Biomedical subjects

Ignacio Sfaello

Publications and source records attributed to Ignacio Sfaello.

5 recordsLinked to original sources

PubMed2006

A new intronic mutation in the DPM1 gene is associated with a milder form of CDG Ie in two French siblings.

Congenital disorders of glycosylation (CDG) type I (CDG I) are rare autosomal recessive diseases caused by deficiencies in the assembly of the dolichol-linked oligosaccharide (DLO) that is required for N-glycoprotein biosynthesis. CDG Ie is due to a defect in the synthesis of dolichyl-phosphoryl-mannose (Dol-P-Man), which is needed for DLO biosynthesis as well as for other glycosylation pathways. Human Dol-P-Man synthase is a heterotrimeric complex composed of DPM1p, DPM2p, and DPM3p, with DPM1p being the catalytic subunit. Here, we report two new CDG Ie patients who present milder symptoms than the five other CDG Ie patients described to date. The clinical pictures of the patients MS and his sister MT are dominated by major ataxia, with no notable hepatic involvement. MS cells accumulate the immature DLO species Dol-PP-GlcNAc2Man5 and possess only residual Dol-P-Man synthase activity. One homozygous intronic mutation, g.IVS4-5T>A, was found in the DPM1 gene, leading to exon skipping and transcription of a shortened transcript. Moreover, DPM1 expression was reduced by more than 90% in MS cells, in a nonsense-mediated mRNA decay (NMD)-independent manner. Full analysis of the DPM2 and DPM3 genes revealed a decrease in DPM2 expression and normal expression of DPM3. This description emphasizes the large spectrum of symptoms characterizing CDG I patients.

Adolescent↗

PubMed2005

Topiramate prevents excitotoxic damage in the newborn rodent brain.

Brain lesions induced in newborn mice by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) and S-bromowillardiine (acting on AMPA-kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Topiramate (TPM), already used in children to manage newly diagnosed and refractory epilepsy, has potential neuroprotective effects that may be useful in human perinatal brain lesions. In the excitotoxic newborn mouse model, TPM provided dose-dependent and long-lasting protection of developing white matter and cortical plate against S-bromowillardiine. TPM had no significant effect on ibotenate-induced brain lesions. TPM-induced neuroprotection potentially involved increased survival of pre-oligodendrocytes, decreased neuronal apoptosis, inhibition of microglial activation and astrogliosis, and decreased seizure activity. Diazepam, phenytoin, and carbamazepine had no neuroprotective effect in this model. The present study provides experimental support for the consideration of TPM as a candidate therapy for excitotoxic perinatal brain lesions.

Alanine↗

PubMed2005

Autism severity and temporal lobe functional abnormalities.

Two independent studies have described bilateral temporal hypoperfusion in autistic children. Temporal regions are implicated in social perception, language, and "theory-of-mind," abilities that are impaired in autism. We investigated a putative relationship between cerebral blood flow (rCBF) measured at rest and clinical profile of 45 autistic children (Autism Diagnostic Interview-Revised [ADI-R] scores). A whole-brain covariance analysis was performed. Significant negative correlation was observed between rCBF and ADI-R score in the left superior temporal gyrus. The more severe the autistic syndrome, the more rCBF is low in this region, suggesting that left superior temporal hypoperfusion is related to autistic behavior severity.

Autistic Disorder↗

PubMed2004

Abnormal cortical voice processing in autism.

Impairments in social interaction are a key feature of autism and are associated with atypical social information processing. Here we report functional magnetic resonance imaging (fMRI) results showing that individuals with autism failed to activate superior temporal sulcus (STS) voice-selective regions in response to vocal sounds, whereas they showed a normal activation pattern in response to nonvocal sounds. These findings suggest abnormal cortical processing of socially relevant auditory information in autism.

Adult↗

PubMedDate not supplied

Patterns of excitotoxin-induced brain lesions in the newborn rabbit: a neuropathological and MRI correlation.

There is pressing need to employ new advances in structural MR brain imaging to better diagnose brain damage in newborn infants. Timely application of such technology will enable improved therapeutic interventions. Diffusion-weighted sequences are a sensitive marker of very early neuronal injury, the spatial pattern of which provides critical information regarding the underlying pathophysiology. We have modified our murine model of excitotoxic neonatal brain injury to the rabbit, an animal whose brain is larger and where the neuroanatomic organization of the subcortical white matter more closely resembles that of the human. Utilizing this rabbit model, we undertook an MRI/histopathologic correlation. We found that as with the mouse, there is a spatiotemporal selectivity to the pattern of brain injury, and that the period from postnatal day (P) 7 to P9 in rabbits corresponds to the time of maximum vulnerability of the brain to excitotoxic white matter damage, which neuropathologically simulates periventricular leukomalacia (PVL). We additionally noted that diffusion-weighted imaging provided the most sensitive means of detecting such lesions and that this method was sensitive to structural maturational changes accompanying the normal cortical ontogeny. Taken together, our findings suggest that this rabbit model of perinatal excitotoxic brain injury will be a valuable addition to experimental approaches to further our understanding of perinatal brain damage, that diffusion-weighted imaging will be an invaluable adjunct to the diagnosis of such injury, and that therapeutic strategies aimed at interrupting the evolution of PVL should include targeting the pathophysiologic cascade induced by excitotoxic neonatal brain injury.

Animals↗