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Biomedical subjects

C Denier

Publications and source records attributed to C Denier.

At least 19 recordsLinked to original sources
PubMed2006

Spectrum and prognosis of neurologic complications after hematopoietic transplantation.

OBJECTIVE: To describe the neurologic complications after hematopoietic progenitor cell transplantation (HPCT) in order to design rules for their management. METHODS: We reviewed 361 consecutive patients over 6 years, including 245 autologous and 116 allogeneic HPCT recipients for hematologic malignancies (87%) and solid cancers (13%). RESULTS: Fifty-seven patients developed 65 symptomatic neurologic complications (16%), with a higher incidence in allogeneic than in autologous HPCT recipients (p = 0.01) and in chronic myelogenous leukemia (42%) than in Hodgkin disease (2.5%) (p < 0.001). CNS infections (4.2%) were the main complications, marked by an early onset (within the first 4 months) after HPCT (87%), diagnostic difficulties, and a high mortality rate (47%). They mainly included cerebral toxoplasmosis, fungal infections, and viral encephalitis. Their incidence was markedly higher in allogeneic than in autologous HPCT recipients (p = 0.002). However, two CD34(+) selected autologous HPCT recipients developed cerebral toxoplasmosis. Other CNS complications included recurrent tumors (3.6%), metabolic encephalopathies (2.8%), and cerebrovascular events (1.7%). Seizures occurred in 5% of patients, most often associated with cerebral lesions. Peripheral nervous system manifestations occurred in 3.3%. Twenty-one patients (5.8%) died directly of neurologic complications. The 4-year probability of survival was markedly lower in the case of neurologic events than in the absence thereof (12% vs 58%, p < 0.0001). CONCLUSIONS: Severe neurologic complications after hematopoietic progenitor cell transplantations are common, vary according to the underlying disease and type of transplantation, and are associated with poor survival rates. Better prophylactic protocols and therapy for CNS infections are required in future studies.

Adolescent↗
PubMed2006

[Diffusion tensor imaging and tractography of central pontine myelinolysis].

OBJECTIVES: To illustrate the value of diffusion tensor imaging and tractography in the diagnosis and follow-up of central pontine myelinolysis. CASE REPORT: We report a case of central pontine myelinolysis in a 29 year old woman, also anorexic, studied using MR Diffusion Tensor Imaging (DTI) and Fibre Tracking (FT) focused on the pons, and compared with the studies of 5 normal volunteers. Tractography showed a swollen aspect of the right corticospinal fiber tract correlating with mild left lower extremity deficit at clinical evaluation. The pontine fibers were posteriorly displaced but intact. The sensory tracts were also intact. Apparent Diffusion Coefficient values were increased and Fractional Anisotropy was decreased in the lesions. Follow up imaging showed persistent abnormal ADC and FA values in the pons although the left cortico-spinal tract returned to normal, consistent with the clinical outcome. CONCLUSION: Diffusion Tensor Imaging MR and Fiber tractography are a new method to analyse white matter tracts. It can be used to prospectively evaluate the location of white matter tract lesions at the acute phase of central pontine myelinolysis and follow up.

Adult↗
PubMed2004

Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and cerebral hemorrhages, which can result in focal neurological deficits. Three CCM loci have been mapped, and loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607 (CCM2) genes. We report herein the identification of PDCD10 (programmed cell death 10) as the CCM3 gene. The CCM3 locus has been previously mapped to 3q26-27 within a 22-cM interval that is bracketed by D3S1763 and D3S1262. We hypothesized that genomic deletions might occur at the CCM3 locus, as reported previously to occur at the CCM2 locus. Through high-density microsatellite genotyping of 20 families, we identified, in one family, null alleles that resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and D3S1614. This de novo deletion encompassed D3S1763, which strongly suggests that the CCM3 gene lies within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional distinct deleterious mutations within PDCD10, one of the five known genes mapped within this interval, were identified in seven families. Three of these mutations were nonsense mutations, and two led to an aberrant splicing of exon 9, with a frameshift and a longer open reading frame within exon 10. The last of the six mutations led to an aberrant splicing of exon 5, without frameshift. Three of these mutations occurred de novo. All of them cosegregated with the disease in the families and were not observed in 200 control chromosomes. PDCD10, also called "TFAR15," had been initially identified through a screening for genes differentially expressed during the induction of apoptosis in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and invertebrates. Its implication in cerebral cavernous malformations strongly suggests that it is a new player in vascular morphogenesis and/or remodeling.

Apoptosis Regulatory Proteins↗
PubMed2004

Mutations within the MGC4607 gene cause cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.

Female↗
PubMed2004

Inhibition of both Trypanosoma brucei bloodstream form and related glycolytic enzymes by a new kolavic acid derivative isolated from Entada abyssinica.

A new kolavic acid derivative known from spectroscopic analyses as monomethyl ester-15-kolavic acid was isolated from the stem bark of Entada abyssinica, a plant traditionally used in West and East Africa for the management of sleeping sickness. The new derivative showed a strong and selective inhibitory activity on the GAPDH enzyme of Trypanosoma brucei with an IC50 value of 0.012 mM.

Animals↗
PubMed2002

Krit1/cerebral cavernous malformation 1 mRNA is preferentially expressed in neurons and epithelial cells in embryo and adult.

Cavernous malformations are capillaro-venous lesions mostly located within the central nervous system (CCM/OMIM#116860) and occasionally within the skin and/or retina. They occur as a sporadic or hereditary condition. Three CCM loci have been mapped, and the sole gene identified so far, CCM1, has been shown to encode KRIT1, a protein of unknown function. In an attempt to get some insight on the relationship between KRIT1 mutations and CCM lesions, we investigated Krit1 mRNA expression during mouse development from E7.5 to E20.5 and in adult tissues, of both mouse and human origin. A ubiquitous Krit1 mRNA expression was detected from E7.5 up to E9.5. Then, it became progressively restricted from E10.5 to E12.5, to become detectable later essentially in the nervous system and various epithelia. Strong labelling was observed in neurons in the brain, cerebellum, spinal cord, retina and dorsal root ganglia. In epithelia, Krit1 mRNA expression was detected in differentiating epidermal, digestive, respiratory, uterine and urinary epithelia. A similar pattern of expression persisted in mouse and man adult nervous system and epithelia. Unexpectedly, in vascular tissues, expression of Krit1 was detected only in large blood vessels of the embryo.

Adult↗
PubMed2002

Modified berberine and protoberberines from Enantia chlorantha as potential inhibitors of Trypanosoma brucei.

Phytochemical study of the stem bark of Enantia chlorantha resulted in the isolation of two protoberberines 1 and 2. These alkaloids as well as commercially available berberine were modified chemically and tested in vitro against Typanosoma brucei proliferation as well as on three targeted glycolytic enzymes. The inhibitory activities observed were in the range of 20 microM (ED50 values).

Animals↗
PubMed2001

The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.

BACKGROUND: Familial hemiplegic migraine, an autosomal dominant disorder characterized by attacks of transient hemiparesis followed by a migraine headache, is classically divided into pure familial hemiplegic migraine (affecting 80 percent of families) and familial hemiplegic migraine with permanent cerebellar signs (affecting 20 percent of families). Mutations in CACNA1A, which encodes a neuronal calcium channel, are present in 50 percent of families with hemiplegic migraine, including all those with cerebellar signs. We studied the various clinical manifestations associated with mutations in CACNA1A in families with hemiplegic migraine with and without cerebellar signs. METHODS: CACNA1A was analyzed and nine mutations were detected in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. Genotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. RESULTS: Eighty-nine percent of the subjects with mutations had attacks of hemiplegic migraine. One third had severe attacks with coma, prolonged hemiplegia, or both, with full recovery. All nine mutations, including five newly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83 percent of the subjects with these six mutations had nystagmus, ataxia, or both. Three mutations were associated with pure hemiplegic migraine. CONCLUSIONS: Hemiplegic migraine in subjects with mutations in CACNA1A has a broad clinical spectrum. This clinical variability is partially associated with the various types of mutations.

Age of Onset↗
PubMed2001

Missense CACNA1A mutation causing episodic ataxia type 2.

OBJECTIVES: To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. BACKGROUND: Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the alpha1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. METHODS: All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. RESULTS: A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. CONCLUSIONS: The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.

Calcium Channels↗
PubMed2001

Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease?

We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examination was performed in one patient and molecular analysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1-2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This late-onset paroxysmal cerebellar ataxia with neuropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process.

Acetazolamide↗
PubMed2001

[Cerebral glioblastomas and systemic metastases].

Glioblastomas are highly malignant but locally invasive tumors. In only rare instances do extra-neural metastasis occur. We report herein 2 cases of such dissemination occurring 9 and 15 month after the initial diagnosis and treatment of supratentorial gliomas. Metastasis involved the lung, the kidney and the liver in one case and the bones in the other case. Both patients died within 3 month after diagnosis of the systemic metastasis despite chemotherapy.

Bone Neoplasms↗
PubMed2000

CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy.

Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, including all families with cerebellar ataxia. A patient with healthy parents, who experienced prolonged attacks of migraine with hemiplegia, coma, and seizures, is reported. The patient also had mental retardation, permanent cerebellar ataxia with cerebellar atrophy, and right-sided brain atrophy. This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations.

Adult↗
PubMed2000

Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene.

We report a reversible reduction of water diffusion in the brain during a prolonged attack of hemiplegic migraine. The patient had a sporadic mutation of the CACNA1A gene. The diffusion changes were observed in the contralateral hemisphere 3 and 5 weeks after the onset of hemiplegia. These results suggest the occurrence of hemispheric cytotoxic edema during severe attacks of hemiplegic aura. The mechanisms underlying such ultrastructural modifications are unknown but an abnormal release of excitatory amino acids can be hypothesized.

Adult↗
PubMed2000

Lower alkaline phosphatase activity and occurrence of an abnormal hybrid intestinal/tissue non-specific isoform in Down's syndrome amniotic fluids.

Quantitative and qualitative analysis of alkaline phosphatases (AP) was performed on amniotic fluid in 59 normal pregnancies and 14 Down's syndrome (DS) pregnancies at 16, 18 and 19 weeks of gestation. In DS cases, intestinal and placental isoenzyme levels were significantly reduced (P<0.001) and the AP electrophoretic pattern was seen to be modified on polyacrylamide gel electrophoresis. A unique component was detected. After extraction and purification of the abnormal isoenzyme, peptide fragments obtained after cyanogen bromide cleavage indicated a hybrid heterodimeric AP composed of intestinal and tissue non-specific subunits, as evaluated by SDS polyacrylamide gel electrophoresis.

Adult↗
PubMed1999

High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).

Adolescent↗