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Biomedical subjects

Laura Flores-Sarnat

Publications and source records attributed to Laura Flores-Sarnat.

17 recordsLinked to original sources
PubMed2006

Cerebral palsy due to chromosomal anomalies and continuous gene syndromes.

When cerebral palsy is defined as a disorder of movement and posture that is due to nonprogressive disturbances that occur in the developing fetal and infant brain, a significant proportion-up to 10%--is the consequence of chromosomal anomalies and continuous gene syndromes. Abnormalities of chromosomes are constitutional or acquired. Acquired chromosomal abnormalities develop postnatally, affect only one clone of cells, and are implicated in the evolution of neoplasia. Constitutional abnormalities develop during gametogenesis or early embryogenesis and affect a significant portion of the subject's cells.

Cerebral Palsy↗
PubMed2006

Population meta-analysis of low plasma glucose thresholds in full-term normal newborns.

There is extreme variation in the definition of low plasma glucose levels in newborn infants in the first postnatal days, ranging from < 30 to < or = 60 mg/dL. The goal of the present study was to define low thresholds (< or = 5th percentile) of plasma glucose concentrations in full-term normal newborns during the first 72 hours of life. Population meta-analysis was performed on published studies of neonatal hypoglycemia ascertained by MedLine search. One-way analysis of variance was computed across the studies for each of the following four postnatal time periods: 1 to 2 (physiological nadir), 3 to 23, 24 to 47, and 48 to 72 hours. The estimated < or = 5th percentiles of neonatal hypoglycemia during 1 to 2, 3 to 23, 24 to 47, and 48 to 72 hours after birth were < or = 28, < or = 40, < or = 41, and < or = 48 mg/dL, respectively. Based on this statistical definition, we recommend that low thresholds of plasma glucose levels of 28, 40, and 48 mg/dL be adopted in full-term normal newborns at 1 to 2, 3 to 47, and 48 to 72 hours of life, respectively.

Analysis of Variance↗
PubMed2006

Deletion of chromosome 21 disturbs human brain morphogenesis.

PURPOSE: Humans with small deletions of chromosome 21 provide important models for understanding the role of dosage-sensitive genes in brain morphogenesis. To identify chromosome 21 genes responsible for defects of the central nervous system, we determined the deleted regions and brain malformations in three unrelated individuals with overlapping partial deletions of chromosome 21. METHODS: Fluorescent in situ hybridization and magnetic resonance imaging were used to define the chromosomal structure and structural brain abnormalities present in these three individuals. RESULTS: The regions of chromosome 21 found to be deleted in these individuals were as follows: case 1: KCNJ6 to the telomere; case 2: ITSN1 to the telomere; and case 3: ITSN1 to PCNT2. The abnormalities of brain structure shared by all included microcephaly, pachygyria, polymicrogyria, colpocephaly, hypoplastic corpus callosum and white matter, hypoplastic cerebellum, and enlarged ventricular system. The clinical features in common included mental retardation, microcephaly, facial dysmorphism, and epilepsy (severe in one patient). CONCLUSION: From analyses of the molecular, cytogenetic, and neuroimaging data from these three individuals, combined with those from previously reported cases, we infer that deletion of an 8.4-Mb region in chromosome band 21q22.2-22.3 (KCNJ6-COL6A2) is associated with cortical dysplasia. We propose that one or more dosage-sensitive genes in this region contributes to cortical development and that deletion of 21q22.2-22.3 should be considered in the diagnosis of mentally retarded patients with facial dysmorphism and cerebral dysplasia.

Adolescent↗
PubMed2006

Plasma glucose concentrations in profound neonatal hypoglycemia.

The study goal was to define low thresholds of plasma glucose concentrations that constitute profound hypoglycemia. Population analysis was performed on research publications on neonatal hypoglycemia ascertained by a Medline search. Eligible patients had neurological sequelae associated directly and primarily with hypoglycemia (profound hypoglycemia). Of 89 infants, more than 95% had plasma glucose levels of less than 25 mg/dL that were first detected at more than 10 hours of age. A breakdown of study patients according to those with or without neurological sequelae, who were exposed to a similar degree of hypoglycemia, showed a combined incidence of neurological injury of 21%, with 95% confidence interval from 14% to 27%.

Blood Glucose↗
PubMed2005

Embryology of the neural crest: its inductive role in the neurocutaneous syndromes.

Neural crest cells are first recognized at the lateral margin of the neural placode shortly after gastrulation, although they are not committed to their diverse fates until later. After dorsal closure of the neural tube, neural crest cells separate and migrate throughout the embryo to form many structures of ectodermal origin (eg, dorsal root and autonomic ganglia, peripheral nerve sheaths) and mesodermal origin (eg, blood vessels, melanocytes, adipose tissue, membranous bone, connective tissue, most of the ocular globe). Terminal differentiation occurs after migration is complete. Three regions of the neural tube generate neural crest: rhombencephalon, mesencephalon, and prosencephalon, each with a different migratory pattern. The most important genes promoting neural crest differentiation and migration are those with a dorsalizing influence in the vertical axis of the neural tube (eg, PAX3, BMP4, ZIC2), some segmentation genes (eg, WNT1), genes that inhibit neural crest (eg, EGR2), and neural crest-specific differentiating genes (eg, SLUG, SOX10). In the neurocutaneous syndromes, diverse features result from abnormal neural crest differentiation, providing a more encompassing embryologic basis for these disorders than the traditional view that these syndromes are somehow related to skin and brain because both are ectodermal derivatives. Abnormal angiogenesis, areas of abnormal pigmentation that sometimes follow the lines of Blashko, nerve sheath proliferations, disorders of chromaffin tissue, lipomes and benign and malignant tumors are frequent features. Many defective genes in neurocutaneous syndromes have an additional function as tumor suppressors. Interactions between genes associated with these disorders and others essential to neural crest formation, migration, and differentiation, are a likely molecular genetic basis for these diseases. The craniofacial abnormalities associated with many cerebral malformations and cutaneous lesions in some neurocutaneous syndromes emphasize an important inductive role of the neural tube in the development of non-neural tissues, mediated through neural crest.

Cell Differentiation↗
PubMed2005

Neurologic aspects of neonatal hypoglycemia.

Profound neonatal hypoglycemia is one of the leading causes of brain injury. Hypoglycemic encephalopathy is caused by lack of glucose availability to brain cells. Although sharing a similar pathogenesis with hypoxic-ischemic encephalopathy, hypoglycemic brain insult has distinctive metabolic, brain imaging, electroencephalographic and histopathologic findings.

Brain Diseases↗
PubMed2004

Integrative classification of morphology and molecular genetics in central nervous system malformations.

We propose a scheme to classify central nervous system (CNS) malformations that integrates morphology and genetics by using patterns of genetic expression as its basis. The precise genetic mutations are not necessary to know in all cases. The premises of this classification are (1) genetic expression in the neural tube follows gradients in the axes that are established at the time of gastrulation: vertical (dorsoventral and ventrodorsal); rostrocaudal; mediolateral. (2) Overexpression in one of these gradients generally results in duplication or hyperplasia of structures, or ectopic segmental (i.e., neuromeric) expression. (3) Underexpression in a gradient generally results in hypoplasia, noncleavage in the midline of paired structures or segmental deletion of neuromeres. These gradients may also affect the formation and migration of neural crest tissue, affecting non-neural structures such as the face in the case of the mesencephalic neural crest, or induction of paraxial mesodermal in the posterior fossa. Additional criteria of the new classification allow for other genetic influences on developmental processes, such as cellular lineage, exemplified by tuberous sclerosis, and hemimegalencephaly. It is essential that the CNS be considered as a whole and classification not be regionalized, as to the cerebral cortex, because the limit of the rostrocaudal gradient may account for variability in clinical manifestations.

Central Nervous System↗
PubMed2003

Hemimegalencephaly: part 2. Neuropathology suggests a disorder of cellular lineage.

Cerebral tissue from hemispherectomy in three children (two 4-month-old girls and one 4-year-old boy) with hemimegalencephaly was studied using histochemical and immunocytochemical markers of neuronal and glial maturation and identity. Histologic abnormalities of cellular growth and cytomorphology, including "balloon cells," were present in both gray and white matter, in addition to disorganized tissue architecture. Cells in the mitotic cycle were absent. Many hypertrophic, atypical cells with enlarged processes exhibited mixed or ambiguous lineage, with immunoreactivity for both glial (glial fibrillary acidic protein [GFAP]; S-100beta) and neuronal proteins (microtubule-associated protein 2 [MAP2], neuronal nuclear antigen, chromogranin A, and neurofilament protein [NFP]). Strong vimentin reactivity was present in neurons, as well as glial cells and cells of mixed lineage, suggesting incomplete maturation. Synaptophysin-reactive axons terminated on a minority of balloon cells and on most heterotopic single neurons in white matter, confirmed by electron microscopy, demonstrating that single heterotopic neurons are not synaptically "isolated," as they may appear; thus, they are capable of contributing to epilepsy. Oligodendrocytes are the least affected cells, at least in some cases. The findings are reminiscent of the hamartomas of tuberous sclerosis. We conclude that hemimegalencephaly is a primary disorder of neuroepithelial lineage and cellular growth. A migratory disturbance contributes to disorderly tissue architecture but is secondary. No pathologic difference is detected between isolated and syndromic forms of hemimegalencephaly.

Biomarkers↗
PubMed2003

Etiological classification of CNS malformations: integration of molecular genetic and morphological criteria.

Classification is a creative activity that helps us understand relationships. The traditional classifications of central nervous system malformations was based exclusively upon descriptive morphology, but these criteria must now be integrated with molecular genetic data to enable an etiological classification that also remains useful to the clinician, radiologist and pathologist, who rely upon imaging and tissue examination for diagnosis. Many cerebral malformations previously thought to be a single disorder are now known to be common end-results of several independent genetic mutations. Examples are holoprosencephaly and lissencephaly. Gradients of genetic expression along the axes of the neural tube, established at the time of gastrulation, may explain many varieties or anatomical and clinical manifestations of cerebral malformations, including the involvement of non-neural tissues such as in midfacial hypoplasia, that may be attributed to abnormal neural crest migration. Genes of cellular lineage and of symmetry may explain some hamartomatous malformations, such as tuberous sclerosis and hemimegalencephaly. Modern classification should be applicable to the entire CNS as well as regions; schemes that attempt to artificially isolate the cerebral cortex for a "regional classification" may be erroneous even though the genetic defect primarily affects cortical structures because genetic gradients in the neuraxis are excluded and some involve a more subtle but still important expression in subcortical structures.

Brain Diseases↗
PubMed2002

Severe mitochondrial cytopathy with complete A-V block, PEO, and mtDNA deletions.

We describe a 17-year-old male with neurologic and cardiovascular disorders characterized by complete atrioventricular block and a mitochondrial cytopathy with clinical, structural, biochemical, and molecular features shared by chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. The patient's manifestations included progressive external ophthalmoplegia, bilateral ptosis, muscle weakness, delayed development, and progressive hearing loss with multiple mitochondrial DNA deletions, including an abundant 11-kb novel deletion and reduced specific activities of respiratory complexes I, III, and IV present in skeletal muscle. Ultrastructural analysis of biopsied muscle revealed a heterogenous mixture of normal and abnormal mitochondria with unusual cristae. This unique mitochondrial DNA deletion, which eliminates the origin of mitochondrial DNA replication for the light strand, may be responsible for generating an intermediate clinical phenotype.

Adolescent↗
PubMed2002

Cajal-Retzius and subplate neurons: their role in cortical development.

Cajal-Retzius (C-R) neurons and their processes form a synaptic network in the marginal zone of the early telencephalon prior to the arrival of the first wave of radial migration of neuroblasts from the subventricular zone. Their origin is not yet proved but may be either the medial ganglionic eminence or the mesencephalic neuromere. These bipolar or multipolar neurons populate the molecular layers of both the fetus and the adult, though sparse in the adult. Their thick axon emits collaterals that make synaptic contact with pyramidal neurons initially in layer 6 and later within all layers. C-R neurons produce GABA, possibly ACh, several calcium-binding proteins (e.g. calmodulin; parvalbumin; possibly calretinin), several neuropeptides and are rich in ribosomes. Subplate neurons, beneath the cortical plate, emit pioneer axons in the incipient formation of the internal capsule and also commissural fibres of the early hippocampus. C-R cells express products of the genes reelin, LIS1 and DS-CAM, that mediate radial neuroblast migration and lamination of the cortical plate and are important in the pathogenesis of lissencephaly. In addition to forming the first intrinsic synaptic circuits of the cortical plate and its first afferent and efferent connections with subcortical structures, they may play additional roles in the formation of ocular dominance columns, in regulating neuronogenesis and in cortical repair. They do not later disappear by apoptosis as we previously thought, but their functional role in the mature brain is unknown.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2002

New insights into craniosynostosis.

Craniosynostosis is a congenital developmental disorder involving premature fusion of cranial sutures, often associated with multiple neurological manifestations. The perspective of this group of disorders has changed dramatically in the new era of molecular genetics. In the last decade a large literature with new concepts in craniosynostosis has appeared. More than 100 syndromes associated with craniosynostosis have been described, and in about a dozen, the molecular defect has been identified. Pediatric neurologists are less aware than geneticists, neurosurgeons, and craniofacial surgeons of these changes. General concepts about craniosynostosis are here presented with updates of clinical and genetic aspects of well-defined syndromes such as Apert, Crouzon, Pfeiffer, Saethre-Chotzen. Evidence of their relationship with fibroblast growth factor receptors (FGFRs) 1, 2, and 3, and with causative genes such as TWIST has been documented. New and other less common syndromes also are discussed. The differences between positional and synostotic plagiocephaly are important, as well as the cause of nonsyndromic craniosynostosis. The prognosis and neurological outcome of patients, including "benign" forms of craniosynostosis, are other important aspects. Major advances have occurred in understanding pathogenesis, diagnosis, and treatment of craniosynostosis. The role of local dura mater and apoptosis; modalities of imaging such as prenatal ultrasound and three-dimensional and spiral CT have improved the accuracy in diagnosis, and the new approaches in surgical treatment involving efficient and less invasive methods, are evidence of these advances.

Apoptosis↗
PubMed2002

Role of Cajal-Retzius and subplate neurons in cerebral cortical development.

A synaptic network is already formed in the marginal zone of the early telencephalon before the arrival of the first wave of radial migration of neuroblasts from the subventricular zone to form the cortical plate. Cells and fibers forming the marginal zone are mainly the Cajal-Retzius (C-R) neurons and their processes. The origin of these cells is not yet proved but is likely either the median ganglionic eminence or the mesencephalic neuromere. The bipolar or multipolar C-R neurons populate the molecular layer of the fetal cortical plate and are sparse in the adult. Their thick axon emits collaterals for synaptic contact with pyramidal neurons initially in layer 6 and later with in all layers. C-R neurons produce GABA, possibly ACh, several calcium-binding proteins (eg, calmodulin, parvalbumin, calretinin) and several neuropeptides; they are rich in ribosomes. Subplate neurons, beneath the cortical plate, emit pioneer axons in the incipient formation of the internal capsule and also commissural fibers of the early hippocampus. C-R cells express products of the genes RELN, LIS1, and DS-CAM, which mediate radial neuroblast migration and lamination of the cortical plate and important in the pathogenesis of lissencephaly. A subpopulation of C-R neurons also expresses a p53 product implicated in cell survival and apoptosis. In addition to forming the first intrinsic synaptic circuits of the cortical plate and its first afferent and efferent connections with subcortical structures, they may play additional roles in the formation of ocular dominance columns, in regulating neuronogenesis, and in cortical repair. They do not disappear by apoptosis at the completion of cell migration, as was previously thought, but their functional role in the mature brain remains unknown.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2002

Molecular genetic and morphologic integration in malformations of the nervous system for etiologic classification.

Molecular genetics has brought new insight into the etiology and pathogenesis of nervous system malformations, and provided a means of precise genetic diagnosis including the prenatal detection of many cerebral dysgeneses. Many cerebral malformations previously thought to be a single disorder are now known to be common end results of many independent genetic mutations. Examples are holoprosencephaly and lissencephaly. Gradients of genetic expression along the axes of the neural tube established at the time of gastrulation may explain many varieties and clinical expressions of cerebral malformations, including the involvement of non-neural tissues, such as midfacial hypoplasia from defective neural crest migration. A new classification of CNS malformations is proposed that integrates, but does not discard traditional morphologic criteria, but integrates them with new molecular genetic criteria.

Animals↗
PubMed2002

Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects.

Hemimegalencephaly is a rare hamartomatous malformation of the brain, remarkable for its extreme asymmetry. It can be isolated or associated with several neurocutaneous syndromes; less frequently, it also involves the brain stem and cerebellum. Traditionally, hemimegalencephaly has been considered a primary neuroblast migratory disturbance. At present, genetic theories of pathogenesis and modern histopathology provide a basis for this complex malformation as a primary disturbance in cellular lineage, differentiation, and proliferation, interacting with a disturbance in gene expression of body symmetry, with earlier onset than radial neuroblast migration. From my personal experience with 10 patients with hemimegalencephaly and review of the literature, I have found the same clinical neurologic, neuroimaging, and neuropathologic features in isolated and syndromic hemimegalencephaly. Magnetic resonance imaging (MRI) reveals abnormal gyration, ventriculomegaly, colpocephaly, an "occipital sign" (displacement of the occipital lobe across the midline), and increased volume and T2 signal of white matter, in addition to the overall increased size of the involved hemisphere. Mild, moderate, and severe grades of severity can be recognized, providing a functional neurologic prognosis and therapeutic plan. Early diagnosis is crucial because despite neuroimaging and pathologic evidence, hemimegalencephaly sometimes still is unrecognized. Also, misdiagnosis of obstructive hydrocephalus or cerebral neoplasm can lead to unnecessary surgical procedures. Although hemispherectomy has a high morbidity, it is recommended early for patients with severe, intractable epilepsy. The mildest forms of hemimegalencephaly are infrequent and the least recognized.

Brain↗
PubMedDate not supplied

Brain imaging findings in neonatal hypoglycemia: case report and review of 23 cases.

A hypoglycemic infant with secondary occipital brain injury defined by serial computed tomography and magnetic resonance imaging is described. An additional 22 similar cases were previously published in the English language literature. A total of 23 cases (including the present case) were reviewed. Abnormal brain imaging findings are associated with profound hypoglycemia and show involvement of the occipital lobes in 82% of affected newborns. Half of these infants had visual impairment, and their median and range of plasma glucose values, and postnatal age when hypoglycemia was first detected, were 7 mg/dL (range, 2-26 mg/dL) and 48 hours (range, 1-72 hours), respectively.

Brain Edema↗