical form of giant axonal neuropathy.
Neurology, 2010
... site principal investigator and research team leader), Alexandra Dürr, MD, PhD (Paris, site c... more ... site principal investigator and research team leader), Alexandra Dürr, MD, PhD (Paris, site coinvestigator), Ebba Lohmann, MD (Paris, site coinvestigator), Marie Vidailhet, MD (Paris, site coinvestigator), Anne-Marie Bonnet, MD, (Paris, site coinvestigator), Michel Borg (Nice, site ...
Neurology, 2006
Background: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral mo... more Background: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin. Objective: To identify mutations in the SH3TC2 gene. Methods: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis. Results: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (Յ34 m/s) were not correlated with disease duration. The functional disability score was Յ3, indicating that the patients could walk without help. Unexpectedly, typical giant axons were observed on biopsies from a large Algerian family. Conclusions: Charcot-Marie-Tooth type 4C (CMT4C) is less severe than other autosomal recessive (AR) CMT. Intrafamilial variability is important, making phenotype-genotype correlations difficult, but spine deformities are clearly a hallmark of CMT4C. In the presence of scoliosis, a neurologic examination is recommended. Giant axons on biopsies are also suggestive of CMT4C. For genetic analysis, the R954X mutation should be looked for before systematic sequencing of exon 11.
Neurology, 2008
Objective: Mutations in various genes of the neuromuscular junction cause congenital myasthenic s... more Objective: Mutations in various genes of the neuromuscular junction cause congenital myasthenic syndrome (CMS). A single truncating mutation (1293insG) in the acetylcholine receptor epsilon subunit gene (CHRNE) was most often identified in CMS families originating from North Africa and was possibly a founder mutation. Methods: Twenty-three families were studied with an early onset form of CMS and originating from Tunisia, Algeria, Morocco, and Libya. Screening for the mutation 1293insG was performed by direct sequencing. Haplotype analysis was done with 9 (CA)n repeat microsatellite markers and 6 SNPs flanking 1293insG on chromosome 17p13-p12. Dating was calculated using the ESTIAGE method for rare genetic diseases. Results: The 1293insG mutation was identified in 14 families (about 60% of the initial 23). The expression of the CMS in affected members of these families was relatively homogeneous, without fetal involvement or being life-threatening, with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. Haplotype analysis revealed a common conserved haplotype encompassing a distance of 63 kb. The estimated age of the founder event was at least 700 years. Conclusions: These results strongly support the hypothesis that 1293insG derives from an ancient single founder event in the North African population. Identification of founder mutations in isolated or inbred populations may have important implications in the context of molecular diagnosis and genetic counseling of patients and families by detection of heterozygous carriers.
Acta Neuropathologica, 2007
We report two sporadic patients of CMT disease in diVerent consanguineous families. The electroph... more We report two sporadic patients of CMT disease in diVerent consanguineous families. The electrophysiological examination led to the diagnosis of a severe demyelinating neuropathy. The nerve biopsies exhibited numerous outfoldings of the myelin sheaths and onion-bulb proliferations. The consanguinity and the histological Wndings pointed to a diagnosis of CMT 4B. However, the detection of abnormal and regular widenings between the major dense lines of the myelin lamellae by electron microscopy led us to search for a P0 gene mutation. Two heterozygous mutations of this gene were identiWed: S63F and N131Y. DiVerent aspects of uncompacted myelin lamellae have been described in some cases of P0 mutations and a few now appear to be quite speciWc to it. More than 30 genes are implicated in CMT and as mutation search is time-and money-consuming, we believe that in some selected patients ultrastructural examination of nerves, among other criteria, helps orientate the molecular diagnosis of CMT.
Nature Genetics, 2004
Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We ha... more Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination. We previously identified a 16-cM interval on chromosome 9q34 associated with an autosomal recessive adolescent-onset cerebellar ataxia segregating in two families 1,2 , one with additional oculomotor apraxia 1 and the second with associated elevated serum AFP, immunoglobulins and creatine kinase levels but no oculomotor apraxia 2,3. We identified nine additional families with ataxia linked to 9q34 by homozygosity mapping (Supplementary Methods online). As most affected individuals had both oculomotor apraxia and elevated AFP levels we assumed that they were affected by the same disorder, which we named AOA2 (OMIM 606002). We identified distal and proximal recombinations in families with two affected individuals (Fig. 1a), localizing the defective gene underlying AOA2 to a 1.1-Mb interval containing 13 genes (Fig. 1b) and
Brain
The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involve... more The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous vari...