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Biomedical subjects

A Gelot

Publications and source records attributed to A Gelot.

At least 19 recordsLinked to original sources
PubMed2003

Perinatal-lethal Gaucher disease.

Gaucher disease is a lysosomal storage disease caused by glucocerebrosidase deficiency. Although purely visceral in most cases, some Gaucher disease patients have neurological signs. Signs of Gaucher disease appear after a symptom-free period, except in rare cases with fetal onset. The description of such cases was based mainly on single reports and siblings. We report here a series of perinatal-lethal Gaucher disease cases highlighting the specificity of this phenotype. We retrospectively studied eight original cases of proven Gaucher disease with fetal onset. Non-immune hydrops fetalis was present in all cases but one, and associated with hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphy. The similarities between our cases and 33 previously described cases allow us to better delineate the perinatal-lethal Gaucher disease phenotype. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurological involvement begins in the first week and leads to death within three months. Hepatosplenomegaly is a major sign, and associated with ichthyosis, arthrogryposis, and facial dysmorphy in some 35-43% of cases. Perinatal-lethal Gaucher disease is a specific entity defined by its particular course and signs that are absent in classical type 2 Gaucher disease. Our study provides clues to the diagnosis of this likely underdiagnosed condition, which must be biochemically confirmed in order to propose appropriate genetic counselling.

DNA Mutational Analysis↗
PubMed2003

Widespread distribution of beta-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol.

Sandhoff disease is a severe inherited neurodegenerative disorder resulting from deficiency of the beta-subunit of hexosaminidases A and B, lysosomal hydrolases involved in the degradation of G(M2) ganglioside and related metabolites. Currently, there is no viable treatment for the disease. Here, we show that adenovirus-mediated transfer of the beta-subunit of beta-hexosaminidase restored Hex A and Hex B activity after infection of Sandhoff fibroblasts. Gene transfer following intracerebral injection in a murine model of Sandhoff disease resulted in near-normal level of enzymatic activity in the entire brain at the different doses tested. The addition of hyperosmotic concentrations of mannitol to the adenoviral vector resulted in an enhancement of vector diffusion in the injected hemisphere. Adenoviral-induced lesions were found in brains injected with a high dose of the vector, but were not detected in brains injected with 100-fold lower doses, even in the presence of mannitol. Our data underline the advantage of the adjunction of mannitol to low doses of the adenoviral vector, allowing a high and diffuse transduction efficiency without viral cytotoxicity.

Adenoviridae↗
PubMed2002

[Management of the dead fetus' body during the pre-or perinatal period: fetal pathologist or fetal physician?].

What's about a practitian that have to care a non-existent and still dead patient? What's about a patient that only exists through pictures and pathology? What's about the expectation of the parents and medical team when the questions are mainly restricted to the cause of the death? Responses to these questions represent the aim of this paper that tries to delineate the ambiguity that exists between the facts and their consequences.

Autopsy↗
PubMed2002

Magnetic resonance imaging of the fetal brain.

US remains the key imaging technique for prenatal screening of CNS pathology. However, MR imaging of the fetal brain is a powerful tool to further characterize CNS anomalies, especially during the third trimester. The prognosis of CNS anomalies detected at fetal MR imaging is not always known. As such, management may be problematic with regards to medical interruption of pregnancy. A multidisciplinary approach is essential in order to insure comprehensive evaluation and management of the pregnancy.

Brain↗
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↗
PubMed1999

Cerebellar atrophy: an important feature of carbohydrate deficient glycoprotein syndrome type 1.

We report three children, all younger than 2 years of age, presenting with cerebellar atrophy related to carbohydrate-deficient glycoprotein syndrome type 1, an autosomal recessive metabolic disease. One patient had multisystem disease; two others had mental retardation with ataxia. In all cases the cerebellar atrophy was diagnosed on magnetic resonance imaging and, in one case, confirmed by autopsy. The cerebellar atrophy predominantly affected the anterior lobe. Vertical orientation of the tentorium cerebelli from the neonatal period in two cases suggests antenatal onset of the disease. Biological tests confirmed the diagnosis in all cases.

Atrophy↗
PubMed1999

Increased density of oligodendrocytes in childhood ataxia with diffuse central hypomyelination (CACH) syndrome: neuropathological and biochemical study of two cases.

We report neuropathological, biochemical and molecular studies on two patients with childhood ataxia with diffuse central nervous system hypomyelination (CACH) syndrome, a leukodystrophy recently defined according to clinical and radiological criteria. Both had severe cavitating orthochromatic leukodystrophy without atrophy, predominating in hemispheric white matter, whereas U-fibers, internal capsule, corpus callosum, anterior commissure and cerebellar white matter were relatively spared. The severity of white matter lesions contrasted with the rarity of myelin breakdown products and astroglial and microglial reactions. In the white matter, there was an increase in a homogeneous cell population with the morphological features of oligodendrocytes, in many instances presenting an abundant cytoplasm like myelination glia. These cells were negative for glial fibrillary acidic protein and antibodies PGM1 and MIB1. Some were positive for myelin basic protein, proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein, but the majority were positive for human 2'-3' cyclic nucleotide 3' phosphodiesterase and all were positive for carbonic anhydrase II, confirming that they are oligodendrocytes. Myelin protein and lipid content were reduced. The PLP gene, analyzed in one case, was not mutated or duplicated. The increased number of oligodendrocytes without mitotic activity suggests an intrinsic oligodendroglial defect or an abnormal interaction with axons or other glial cells. This neuropathological study supports the notion that CACH syndrome constitutes a specific entity.

Ataxia↗
PubMed1998

Anti-opioid efficacy of neuropeptide FF in morphine-tolerant mice.

The modulatory effects of 1DMe (d-Tyr-Leu-(NMe)Phe-Gln-Pro-Gln-Arg-Phe-NH2), an agonist of Neuropeptide FF (NPFF) receptors, on opioid antinociceptive activity have been compared in naive and tolerant mice in the tail-flick and the hot-plate tests. In naive mice, 1DMe alone had no effect on pain threshold but decreased dose-dependently (3-22 nmol) the analgesic activity of morphine in both tests. In tolerant mice, injections of 60-fold lower doses of 1DMe (0.05-0.5 nmol) reverse morphine-induced analgesia in the tail-flick test but this anti-opioid effect was no longer observed with the highest doses of 1DMe tested (3-22 nmol). In the hot-plate test, the anti-opioid action of 1DMe was not detected, whatever doses tested. Neither the NPFF-like immunoreactivity content of spinal cord and of olfactory bulbs, nor the density of NPFF receptors in olfactory bulbs, were altered. These results indicate that a chronic morphine treatment modifies the pharmacological properties of NPFF but the type of pain test is crucial in determining NPFF effects.

Animals↗
PubMed1998

Antisense oligonucleotides to human SQA-neuropeptide FF decrease morphine tolerance and dependence in mice.

Neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) is able to modulate opioid analgesia. Intracerebroventricular treatment for 5 days with antisense-oligodeoxynucleotides complementary to the sequence of human SQA-neuropeptide FF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) precursor gene or by mismatch-oligodeoxynucleotides did not change the antinociceptive activity of morphine in the mouse tail flick test. In contrast, antisense- but not mismatch-oligodeoxynucleotides attenuated significantly the tolerance to the analgesic activity of morphine and the withdrawal syndrome precipitated by naloxone in morphine-treated mice. These treatments with oligodeoxynucleotides did not modify neuropeptide FF-immunoreactivity content in whole brain but repeated injections of an agonist of neuropeptide FF receptors increased the intensity of morphine tolerance. These results demonstrate the important role of neuropeptide FF in opioid pharmacodependence.

Amino Acid Sequence↗
PubMed1998

Biochemical, cellular and pharmacological activities of a human neuropeptide FF-related peptide.

We report on the biochemical, cellular and pharmacological activities of SQA-neuropeptide FF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2), a peptide sequence contained in the human neuropeptide FF (neuropeptide FF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) precursor. Quantitative autoradiography revealed that, in the superficial layers of the rat spinal cord, SQA-neuropeptide FF displayed the same high affinity for [125I]1DMe ([125I]D-Tyr-Leu-(NMe)Phe-Gln-Pro-Gln-Arg-Phe-NH2) binding sites (Ki = 0.33 nM) as did neuropeptide FF (Ki = 0.38 nM). In acutely dissociated mouse dorsal root ganglion neurones, SQA-neuropeptide FF reduced by 40% the depolarisation-induced rise in intracellular Ca2+ as measured with the Ca2+ indicator, Fluo-3. In mice, 1DMe and SQA-neuropeptide FF dose-dependently inhibited the antinociceptive effect of intracerebroventricular (i.c.v.) injections of morphine, but SQA-neuropeptide FF was less potent than 1DMe. Furthermore, SQA-neuropeptide FF, as well as 1DMe, produced marked hypothermia following third ventricle injections in mice. These data demonstrate that the human peptide, SQA-neuropeptide FF, exhibits biochemical and pharmacological properties similar to those of neuropeptide FF or neuropeptide FF analogues, and belongs to the neuropeptide FF family.

Analgesics, Opioid↗
PubMed1998

A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome.

X-SCLH/LIS syndrome is a neuronal migration disorder with disruption of the six-layered neocortex. It consists of subcortical laminar heterotopia (SCLH, band heterotopia, or double cortex) in females and lissencephaly (LIS) in males, leading to epilepsy and cognitive impairment. We report the characterization of a novel CNS gene encoding a 40 kDa predicted protein that we named Doublecortin and the identification of mutations in four unrelated X-SCLH/LIS cases. The predicted protein shares significant homology with the N-terminal segment of a protein containing a protein kinase domain at its C-terminal part. This novel gene is highly expressed during brain development, mainly in fetal neurons including precursors. The complete disorganization observed in lissencephaly and heterotopia thus seems to reflect a failure of early events associated with neuron dispersion.

Adolescent↗
PubMed1998

In vivo diagnosis of Kufs' disease by extracerebral biopsies.

In almost all of the earlier reported cases of Kufs' disease, the adult form of ceroid lipofuscinosis, the diagnosis was ascertained by cerebral tissue examination, while peripheral biopsy examination revealed an apparent poor diffusion of specific lipofuscinic deposits, the finger print profiles (FPs). We report the ultrastructural data from skin, muscle and rectal biopsy specimens from two siblings, both still living, who present clinical features of Kufs' disease. We observed the presence of FPs in locations that differ from the previous classic reports. Our results emphasize the value of extracerebral biopsies for the diagnosis of Kufs' disease in vivo, and suggest some physiopathological assumptions based on vascular wall involvement.

Adult↗
PubMed1998

[Histogenesis of the corpus callosum].

The corpus callosum results from neocortical commissural axon fasciculation. Its development reflects the interhemispheric circuitry and then follows the successive steps of synaptogenesis. The first stage consists of callosal neuron differentiation, which allows the extention of the future callosal axon; this is an early event that occurs while neuronal migration to the cortical plate is still ongoing. Callosal axon guidance towards its specific target is the second step which includes reaching and crossing the midline and further target recognition with formation of initial synapses. This period extends from 12 to 22 post-conceptional weeks and corresponds to the following histological features: i) progressive invasion by callosal growth cones of the dorsal part of lamina reuniens through a preformed glial pathway; ii) appearence of the three parts of corpus callosum, namely truncus, rostrum and lastly the splenium. Both these stages are genetically controlled either directly by developmental gene expression (neurogenesis genes) or indirectly by the establishment of cue maps (spatial expression of extra-cellular matrix proteins). The third step is that of synapse remodeling by synaptic activity, giving rise to axonal elimination, macroscopically revealed by a transitory thinning of corpus callosum. This perinatal event contributes to the corpus callosum acquiring a mature topography. Finally, analysis of corpus callosum ontogenesis appears as a striking model of synaptogenesis study and provides physiopathological assumptions for a understanding of the corpus callosum agenesis.

Animals↗
PubMed1998

[Agenesis of the corpus callosum. Neuropathologic study and physiopathologic hypotheses].

The neuropathological study of corpus callosum agenesis requires a two-phase approach: first it should analyze the putative causal factors, i.e. absence of callosal neurons, commissuration inability or synapse remodelling defect; secondly it has to detect any morphogenetic effects stemming from the absence of commissure such as nonregression of archicortical structures, ventricular enlargement or possible invasion of the remaining telencephaplic commissure by callosal neurons. Absence of callosal neurons due to abnormal corticogenesis gives rise to corpus callosum agenesis without callosal axon, that is without Probst's bundles. Conversely, corpus callosum agenesis occurring secondary to a commissuration default is associated with the presence of callosal axons which travel along the midline instead of crossing, that leads to the formation of Probst's bundles. This inability to cross the midline could be secondary to an obstacle, such as lipoma or as interhemispheric cysts, or primitive due to axonal guidance disturbance. In the latter situation, the commissural defect could affect the other cerebral commissures i.e. anterior or hippocampal commissures, or could become integrated into a more diffuse midline pathology involving both cerebral and extracerebral structures. Finally, it could be assumed that a synapse remodelling defect could lead to atrophy or hypertrophy of the commissure, that occurs in the absence of white matter pathology.

Agenesis of Corpus Callosum↗
PubMed1997

[Prenatal MRI of the brain. Retrospective study apropos of 34 tests].

We performed 34 antenatal MRI, in utero in 29 foetuses with cerebral malformations depicted by US. For five patients, a second antenatal MRI was performed because of a technical failure or of diagnosis doubt. We considered that MRI is a valuable imaging method. We have observed 2 false negatives (myelomeningocele, gyration abnormality) on MR study (n = 34). MRI is more contributive that US for the etiological diagnosis of ventricular enlargement: 83% versus 46%. MRI depicted corpus callosum agenesis misdiagnosed in 5 patients by US. MR results modified the therapeutic procedure in 37% of our patients. We think that the optimal term to perform MRI study is after 28 weeks gestational age because of the size of the fetus and for the timing of cerebral development. Ventricular dilatation (criteria: occipital horn size more that one centimeter at 25 weeks of term) is the main indication of MR study.

Brain↗
PubMed1996

Alpha-brain spectrin mRNA belongs to the population of intradendritically transported mRNAs.

Brain spectrin is a cytoskeletal protein involved in neuronal polarization and differentiation. We have studied the intraneuronal expression of non-erythroid (NE) alpha-spectrin mRNA in the rat brain during the development of the CA3 pyramidal cells, and compared it with alpha-tubulin mRNA expression. In contrast to alpha-tubulin expression, which remains located in the neuronal somata, NE alpha-spectrin mRNA was present in the dendritic compartment during the first 2 weeks of life. NE alpha-Brain spectrin mRNA transport into the dendrites coincides with critical development events, including dendritic arborization, growth and synaptogenesis, and could be dependent on the appearance of synaptic activity at the mossy fibre/CA3 synapse.

Animals↗
PubMed1996

[MRI and computer-assisted tomography in Kufs disease. Apropos of a familial form].

Kufs disease is the adult form of ceroid neurolipofuscinosis, and an uncommon cause of degenerative nervous system disease affecting young adults. We present here 4 cases of family form revealed by a demential syndrome. In all 4 patients MRI showed diffuse cortical atrophy predominant in the parietal regions. In 3 of these 4 patients MRI also exhibited a low signal in T2-weighted sequences on the putamens. There was no abnormality of the white matter. Diagnosis was made by cerebral biopsy in one case and by rectal biopsy in all other cases. Although the MRI images are not specific, they must be used when the diagnosis of Kufs disease is suspected in young patients with demential syndrome.

Adult↗