Biomedical subjects
H B Sarnat
Publications and source records attributed to H B Sarnat.
Kearns-Sayre syndrome with a novel mitochondrial DNA deletion.
We describe a 17-year-old boy with a clinical neurologic picture consistent with Kearns-Sayre syndrome. His manifestations included progressive external ophthalmoplegia, bilateral ptosis, retinitis pigmentosa, and muscle weakness. He was found to harbor an abundant novel deletion in skeletal muscle mitochondrial DNA. Biochemical analysis of the patient's biopsied skeletal muscle showed that the specific activities of all four respiratory complexes with mitochondrial DNA-encoded subunits were markedly reduced in contrast to normal activity levels of entirely nuclear DNA-encoded enzyme activities (eg, complex II and citrate synthase). Ultrastructural analysis also indicated the presence of strikingly abnormal mitochondria with both unusual cristae and frequent paracrystalline inclusions. The great amount of the deleted mitochondrial DNA in this patient's muscle, as well as the concomitant reduction in specific respiratory complex activity, suggests that the mitochondrial DNA deletion plays a role in the pathogenesis of this neurologic disease.
Molecular genetic classification of central nervous system malformations.
Traditional schemes of classifying nervous system malformations are based on descriptive morphogenesis of anatomic processes of ontogenesis, such as neurulation, neuroblast migration, and axonal pathfinding. This proposal is a first attempt to incorporate the recent molecular genetic data that explain programming of development etiologically. A scheme based purely on genetic mutations would not be practical, in part because only in a few dysgeneses are the specific defects known, but also because several genes might be involved sequentially and many genes inhibit or augment the expression of others. The same genes serve different functions at different stages and are involved in multiple organ systems. Some complex malformations, such as holoprosencephaly, result from several unrelated defective genes. Finally, a pure genetic classification would be too inflexible to incorporate some anatomic criteria. The basis for the proposed scheme is, therefore, disturbances in patterns of genetic expression; polarity gradients of the axes of the neural tube (eg, upregulation or downregulation of genetic influences); segmentation (eg, deletions of specific neuromeres, ectopic expression); mutations that cause change in cell lineage (eg, dysplastic gangliocytoma of cerebellum, myofiber differentiation within brain); and specific genes or molecules that mediate neuroblast migration in its early (eg, filamin-1), middle (eg, LIS1, double-cortin), or late course (eg, reelin, L1-CAM). The proposed scheme undoubtedly will undergo many future revisions, but it provides a starting point using currently available data.
Synaptophysin immunocytochemistry with thermal intensification: a marker of terminal axonal maturation in the human fetal nervous system.
Synaptophysin is a protein of synaptic vesicles and may be demonstrated in tissue sections of human brain and spinal cord by immunocytochemistry using a monoclonal antibody. Synaptophysin immunoreactivity was studied in paraffin-embedded sections of the central nervous system (CNS) in 14 normal human fetuses and neonates ranging in age from 8 to 41 weeks gestation, and in three brains with heterotopic neurons or malformations. A progressive expression of synaptophysin is seen in axonal terminals within grey matter in various parts of the CNS, beginning in the ventral horns of the spinal cord and brainstem tegmentum at 12-14 weeks. In the cerebellum, the molecular layer shows a band of reactivity from 18 weeks; by term two parallel bands of synaptophysin are seen in the molecular layer and reactivity also is demonstrated in the Purkinje and internal granular layers. In the cerebral neocortex, the molecular zone has weak synaptophysin reactivity as early as 10 weeks, though reactivity is not detected in the deep layers of the cortical plate until 19 weeks and in layers 2-4 until 25 weeks gestation. Synaptophysin reactivity is strong at the surface of neurons but not detected in their somatic cytoplasm; coarsely beaded reactivity within the neuropil probably corresponds to synaptic vesicles in terminal axons. Similar granular synaptophysin reactivity is seen around heterotopic neurons in the subcortical white matter, in dysgenesis of the cerebellar cortex and in the residual anencephalic forebrain. Thermal intensification by heating the incubating solution in a microwave oven often enhances immunoreactivity because of more complete antigen retrieval and is recommended for tissue stored in formalin or in paraffin for long periods. Synaptophysin provides a useful tissue marker of synaptogenesis during normal development and in cerebral dysgeneses, and may provide useful correlations with functional imaging of the brain in living patients. Used in conjunction with other neuronal markers, the expression of synaptophysin in terminal axons of distant neurons, in temporal relation to the maturation of the neurons they innervate, may provide clues to the pathogenesis of epilepsy in early infancy.
Skeletal muscle mitochondrial defects in nonspecific neurologic disorders.
A group of 25 children (5 months to 20 years of age) presenting with intractable seizures, developmental delay, and severe hypotonia, who did not fall into the known categories of mitochondrial encephalomyopathies, underwent muscle biopsy for evaluation of mitochondrial function and were compared with age-matched control subjects. Biopsied skeletal muscle was analyzed for six mitochondrial enzyme-specific activities, mitochondrial DNA point mutations and deletions, and mitochondrial DNA levels. The data reveal a high incidence of specific mitochondrial enzyme activity defects. Reduced activity levels were evident in complex I (11 patients), III (24 patients), IV (nine patients), and V (10 patients). Two patients also exhibited pronounced reduction in mitochondrial DNA levels (80% reduction compared with control subjects). Two patients manifested increased levels of 5-kb and 7.4-kb mitochondrial DNA deletions. Pathogenic mutations previously described in association with mitochondrial encephalomyopathies were not evident. The data suggest that mitochondrial dysfunction, including extensive defects in specific enzyme activities, may be frequently present in children with seizures, developmental delay, and hypotonia that do not fall within the known mitochondrial encephalomyopathies. These mitochondrial deficiencies can be primarily ascertained by biochemical analysis and are rarely accompanied by mitochondrial ultrastructural changes. The molecular basis of these defects, their role in these disorders, and potential treatment warrant further study.
Central nervous system malformations: locations of known human mutations.
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Histochemistry and immunocytochemistry of the developing ependyma and choroid plexus.
The adult human ependyma expresses no intermediate filament proteins or secretory proteins; the fetal ependyma shows strong immunocytochemical (ICC) expression of vimentin, glial fibrillary acidic protein (GFAP), cytokeratins (CKs) of high molecular weight, glycoproteins, and S-100beta protein. Each has a precise and specific spatial distribution within the developing ependyma and a predictable time of appearance and regression in each region of the ventricular system. Several are coexpressed, but some appear earlier or persist longer than others. Secretory proteins of ependymal cells are important in several developmental processes such as the guidance of axonal growth cones. GFAP is not expressed in the floor plate ependyma at any stage of development, unlike vimentin and CK. The choroid plexus epithelium is a specialized ependyma, with an ICC profile that differs from the surface ependyma: vimentin, CK, and S-100beta protein continue to be expressed throughout fetal and adult life, but GFAP is not expressed. Certain cerebral malformations are associated with specific ICC abnormalities: ependymal S-100beta protein continues to be immunoreactive in disorders of neuroblast migration; ependymal vimentin is focally upregulated in Chiari malformations and congenital aqueductal stenosis. Other mammalian and nonmammalian species have characteristic profiles of ependymal immunoreactivity to the same proteins expressed in humans but exhibit interspecific differences.
Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in early human fetal nervous system.
Neuronal nuclear antigen (NeuN) immunocytochemistry was studied in 15 normal human fetal nervous systems of 8-24 weeks gestation and in four term neonates. Material was derived from products of conception or from autopsy. Antigen retrieval was enhanced for immunocytochemistry by microwave heating of formalin-fixed paraffin sections. NeuN appears highly specific as a marker of neuronal nuclei in human fetal brain. Only rare nuclei are recognized in the germinal matrix. Cerebellar external granule cells are more strongly immunoreactive than postmigratory internal granule cells until 24 weeks gestation; by term most internal and only a few external granule cells are recognized by NeuN antibody. In the cerebrum, some reactive nuclei are demonstrated along radial glial fibers, particularly near the cortical plate. Within the cortical plate, only deep neurons (future layers 4-6) are marked at 19-22 weeks, but by 24 weeks most neurons in the cortical plate exhibit immunoreactivity, though at term some in layer 2 are still non-reactive. Some neurons fail to be recognized by NeuN at all ages: Cajal-Retzius cells, Purkinje cells, inferior olivary and dentate nucleus neurons, and sympathetic ganglion cells are examples. Despite their common origin in the cerebellar tubercle, basal pontine neurons are strongly reactive even before midgestation, hence NeuN does not predict embryonic origin. Neurons of dorsal root and cranial nerve ganglia are reactive even at 8 weeks. This study of normal fetal central nervous system provides a basis for neuropathological evaluation and as a prelude to applications in cerebral dysgeneses.
The pachygyria-polymicrogyria spectrum of cortical dysplasia in X-linked hydrocephalus.
Neural cell adhesion molecules (CAM) play important roles in neural development, neurite outgrowth, axonal guidance, fasciculation and synapse formation. Neuropathological studies of X-linked hydrocephalus (XLH) associated with L1 CAM mutations emphasize marked hypoplasia of the pyramidal tract, agenesis of the corpus callosum and septum pellucidum, and a thin cerebral mantle with hypoplastic white matter, but there are no detailed studies of the cerebral cortex in the literature. We report clinical, neuroimaging, and neuropathological findings in three boys with XLH. All had severe congenital hydrocephalus with marked thinning of the cerebral mantle and severe development disabilities. The brain specimens from the three boys showed both pachygyria and polymicrogyria, hypoplasia of the medullary pyramids, hypoplasia of the corpus callosum, small anterior commissure, hypoplasia and poorly differentiated hippocampi. A small but patent aqueduct was present in all three brains. Despite the extensive cerebral malformations, the cortex in all three brains showed normal-appearing laminar cortical neuronal architecture and absence of gliosis. In XLH, it is likely that the poor developmental outcome of spasticity, contractures and severe mental retardation results from a disturbance of neuronal connectivity, fasciculation, and synapse formation rather than aqueductal stenosis, increased intracranial pressure, or abnormal neuroblast migration.
Why should neurologists be interested in Williams syndrome?
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[Neuroblastic migration: embryological aspects and mechanisms].
INTRODUCTION: The migration of immature neurons of the cerebrum is genetically programmed from the primitive neuroepithelium before the end of the final mitotic cycle. The orientation of the mitotic spindle determines when a neuroepithelial cell is ready to start migration and the proportion of major genetic material it is destined to receive. DEVELOPMENT: The gene LIS1, defective in lissencephaly type 1 of Miller and Dieker, is expressed in the neuroepithelial cells, in the ependyma and the Cajal-Retzius neurons. These transitory fetal cells are the first neurons of the cerebral cortex. Most of the neurons of the cortical plate arrive by means of glial radial cells which guide them towards their destination. Cell adhesion molecules from the neuroblasts themselves, the glial radial cell, the extracellular matrix and perhaps the ependymal cells are important in adhering the neuroblasts to the glial radial cells. Genetic deficiency of these molecules results in defective migration. The mechanism of cellular movement is still not fully understood. Disorders of migration may also be induced by non-genetic factors, such as infarcts or other lesions which damage or destroy the glial radial fibres during the fetal period.
D-2-hydroxyglutaric aciduria: hypotonia, cortical blindness, seizures, cardiomyopathy, and cylindrical spirals in skeletal muscle.
An infant girl was demonstrated to have D-2-hydroxyglutaric aciduria, the fifth case described and the first with muscle biopsy of this rare organic aciduria that differs clinically and genetically from the more common L-2-hydroxyglutaric aciduria. Her clinical features included mildly dysmorphic facies, developmental delay, generalized hypotonia, myoclonic seizures, cortical blindness, and dilated cardiomyopathy requiring treatment. Muscle biopsy demonstrated only excessive glycogen histochemically, but ultrastructural examination revealed subsarcolemmal cylindrical spirals and normal mitochondria. Because of the metabolism of D-2-hydroxyglutaric aciduria, we regard valproic acid as contraindicated in the treatment of epilepsy in this disease.
Ectopic or heterotopic? An appeal for semantic precision in describing developmental disorders of the nervous system.
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Siblings with rigid spine syndrome and nemaline rod myopathy, a unique association.
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Ependymal reactions to injury. A review.
The ependyma reacts to injury with a few stereotypical responses and does not regenerate at any age. Non-neoplastic ependymal cells do not undergo mitotic proliferation and do not re-express fetal cytoskeletal or secretory proteins. Atrophy of ependymal cells accompanies generalized cerebral atrophy. The ependyma may be damaged by stretching during ventricular dilatation, by infarcts of the ventricular wall or by infection and inflammation. Tearing of the epithelium leaves discontinuities that become filled with processes of subventricular astrocytes. In some cases reactive gliosis is minimal, but in most it is extensive and gliotic nodules form beneath intact ependyma and within gaps between ependymal islands. Ependymal rosettes may form in several ways: sequestration of diverticuli from the surface; curling of a torn edge or penetration of an edge into the parenchyma; reactive gliosis overgrowing an ependymal edge; in situ differentiation of ependymal cells from deep neuroepithelial cells. Migration and metaplasia are unlikely mechanisms. Bacterial and fungal ependymitis are highly destructive. Several viruses, especially mumps, selectively infect ependymal cells and are an important cause of acquired aqueductal stenosis without inflammation. Damaged ependyma may not be able to perform its function in the regulation of transport of fluid, ions and small molecules between cerebral parenchyma and ventricular fluid and thus may contribute to hydrocephalus. Damage to the fetal ependyma may result in secondary focal dysplasias of the developing brain.
Autosomal recessive, fatal infantile hypertonic muscular dystrophy among Canadian Natives.
We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.
New insights into the pathogenesis of congenital myopathies.
Congenital myopathies are developmental disorders of muscle that are best understood in the context of ontogenesis. Segmental amyoplasia results from a defective somite, usually because of lack of induction by the notochord and neural tube; the connective tissue matrix of the muscle is derived from lateral mesoderm and is present, but the myocytes are derived from somitic mesoderm and are replaced by adipose cells. Generalized amyoplasia is due to defective myogenic regulatory genes. X-linked recessive myotubular myopathy is associated with overexpression of vimentin and desmin, fetal intermediate filaments that attach to nuclear, mitochondrial, and inner sarcolemmal membranes and Z-bands of sarcomeres to preserve the morphologic organization of the myotube. Neonatal myotonic dystrophy is a true maturational delay in muscle development. Congenital muscle fiber-type disproportion is a syndrome of multiple etiologies but in some cases is associated with cerebellar hypoplasia and may be the result of abnormal suprasegmental stimulation of the developing motor unit at 20 to 28 weeks' gestation, mediated through bulbospinal pathways but not the corticospinal tract. Maturational delay of muscle in late developmental stages is less specific than in stages before midgestation. The Proteus syndrome is a muscular dysgenesis; abnormal paracrine growth factors and perhaps altered genes that regulate muscle differentiation and growth, such as myoD and myogenin, are the suspected cause. Focal proliferative myositis may be another example of a "paracrine myopathy."