Siblings with rigid spine syndrome and nemaline rod myopathy, a unique association.
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Humans↗
Biomedical subjects
H B Sarnat
Publications and source records attributed to H B Sarnat.
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.
Animals↗
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.
Canada↗
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."
Cell Differentiation↗
Vagal nerve maturation in the fetal lamb: an ultrastructural and morphometric study.
The maturation of the left vagal nerve was studied in the fetal lamb by transmission electron microscopy and by computer-assisted morphometry of sections of the entire nerve at seven gestational ages between 79 and 145 days (term is 147 days) and in the adult ewe. The number of unmyelinated axons per Schwann cell progressively decreased from 25 to 55 at 79 days to 1 to 5 at near-term. Unmyelinated axons of various sizes were enclosed within a single Schwann cell at all ages, but the mean axonal diameter increased in inverse relation to the number of unmyelinated axons. A few Schwann cells enclosed two myelinated axons, but in most instances myelination did not begin until a 1:1 ratio was achieved; some single axons with a Schwann cell remained unmyelinated in the adult. Myelinated fibers were rare at 79 days but myelination progressed rapidly thereafter until the adult ratio of myelinated: unmyelinated fibers was reached at about 100 days; myelinated axons were not uniformly distributed. The myelin sheaths and axons of small fibers progressively increased in diameter in late gestation, but new large fibers were not added. Early myelinating fibers and immature unmyelinated axons contained more microtubules than neurofilaments; neurofilaments predominated in mature axons with or without myelin. Cross-linkages between neurofilaments were already evident by 79 days. Maturation of the vagal nerve thus occurs first by an increase in number of myelinated fibers and then by an increase in the size of each fiber in this fixed population. The bimodal distribution in the size histogram of myelinated fibers is not achieved until 134 days gestation and correlates well with physiological maturation of respiratory patterns.
Animals↗
Myopathy of the Proteus syndrome: hypothesis of muscular dysgenesis.
The Proteus syndrome is a congenital disorder of growth regulation affecting tissues of mesodermal and ectodermal origin. It is expressed as hemihypertrophy, hemimegalencephaly, muscular overgrowth, verrucous epidermal nevi, haemangiomas and bony dysplasias. Muscle biopsies were examined at 7 and 10 yr of age from a girl with this disease. Several cytoarchitectural alterations of myofibres, proliferation of sarcolemmal nuclei, and other myopathic changes were demonstrated in regions adjacent to other with normal myofibres; the boundaries did not correspond to fascicular margins. A perinuclear and subsarcolemmal distribution of excessive desmin was also found. It is suggested that this myopathy represents a new category of neuromuscular disease, "muscular dysgenesis", due to faulty paracrine growth factors.
Biopsy↗
Does increased desmin in myofibres constitute a storage disease?
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Desmin↗
Ependymal abnormalities in lissencephaly/pachygyria.
The ependyma was examined in eight children with neuroblast migratory disorders of diverse origin: three cases of lissencephaly type 1 with severe to mild degrees of agyria/pachygyria, four cases of lissencephaly type 2 in Fukuyama muscular dystrophy and the Walker-Warburg syndrome, and one case of hemimegalencephalic pachygyria. Morphological and immunohistochemical abnormalities of the ependyma were strikingly similar in all. Discontinuities were disproportionate to the degree of ventriculomegaly. In some regions, the ependyma remained a pseudostratified columnar epithelium, though basal processes were absent. The poles of the horns of the lateral ventricles were replaced by extensive heterotopic ependymal rosettes. Rosettes and rows of ependyma also were in other subventricular sites. Subependymal nodules of large astrocytes and their processes bulged into the ventricular lumen after infancy. Ependymal cells did not express glial fibrillary acidic protein, but showed persistent expression of S-100 protein, cytokeratin CK-904 and sometimes vimentin long after these proteins normally disappear. An abnormal ependyma in lissencephaly/pachygyria may contribute to disturbances in neuronogenesis, guidance of axonal projections and neuroblast migrations; it may be a primary factor in pathogenesis.
Brain↗
Immunohistochemical evaluation of dystrophin expression in small round cell tumors of childhood.
Dystrophin, the protein product of the Duchenne muscular dystrophy locus, is a major component of the subsarcolemmal cytoskeleton in skeletal muscle cells and is a relatively muscle specific protein. We evaluated, retrospectively, the expression of dystrophin in 23 small round cell tumors of childhood including: 9 rhabdomyosarcomas, 4 neuroblastomas, 1 ganglioneuroblastoma, 2 small noncleaved cell lymphomas, 1 lymphoblastic lymphoma, 2 medulloblastomas, 2 primitive neuroectodermal tumors, 1 Wilms' tumor, and 1 undifferentiated sarcoma. Frozen sections were stained by the avidin biotin immunoperoxidase technique using a commercially available monoclonal antibody NCL-DYS1 (Novocastra) that recognizes the mid-rod domain (between amino acids 1181 and 1388) of human dystrophin. Positive controls were represented by frozen sections of normal skeletal muscle. Negative controls consisted of substituting the dystrophin antibody for normal rabbit serum. Eight of nine rhabdomyosarcomas revealed positivity whereas, none of the other tumors stained for dystrophin. This study provides evidence that monoclonal antibodies to dystrophin may be a potential useful addition to the panel of muscle markers used to diagnose small round cell tumors of childhood.
Adult↗
Commentary: epilepsia partialis continua and neuroblast migrational disorders.
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Cell Movement↗
Regional differentiation of the human fetal ependyma: immunocytochemical markers.
The development of the ependyma from 6 weeks (wk) gestation to term was studied in 26 human fetuses and infants for immunocytochemical differentiation using antibodies against vimentin, several cytokeratins, glial fibrillary acidic protein (GFAP) and S-100 protein. Acridine orange-RNA fluorescence was uniform in all differentiated ependymal cells. Marked differences were demonstrated among various anticytokeratin antibodies. Vimentin was demonstrated in undifferentiated cells, particularly during mitosis, and persisted as the ependyma matured. It was strong in floor plate cells and processes forming the ventral median septum. Vimentin and cytokeratin CK-904 coexisted with other immunoreactive proteins but disappeared in a caudorostral gradient with maturation. At 8 wk gestation, GFAP was detected in roof plate cells and their processes forming the dorsal median septum. S-100 protein appeared as early as 6 wk and had a more restricted regional distribution than GFAP at all ages. It was strong in the basal plate ependyma of the spinal cord in young fetuses. The temporal and spatial distributions of the immunoreactive proteins studied correlate with evidence that fetal ependymal cells synthesize compounds that attract or repel axonal growth cones to prevent axons from entering the ventricles or deviating from programmed projection pathways. An additional role may be to induce the transformation of radial glial cells in the subventricular zone.
Biomarkers↗
Vimentin and desmin in maturing skeletal muscle and developmental myopathies.
I studied vimentin and desmin immunoreactivities in the skeletal muscle of 30 human fetuses and children ranging from 8 weeks' gestation to 2 years of age, and in 45 infants and children and five adults with developmental neuromuscular diseases. Acridine orange-RNA fluorescence also identified regenerating myofibers in Duchenne muscular dystrophy and dermatomyositis for comparison with congenital myopathies. Vimentin and desmin are both strongly expressed in fetal myotubes and their immunohistochemical demonstration persists until 36 weeks' gestation. These cytoskeletal proteins are uniformly expressed in myofibers of neonates with X-linked recessive myotubular myopathy. Desmin but not vimentin is diffusely increased in infantile cases of myotonic dystrophy, in some cases of congenital muscle fiber-type disproportion, and in cerebrohepatorenal disease. In nemaline rod myopathy, desmin is focally increased in perinuclear zones and in regions of aggregated rods. The small myofibers in infantile spinal muscular atrophy show increased vimentin and desmin in the subsarcolemmal region. The demonstration of these intermediate filament proteins provides markers to enhance diagnostic precision in the interpretation of the infant muscle biopsy. Furthermore, persistently high fetal concentrations of vimentin/desmin may play a role in the pathogenesis of some developmental myopathies.
Desmin↗
Varicella embryopathy.
Varicella embryopathy is a rare entity afflicting infants born to mothers who have contracted varicella during the first 20 weeks of pregnancy. The teratogenicity of varicella has not been established from epidemiologic studies, but isolated case reports describe characteristic malformations following early maternal infection. We describe a male neonate delivered at 40 weeks' gestation to a 26-year-old grava 2, para 2 mother who developed varicella during the first trimester. The infant lived 7 days and died of bronchopneumonia. At postmortem examination there was growth retardation, multiple cicatricial skin lesions, flexion contractures of all major joints, hypoplastic right diaphragm, bilateral hydroureters and mucosal fibrosis of the trachea, as well as intestinal fibrosis and colonic stricture. The brain contained areas of cystic necrosis involving the frontal, parietal, temporal, and occipital lobes, with generalized ventriculomegaly. The midbrain, pons, and medulla were hypoplastic. There was denervation atrophy of muscles of the lower limbs and loss of dorsal root ganglia as well as of neurons of the anterior horn of the spinal cord. The cerebral white matter was degenerated, with proliferation of reactive astrocytes. Chorioretinitis was not observed. Immunocytochemical stains using two commercially available antivaricella antibodies were negative in all tissues examined. The sporadic nature and pathogenesis of the varicella embryopathy, which may have been caused by focal defects in the fetal T-cell immune response, are discussed.
Abnormalities, Multiple↗
Cerebral dysplasias as expressions of altered maturational processes.
This review identifies the fundamental anatomical and physiological processes that provide the substrates of maturation in the developing nervous system. Cerebral malformations may be viewed from the perspective of aberrations in one or more of these processes. The maturational processes are generally sequential but with considerable temporal precision and overlap: 1) neuronogenesis and gliogenesis, including neural induction by the notochord and primary segmentation of the nervous system; 2) programmed cell death of excess neuroblasts and glioblasts; 3) neuroblast migration; 4) formation and growth of neurites; 5) development of membrane polarity and excitability; 6) synaptogenesis; 7) biosynthesis of neurotransmitters and other secretory products; and 8) myelination of axons. The anatomical and synaptic organization of the fetal brain differs greatly from the mature state. An excess of axonal collaterals, dendritic branches, spines and synapses are formed and later selectively deleted Transitory neurons, specialized glial cells, synaptic circuits and transient neurotransmitter systems serve as functional elements for a limited time. The clinical expression of these transitory features of the fetal brain are incompletely understood, particularly in the context of embryonic cerebral plasticity.
Axons↗
Vimentin/desmin immunoreactivity of myofibres in developmental myopathies.
Immunoreactivity for the intermediate filament proteins vimentin and desmin was studied in muscle biopsies of 33 children with neuromuscular diseases and in postmortem muscle of 15 fetuses and neonates at 8-42 weeks gestation. Fetal myotubes exhibited strong reactions for vimentin and desmin; reactivity was still present, though weaker, by 31 weeks and was no longer demonstrable at term. In X-linked myotubular myopathy (5 cases) myofibres showed strong reactivity for both vimentin and desmin; in myotonic dystrophy desmin but not vimentin had strong reactivity in myofibres of neonates and children. A similar but much weaker pattern of desmin reactivity was seen in nemaline rod disease and in congenital muscle fibre-type disproportion. The small myofibres in spinal muscular atrophy were reactive for both vimentin and desmin, as were regenerating myofibres in Duchenne muscular dystrophy and dermatomyositis. Acridine orange fluorochrome distinguished vimentin/desmin-reactive myofibres that were regenerating from those of developmental myopathies because the RNA fluorescence was strong in regenerating myofibres and in fetal myotubes, but was absent from myofibres in developmental disorders of muscle. A failure to regress of fetal cytoskeletal proteins may contribute to the apparent arrest in morphogenesis of myofibres. These stains are useful in studying the muscle biopsies of children with developmental myopathies because they demonstrate an aspect of muscle maturation not detected by standard histochemical methods.
Biopsy↗
Visual and auditory evoked potential correlates of cerebral malformations.
To date there are no systematic studies of the evoked potential correlates of cerebral malformations. A total of 109 sensory evoked potential studies (20 ERGs, 61 VEPs and 28 ABRs) were performed in 27 children with defined cerebral malformations. Diagnoses were confirmed by CT scan, supplemented by MRI, cranial ultrasound, or neuropathological examination. Sensory evoked potential studies were abnormal in over half of patients studied, but the VEP was unable to identify or distinguish specific supratentorial cerebral malformations. ABR abnormalities were documented in cases of holoprosencephaly, lissencephaly, pachygyria and generalized megalencephaly. ABR abnormalities were not observed in septo-optic dysplasia or focal dysplasia of the cerebral cortex. We conclude that evoked potentials are not a diagnostic criterion of severe dysplasias, but rather serve as a supplementary tool for detecting the variable associated abnormalities of brain development that may affect visual and central auditory pathways or their cerebral cortical or brainstem targets.
Brain↗
Myotubular myopathy: arrest of morphogenesis of myofibres associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle.
Vastus lateralis muscle biopsies of four unrelated male neonates showing myotubular (i.e. centronuclear) myopathy (MM) were compared with muscle from four human fetuses in the myotubular stage of development, a 31 week preterm infant and four term neonates. The perimysium, blood vessels, spindles, myelinated intramuscular nerves, and motor end-plates in MM are as well developed as in term neonatal muscle. The cytoarchitecture of myofibres in MM is more mature than that of fetal myotubes in the spacing of central nuclei, Z-band registry, development of the sarcotubular system, and in the condensation of nuclear chromatin and nucleoli. Triads in MM may retain an immature oblique or longitudinal orientation. Myofibrillar ATPase shows normal differentiation of fibre types, consistent with normal innervation. Spinal motor neurons are normal in number and in RNA fluorescence. Immunoreactivity for vimentin and desmin in myofibres of MM is uniformly strong, as in fetal myotubes and unlike mature neonatal muscle. Maternal muscle biopsies of two cases also showed scattered small centronuclear myofibres reactive for vimentin and desmin. The arrest in morphogenesis of fibre architecture in MM is not a general arrest in muscle development. Persistence of fetal cytoskeletal proteins that preserve the immature central positions of nuclei and mitochondria may be important in pathogenesis. Vimentin/desmin studies of the infant and maternal muscle biopsies are useful in establishing the diagnosis.
Biopsy↗
Acridine orange--RNA histofluorescence of sarcomas and small round cell tumors of childhood.
Forty-nine pediatric malignant neoplasms were stained with acridine orange (AO) fluorochrome to qualitatively evaluate cytoplasmic RNA content. The application of AO as a supplementary stain in surgical pathologic diagnosis is based on the premise that specific neoplastic cell types characteristically and consistently contain few or many cytoplasmic ribosomes. Primitive tumors such as Ewing's sarcoma and primitive neuroectodermal tumors showed negative or low-intensity AO-RNA cytoplasmic staining. Differentiated sarcomas such as rhabdomyosarcomas and lymphomas exhibited moderate to strong AO-RNA cytoplasmic fluorescence. Acridine orange--RNA staining provides an easy, convenient, and inexpensive adjunct in the histopathologic differential diagnosis of sarcomas. It is particularly useful for distinguishing Ewing's sarcomas from other small round cell sarcomas of childhood.
Acridine Orange↗