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O Boespflug-Tanguy

Publications and source records attributed to O Boespflug-Tanguy.

At least 19 recordsLinked to original sources
PubMed2006

The large spectrum of eIF2B-related diseases.

eIF2B (eukaryotic initiation factor 2B) is a GEF (guanine nucleotide-exchange factor) that plays, with its substrate eIF2, a key regulatory role in the translation initiation phase of protein synthesis. The importance of correct control of eIF2 and eIF2B for normal physiology is underlined by the recent involvement of the five genes that encode the five eIF2B subunits in a severe autosomal recessive neurodegenerative disease, described in young children as CACH (childhood ataxia with central nervous system hypomyelination)/VWM (leukoencephalopathy with vanishing white matter) syndrome. The syndrome is characterized by episodes of rapid deterioration during febrile illnesses or following head trauma and symmetrical demyelination of the brain white matter with cavitation aspects, leading to a progressive vanishing of the white matter replaced by CSF (cerebrospinal fluid). However, a wide clinical spectrum has been observed in the 148 patients presently reported, from congenital forms with rapid death to adult-onset forms with slow mental decline and progressive motor dysfunction, sometimes associated with congenital eye abnormalities or ovariodysgenesis. So far, 77 different mutations in each of the five EIF2B genes (EIF2B1-5), encoding subunits eIF2Balpha-epsilon, have been found, with two-thirds affecting the eIF2Bepsilon subunit. The correlation found between the level of GEF activity of eIF2B in the mutated white blood cells and the age at disease onset suggests a direct role of the abnormal translation control in the pathophysiology of the disease.

Ataxia↗
PubMed2006

Golli-MBP copy number analysis by FISH, QMPSF and MAPH in 195 patients with hypomyelinating leukodystrophies.

The inherited disorders of CNS myelin formation represent a heterogeneous group of leukodystrophies. The proteolipoprotein (PLP1) gene has been implicated in two X-linked forms, Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2, and the gap junction protein alpha12 (GJA12) gene in a recessive form of PMD. The myelin basic protein (MBP) gene, which encodes the second most abundant CNS myelin protein after PLP1, presents rearrangements in hypomyelinating murine mutants and is always included in the minimal region deleted in 18q- patients with an abnormal hypomyelination pattern on cerebral MRI. In this study, we looked at the genomic copy number at the Golli-MBP locus in 195 patients with cerebral MRI suggesting a myelin defect, who do not have PLP1 mutation. Although preliminary results obtained by FISH suggested the duplication of Golli-MBP in 3 out of 10 patients, no abnormal gene quantification was found using Quantitative Multiplex PCR of Short Fluorescent fragments (QMPSF), Multiplex Amplifiable Probe Hybridization (MAPH), or another FISH protocol using directly-labelled probes. Pitfalls and interest in these different techniques to detect duplication events are emphasised. Finally, the study of this large cohort of patients suggests that Golli-MBP deletion or duplication is rarely involved in inherited defects of myelin formation.

DNA Primers↗
PubMed2005

An unusual familial chromosome 9 "variant" with variable phenotype: characterization by CGH analysis.

Heterochromatin confined to pericentromeric and secondary constriction regions plays a major role in morphological variation of chromosome 9, because of its size and affinity for pericentric inversion. We report on a 6-year-old boy with growth and language delay, minor facial anomalies and unusual chromosome 9 variant with an extra-band in the centromeric region on the conventional karyotype. Subsequent analysis by FISH and CGH identified this variant as a dicentric chromosome 9 with a duplication of the 9p12-q21 region. An identical chromosome 9 variant was found in the mild language retarded brother and in the phenotypically normal father and grandfather. The presumed mechanism accounting for the phenotypic discordance observed in this family and the usefulness of CGH in characterization of such variants are discussed. To our knowledge, this is the first investigation of an unusual chromosome 9 variant by CGH.

Child↗
PubMed2004

De novo interstitial direct duplication of Xq21.1q25 associated with skewed X-inactivation pattern.

Genotype-phenotype correlation in women with an abnormal phenotype associated with a duplication of the long arm of the X chromosome remains unclear. We report on prenatal diagnosis and follow-up of a girl with an Xq duplication and dysmorphic features. The abnormal phenotype included growth retardation, hypotonia, and nystagmus. In order to improve the resolution of the cytogenetic analysis, we used both conventional and array-based comparative genomic hybridization to perform a global molecular cytogenetic analysis of the genome. These molecular cytogenetic analyses showed a direct duplication Xq21.1 --> q25 without other chromosomal abnormalities. This duplication was originating from the paternal X chromosome. Moreover, a skewed X-inactivation pattern was observed leading to a partial functional disomy of the chromosomal region Xq21.1q25. This report and review of the literature suggest that functional disomy for chromosome X could explain the abnormal phenotype. In prenatal diagnosis, this can have implication for patient management and genetic counseling.

Base Sequence↗
PubMed2004

DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection.

Endometriosis, a common gynecological disorder that causes infertility and pelvic pain, is defined as the presence of endometrial glands and stroma within extra-uterine sites. However, despite extensive studies its etiology and pathogenesis are not completely understood. Differentially expressed genes were investigated in epithelial and stromal cells from deep endometriosis and matched eutopic endometrium using cDNA microarrays and laser capture microdissection. Validation of results of several up- and down-regulated genes was performed by quantitative real-time RT-PCR. Our data showed that platelet-derived growth factor receptor alpha (PDGFRA), protein kinase C beta1 (PKC beta1) and janus kinase 1 (JAK1) were upregulated, and Sprouty2 and mitogen-activated protein kinase kinase 7 (MKK7) were downregulated in endometriosis stromal cells, suggesting the involvement of the RAS/RAF/MAPK signaling pathway through PDGFRA in endometriosis pathophysiology. In addition, two potential negative regulators of aromatase expression, chicken ovalbumin upstream promoter transcription factor 2 (COUP-TF2) and prostaglandin E2 receptor subtype EP3 (PGE2EP3), were downregulated in endometriosis epithelial cells, which might result in increased local production of estrogen in endometriosis epithelial cells. Furthermore, three potential candidate genes that might be involved in endometriosis related pain were identified: tyrosine kinase receptor B (TRkB) in endometriosis epithelial cells, and serotonin transporter (5HTT) and mu opioid receptor (MOR) in endometriosis stromal cells were all upregulated. One of the candidate genes, MOR, may be involved in a defective immune system in endometriosis. This study has provided new insights into endometriosis pathophysiology.

Endometriosis↗
PubMed2004

The effect of genotype on the natural history of eIF2B-related leukodystrophies.

BACKGROUND: Recessive mutations in the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of variable age at onset and severity. OBJECTIVES: To evaluate the clinical spectrum of eIF2B-related disorders and search for a phenotype-genotype correlation. METHODS: Ninety-three individuals (78 families) with an undetermined leukodystrophy were selected on MRI-based criteria of childhood ataxia with central hypomyelination/vanishing white matter (CACH/VWM) for EIF2B genes analysis. RESULTS: Eighty-nine percent of individuals with MRI criteria of CACH/VWM have a mutation in one of the eIF2B beta to epsilon subunits. For 83 individuals (68 families), 46 distinct mutations (90% missense) in four of the five eIF2B subunits (beta, gamma, delta, epsilon) were identified. Sixty-four percent were in the epsilon subunit, a R113H substitution was found in 71% of eIF2B epsilon-mutated families. A large clinical spectrum was observed from rapidly fatal infantile to asymptomatic adult forms. Disease severity was correlated with age at onset (p < 0.0001) but not with the type of the mutated subunit nor with the position of the mutation within the protein. Mutations R113H in the epsilon subunit and E213G in the beta subunit were significantly associated with milder forms. CONCLUSIONS: The degree of eIF2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders.

Adolescent↗
PubMed2004

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.

Alleles↗
PubMed2004

Alexander disease: putative mechanisms of an astrocytic encephalopathy.

Alexander disease (AXD) is the first primary astrocytic disorder. This encephalopathy is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene, encoding the main intermediate filament of astrocyte. Pathologically, this neurodegenerative disease is characterised by dystrophic astrocytes containing intermediate filament aggregates associated with myelin abnormalities. More than 20 GFAP mutations have been reported. Many of them cluster in highly conserved regions between several intermediate filaments. Contrary to other intermediate filament-related diseases, AXD seems to be the consequence of a toxic gain of function induced by aggregates. This is supported by the phenotype of mice overexpressing human GFAP. Nevertheless, GFAP null mice display myelin abnormalities and blood-brain barrier dysfunction that are present in AXD. Given the pivotal role of astrocytes in brain physiology, there are many possibilities for astrocytes to dysfunction and to impair the functions of other cells. Physiopathological hypotheses are discussed in the frame of AXD.

Alexander Disease↗
PubMed2003

Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.

Reported are the clinical, neuroradiologic, and molecular findings in 18 patients with megalencephalic leukoencephalopathy and subcortical cysts (MLC) syndrome. Marked clinical intrafamilial and interfamilial variability in mutation-proven cases was found. A broad spectrum of pathogenetic mutations (missense, splice site, insertion, and deletions) were identified in the MLC1 gene, enlarging the spectrum of allelic variants without a straightforward genotype-phenotype correlation. Five patients did not harbor mutations in MLC1, supporting the existence of at least one other MLC locus.

Adolescent↗
PubMed2003

Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families.

OBJECTIVE: To report clinical, neuroradiologic, neurophysiologic, and genetic findings on 16 patients from 11 unrelated families with a remarkable uniform phenotype characterized by infantile ascending hereditary spastic paralysis (IAHSP). METHODS: Sixteen patients from 11 families, originating from North Africa and Europe, who presented severe spastic paralysis and ascending progression were studied. RESULTS: Spastic paraplegia started in the first 2 years of life in most patients and extended to the upper limbs by the end of the first decade. The disease progressed to tetraplegia, anarthria, dysphagia, and slow eye movements in the second decade. The clinical course showed a long survival and preservation of intellectual skills. Clinical, neuroradiologic, and neurophysiologic findings were consistent with a relatively selective early involvement of the corticospinal and corticobulbar pathways. No signs of lower motor neuron involvement were observed, whereas motor evoked potentials demonstrated predominant involvement of the upper motor neurons. MRI was normal in young patients but showed brain cortical atrophy in the oldest, predominant in the motor areas, and T2-weighted bilateral hyperintense signals in the posterior arm of the internal capsule. The ALS2 gene, recently found mutated in consanguineous Arabic families with either an ALS2 phenotype or a juvenile-onset primary lateral sclerosis, was analyzed. Alsin mutations were found in only 4 of the 10 families, whereas haplotype analysis excluded the ALS2 locus in one family. CONCLUSIONS: The syndrome of IAHSP is genetically heterogeneous, and no clinical sign can help to distinguish patients with and without Alsin mutations.

Adolescent↗
PubMed2002

A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation.

Childhood ataxia with central hypomyelination (CACH)/vanishing white matter (VWM) leukoencephalopathy is related to mutations in all five genes of the eukaryotic translation initiation factor (eIF2B). In a fatal infantile leukoencephalopathy, which the authors previously classified as a severe variant of CACH/VWM, a new homozygous missense mutation in the EIF2B5 gene was found. Abnormal decrease in blood uric acid and increase of erythrocyte guanosine 5'-diphosphate sugars found in two siblings may contribute to the explanation of this particularly severe condition.

Ataxia↗
PubMed2001

Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation.

Heterozygous, de novo mutations in the glial fibrillary acidic protein (GFAP) gene have recently been reported in 12 patients affected by neuropathologically proved Alexander disease. We searched for GFAP mutations in a series of patients who had heterogeneous clinical symptoms but were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. Missense, heterozygous, de novo GFAP mutations were found in exons 1 or 4 for 14 of the 15 patients analyzed, including patients without macrocephaly. Nine patients carried arginine mutations (four had R79H; four had R239C; and one had R239H) that have been described elsewhere, whereas the other five had one of four novel mutations, of which two affect arginine (2R88C and 1R88S) and two affect nonarginine residues (1L76F and 1N77Y). All mutations were located in the rod domain of GFAP, and there is a correlation between clinical severity and the affected amino acid. These results confirm that GFAP mutations are a reliable molecular marker for the diagnosis of infantile Alexander disease, and they also form a basis for the recommendation of GFAP analysis for prenatal diagnosis to detect potential cases of germinal mosaicism.

Adolescent↗
PubMed2001

Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27.

OBJECTIVE: To describe clinical and neuropathologic studies and linkage analysis on two sisters with a severe form of leukodystrophy. METHODS: A detailed study was performed on the second sister. Genotyping markers for chromosome 3, including eight additional markers surrounding the vanishing white matter (VWM) locus, were used. RESULTS: During the first year of life, two sisters developed a severe neurologic condition after an intercurrent infection. It was accompanied by irritability and stupor with rapid loss of their motor abilities. Results of extensive metabolic studies were negative. Brain MRI showed severe and diffuse abnormalities of the encephalic white matter. Neuropathologic examination showed a severe lack of myelin with diffuse vacuolating white matter lesions in the brain, associated with an increased density of oligodendrocytes and a reduced number of astrocytes on morphometric analysis. In sharp contrast, the spinal cord white matter was preserved. The affected sibpairs shared a common haplotype for a broad region in chromosome 3. They were homozygous between markers D3S1565 and D3S3669, including the VWM locus. CONCLUSIONS: This condition is an unusual variant of childhood ataxia with diffuse central hypomyelination (CACH)/VWM, with characteristic shrinking and perivascular clustering of astrocytes. Haplotype analysis suggests that this variant is allelic to the VWM locus located on chromosome 3q27.

Alleles↗
PubMed2001

The SOX10 transcription factor: evaluation as a candidate gene for central and peripheral hereditary myelin disorders.

The SOX10 transcription factor is involved in development of neural crest derivatives and fate determination in glial cells. SOX10 mutations have been found in patients with intestinal aganglionosis and depigmentation with deafness (Waardenburg-Hirschsprung). Associated neurological signs have been reported in some cases, including a patient exhibiting a central and peripheral myelin deficiency. Therefore, we screened for SOX10 mutations in a large cohort of patients with peripheral and central myelin disorders. 56 were affected by classical demyelinating Charcot-Marie-Tooth disease without identified mutations in the genes encoding PNS myelin proteins (PMP22, P0), connexin 32 and the zinc-finger transcription factor, EGR2. 88 patients with undetermined leukodystrophy were selected from a large European prospective study. Associated clinical, magnetic resonance imaging and electrophysiological signs were consistent with a defect in CNS myelination in 83 and with an active degeneration of the CNS myelin in 5. No abnormalities in the proteolipid protein gene (PLP) were found. The absence of SOX100 mutation in this large cohort of patients suggests that this gene is not frequently involved in peripheral or central inherited myelin disorders.

Charcot-Marie-Tooth Disease↗
PubMed2001

Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.

Alexander disease is a rare disorder of the central nervous system of unknown etiology. Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation, leading to death usually within the first decade; patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathological hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins. We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers. These results suggested that a primary alteration in GFAP may be responsible for Alexander disease. Sequence analysis of DNA samples from patients representing different Alexander disease phenotypes revealed that most cases are associated with non-conservative mutations in the coding region of GFAP. Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS.

Adolescent↗
PubMed2000

Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease.

Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central nervous system (CNS). They differ clinically in the onset and severity of the motor disability but both are allelic to the proteolipid protein gene (PLP), which encodes the principal protein components of CNS myelin, PLP and its spliced isoform, DM20. We investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by genomic PCR amplification and sequencing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, with a continuum between severe forms of PMD, without motor development, to pure forms of SPG. Clinical severity was found to be correlated with the nature of the mutation, suggesting a distinct strategy for detection of PLP point mutations between severe PMD, mild PMD and SPG. Single amino-acid changes in highly conserved regions of the DM20 protein caused the most severe forms of PMD. Substitutions of less conserved amino acids, truncations, absence of the protein and PLP-specific mutations caused the milder forms of PMD and SPG. Therefore, the interactions and stability of the mutated proteins has a major effect on the severity of PLP-related diseases.

Adolescent↗
PubMed1999

Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. The Clinical European Network on Brain Dysmyelinating Disease.

Pelizaeus-Merzbacher Disease (PMD) is an X-linked developmental defect of myelination affecting the central nervous system and segregating with the proteolipoprotein (PLP) locus. Investigating 82 strictly selected sporadic cases of PMD, we found PLP mutations in 77%; complete PLP-gene duplications were the most frequent abnormality (62%), whereas point mutations in coding or splice-site regions of the gene were involved less frequently (38%). We analyzed the maternal status of 56 cases to determine the origin of both types of PLP mutation, since this is relevant to genetic counseling. In the 22 point mutations, 68% of mothers were heterozygous for the mutation, a value identical to the two-thirds of carrier mothers that would be expected if there were an equal mutation rate in male and female germ cells. In sharp contrast, among the 34 duplicated cases, 91% of mothers were carriers, a value significantly (chi2=9. 20, P<.01) in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 9.3. Moreover, we observed the occurrence of de novo mutations between parental and grandparental generations in 17 three-generation families, which allowed a direct estimation of the k value (k=11). Again, a significant male mutation imbalance was observed only for the duplications. The mechanism responsible for this strong male bias in the duplications may involve an unequal sister chromatid exchange, since two deletion events, responsible for mild clinical manifestations, have been reported in PLP-related diseases.

Cystic Fibrosis Transmembrane Conductance Regulato↗