Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure.

Non-mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal-onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi-stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post-mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9-nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2-/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.

Rett syndrome neuropathology review 2000.

This paper will review the study of the neuropathology of Rett syndrome as it has evolved through several phases. In the 1986 the first descriptions of the Rett brain, by Seitelberger and Jellinger, identified that the brains were small, and that there was quantitatively less melanin in the pars compacta of the substantia nigra than in non-Rett brains. There were reports of non- specific gliosis and cell loss in the spinal cords and in the cerebellum, but with traditional neuropathology techniques there were no pathognomonic features that defined a specific neuropathology for Rett syndrome. This apparent absence of pathology was enigmatic in view of the profound clinical phenotype which involved dysfunction of cortex, basal ganglia, the limbic. autonomic and peripheral nervous systems. In the 1990's evaluation of the accumulating and careful reports of the clinical, functional, anatomic and chemical features of Rett syndrome suggested that the basis of Rett syndrome could be an interruption of brain development. MRI and autopsy examinations revealed that the brain in Rett syndrome was small, and that, unlike the brain in a degenerative disease, it did not become progressively smaller over time. Moreover, only the brain, and no other organ was small, emphasizing the susceptibility of the nervous system in the Rett disorder. Using Golgi studies a selective alteration in the size of dendrites of pyramidal neurons in the frontal, motor and temporal lobes was defined. Regional decreases of dendritic spines were also observed and immunocytochemical studies defined alterations in synaptic sites, early response gene activity and interneurons. MAP-2 immunoreactivity was found to be altered in selected neuronal populations. Studies of neurotransmitters using various techniques in various brain regions and CSF defined alterations (increases or decreases) in most systems, with only, according to Wenk, the studies of the cholinergic system being consistently decreased. The hypothesis that there are decreased neurotransmitters in Rett syndrome remains attractive, for it explains many of the functional deficits in Rett syndrome, and suggests a mechanism for defective brain maturation. However, the measurement of neurotransmitters and the interpretation of the results is problematic; the studies have included girls and women at various stages of the Rett disorder, using numerous techniques and various Rett tissues. In 2000 Rett families and researchers rejoiced at the long awaited identification of a mutated gene in Rett syndrome. Now MeCP2 is the focus of research into the neuropathology of Rett syndrome. An understanding of how this DNA methylating protein contributes to normal brain development should allow us to understand the deficits in Rett syndrome. Most importantly, it may allow us to devise strategies for therapy.

Altered mitochondrial sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice.

Voltage-dependent anion channels (VDACs) form the main pathway for metabolites across the mitochondrial outer membrane. The mouse vdac1 gene has been disrupted by gene targeting, and the resulting mutant mice have been examined for defects in muscle physiology. To test the hypothesis that VDAC1 constitutes a pathway for ADP translocation into mitochondria, the apparent mitochondrial sensitivity for ADP (Km(ADP)) and the calculated rate of respiration in the presence of the maximal ADP concentration (Vmax) have been assessed using skinned fibers prepared from two oxidative muscles (ventricle and soleus) and a glycolytic muscle (gastrocnemius) in control and vdac1(-/-) mice. We observed a significant increase in the apparent Km((ADP)) in heart and gastrocnemius, whereas the V(max) remained unchanged in both muscles. In contrast, a significant decrease in both the apparent Km((ADP)) and V(max) was observed in soleus. To test whether VDAC1 is required for creatine stimulation of mitochondrial respiration in oxidative muscles, the apparent Km((ADP)) and Vmax were determined in the presence of 25 mm creatine. The creatine effect on mitochondrial respiration was unchanged in both heart and soleus. These data, together with the significant increase in citrate synthase activity in heart, but not in soleus and gastrocnemius, suggest that distinct metabolic responses to altered mitochondrial outer membrane permeability occur in these different striated muscle types.

Substance P immunoreactivity in Rett syndrome.

Severe autonomic dysfunction occurs in Rett syndrome (RS). Substance P, a tachykinin peptide that localizes to several brain regions, including the autonomic nervous system, is reduced in the cerebrospinal fluid of patients with RS. The anatomic localization and intensity of substance P immunoreactivity and glial fibrillary acidic protein-positive astrocytes in the brains of 14 patients with RS were compared with those in the brains of 10 age-matched normal patients. Substance P immunoreactivity expression was significantly decreased in RS tissue compared with control tissue in the following regions: dorsal horns, intermediolateral column of the spinal cord, spinal trigeminal tract, solitary tract and nucleus, parvocellular and pontine reticular nuclei, and locus ceruleus. A less significant decrease of substance P immunoreactivity occurred in the substantia nigra, central gray of the midbrain, frontal cortex, caudate, putamen, globus pallidus, and thalamus. Antiglial fibrillary acidic protein-positive astrocytes were increased in the areas in which substance P immunoreactivity was decreased and in other brain regions. Because many of the brain regions with the greatest decrease in substance P immunoreactivity are involved in the control of the autonomic nervous system, especially the solitary tracts and reticular formation, reduced substance P may contribute to the autonomic dysfunction in RS.

Periventricular leukomalacia: relation to gestational age and axonal injury.

Eighty-five infants ranging from 22 to 41 weeks gestation were diagnosed as having periventricular leukomalacia (PVL) using traditional neuropathologic methods. The lesions were also studied by immunocytochemistry for beta-amyloid precursor protein (beta-APP), a glycoprotein that has been observed in PVL. Using this technique, the distribution of white matter tissue necrosis was defined as focal, widespread, and diffuse. The type of PVL correlated with the gestational age at birth. The youngest infants tended to demonstrate widespread necrosis, and the oldest infants exhibited more focal necrosis. beta-APP immunopositivity was present in the axons around the foci of white matter necrosis in 76% of the patients and in the neurons of the adjacent cortex in 66% of the patients. In age-matched control patients, there was no beta-APP reactivity in the cerebral white matter or the cortex. In most patients the distribution of beta-APP-positive axons proved to be a useful marker for demonstrating the type of PVL; however, the relationship of beta-APP to the pathogenesis of PVL requires further study.

Organ growth in Rett syndrome: a postmortem examination analysis.

Rett syndrome is a disorder of unknown etiology in females that manifests as severe mental and motor retardation during the first years of life. A postnatal pattern of altered growth is its earliest clinical expression. Head growth decelerates during the first year of age and is followed by a decline in somatic (height/weight) growth. The decreased occipitofrontal circumference (OFC) is reflected in decreased brain size, and measurements of the dendrites of cortical neurons suggest that a developmental and growth arrest have occurred. To further document growth in Rett syndrome, measurements of organ weights, as recorded in 39 postmortem examination studies were compared with normal organ weights for females of comparable age and height. These organ weights suggest that the pattern of growth failure in Rett syndrome, as compared with other forms of mental handicap, such as Down syndrome and Turner's syndrome, may be unique. In Rett syndrome the rate of brain growth, as derived from OFC, decelerates after birth. The increment in normal brain weight after 4 years of age, the age of the first postmortem examinations, is not observed in the Rett brain. The heart, kidneys, liver, and spleen grow at the normally defined rate until 8-12 years of age, when their growth rate decelerates, but their growth continues achieving organ weights that are appropriate for the height of the female. Adrenal weights are normal. These observations suggest that despite a generalized decreased growth in Rett syndrome the brain may be preferentially affected in this syndrome.

Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21.

The branching of dendrites of pyramidal neurons in premotor frontal, motor and limbic cortex have been identified by us using Golgi technique to be less in Rett Syndrome (RS) brains than in non-Rett control brains. Decreased dendritic branching per se is not pathognomonic of a particular condition and has been reported in numerous disorders associated with mental retardation. This study was designed to test whether the dendritic alterations in Rett Syndrome are the same or different from the alterations present in Down Syndrome (DS), 1 specific form of mental retardation. Sections from Brodmann's areas 6, 4, 20, 43, 28, and 17 of premotor frontal, motor cortex, inferior temporal gyrus, hippocampal formation and the striate cortex from 16 Rett brains, 9 non-Rett brains and 9 Down's brains were prepared for dendrite analysis using the rapid Golgi technique. Drawings of apical and basilar dendrites of pyramidal neurons from 2 cortical layers and Cal were submitted to Sholl analysis. The analyses of Rett brains were compared with the analyses of the Trisomy 21 brains using the repeated measures analysis of covariance, with age as a covariate. The studies demonstrate in our sample that basal dendrites of layer III and V of frontal, layer IV of subiculum, and layer V of motor cortex and apical dendrites of layer III of frontal cortex have a significantly reduced dendritic arborization in RS compared with Trisomy 21. This study suggests that the cortical distribution of the dendritic alterations is specific for Rett Syndrome, and that the premotor frontal, motor and subicular cortex are preferentially involved in the, as yet, undefined process which affects brain growth and function in RS.

Pathologic basis of the symptomatic epilepsies in childhood.

The epilepsies in childhood are classified as primary (or idiopathic) and secondary (or symptomatic). The primary epilepsies account for two thirds of all childhood epilepsies and are presumed to be genetically determined. In the remaining one third of cases, a neuropathologic lesion can be identified. This paper summarizes the etiologies of the symptomatic epilepsies. They are classified according to the pathologic processes; malformative, metabolic, neoplastic and phakomatoses, hypoxic-ischemic, infectious, and of unknown pathologic process.

Cytogenetic analysis of 120 primary pediatric brain tumors and literature review.

We report chromosome results from 108 pediatric central nervous system (CNS) tumors. From our data and those in the literature we found that (1) cerebellar and low-grade astrocytic tumors, including gangliogliomas, are most often karyotypically normal; (2) supratentorial tumors were more frequently high-grade tumors that demonstrated a complex karyotype. Chromosome abnormalities were similar to those described in adult astrocytic tumors, namely, +7, 9p abnormalities, and -10; (3) primitive neuroectodermal tumors (PNETs) were virtually always karyotypically abnormal with a high frequency of +7, -8, i(17q), and -22. PNETs with -22 may represent a subset of tumors; (4) typical choroid plexus papillomas showed a normal karyotype, atypical papillomas showed a hyperdiploid karyotype (with +7, +12, and +20), choroid plexus carcinomas showed a hyperhaploid karyotype; (5) a few ependymomas showed hyperdiploidy or hypertetraploidy; (6) germ cell tumors showed complicated karyotypes; (7) monosomy 22 or 22q abnormalities appear to be a recurring finding in the malignant rhabdoid tumors; and (8) meningiomas showed -22 or 22q abnormalities associated with a complex karyotype. In general, in pediatric CNS tumors the least differentiated neoplasms have the greatest number of cytogenetic abnormalities. However, our present morphologic criteria for tumor diagnosis do not always correlate with a consistent karyotype, and further study of pediatric brain tumor morphology, site, behavior, and karyotype is required.

Rett syndrome: analysis of deaths in the British survey.

The mortality rate in Rett syndrome is 1.2% per annum, 48% of deaths occurring in debilitated people, 13% from natural causes, 13% with prior severe seizures and 26% sudden and unexpected. Respiratory dysrhythmias were usually present. Neuropathology confirmed reductions in cortical dendrites and in one case immaturity of cardiac conducting tissues.

The neuropathology of Rett syndrome--overview 1994.

The syndrome which Andreas Rett and Bengt Hagberg first brought to our attention has been observed for eighteen years. It appears to be unlike any other disease of childhood. The original descriptions of Rett syndrome, as being autistic, degenerative and progressive are now, based on longitudinal observations, being questioned. In this paper the morphologic changes in the nervous system in Rett syndrome are summarized. The evidence against a degenerative process are presented, and the alternations are considered, along with the clinical features in terms of a possible arrest of brain development.

Multicore myopathy, microcephaly, aganglionosis, and short stature.

Multicore myopathy, classified with the benign congenital myopathies, is manifest clinically as proximal muscle weakness, hypotonia, and delayed motor development. We report an unusual case of multicore myopathy with an expanded clinical syndrome involving the central nervous system, as well as additional congenital malformations. Clinical manifestations included microcephaly, mental retardation, spasticity with hyperreflexia, cerebellar dysfunction, short stature, Hirschsprung's disease, pharyngeal web, and facial dysmorphism.

Neurological complications from fat emulsion therapy.

Fat emulsion therapy is convenient for parenterally administering calories and essential fats. We report 2 children with neurological complications of fat emulsion therapy that arose before any systemic findings. The complications included focal and generalized seizures, weakness, and altered mental status. Biopsy and autopsy findings included cerebral endothelial and intravascular lipid deposition. Early recognition of fat emulsion therapy complications is essential as the neurological complications are potentially reversible with alteration of the parenteral diet.

Globoid cell leukodystrophy: comparison of neuropathology with magnetic resonance imaging.

Previous imaging studies in infants with globoid cell leukodystrophy (GLD) using computed tomography have demonstrated a reduction in cerebral white matter and increased density symmetrically in the regions of the thalami, periventricular white matter, and the internal capsules. Correlation of these findings with morphologic studies at necropsy has not been made. In particular, deposition of calcium has not been described. We have evaluated two children with GLD confirmed by the absence of leukocyte galactosylceramide beta-galactosidase activity using repeated magnetic resonance (MR) scans in each and correlated the imaging results with post-mortem analyses in one. Neuropathologic examination revealed abnormalities typical for GLD. In addition to the absence of normal myelination throughout cerebral and cerebellar white matter, MR images demonstrated the presence of a paramagnetic effect in the regions of the thalami, corona radiata, and centra semiovale. We have observed in histologic preparations from these areas a dense accumulation of globoid cells and some calcium, which we suggest may be responsible for producing the paramagnetic effect.

The neuropathology of temporal lobe epilepsy.

Complex partial epilepsy arising in the temporal lobe has been associated with several types of pathologic lesions including Ammon's horn sclerosis, malformations, neoplasms, and inflammatory scars from infarcts or infection. These lesions are usually situated at various sites in the medial temporal lobe, so that one of the enigmas of attempting to understand the pathogenesis of TLE pertains to the clinical manifestation of a single epileptic disorder which is associated with dissimilar lesions at dissimilar sites. Recent demonstrations of an alteration in temporal lobe anatomy, i.e. malformations of the normal circuitry of the temporal lobe and foci of microdysgenesis, have given rise to the hypothesis that insults which occur during a critical period of brain development could alter the connections within the hippocampus and predispose it to increased excitability and seizurogenesis. Such a hypothesis forces us to reconsider TLE in reference to risk factors which may act as "teratogens" and produce these malformations. These malformations may range from a subtle alteration in the neurotransmitters of the dentate gyrus to large areas of cortical dysplasia or the hamartomatous neoplasms seen in TLE. A reevaluation of the neuroanatomical disruptions created by the various lesions may allow us to define a minimal optimal surgical resection for each lesion; or, the definitions of neurotransmitter deficits may lead to alternative pharmacologic therapies. As neuropathologists we have the exciting opportunity to participate in the definition of the neuropathology of temporal lobe epilepsy.

The pattern of growth failure in Rett syndrome.

OBJECTIVE: To define the growth pattern of girls with Rett syndrome with respect to height, weight, and fronto-occipital head circumference. DESIGN: Longitudinal with irregular intervals between measurements. SETTING: Rett Syndrome Program Project at Baylor College of Medicine, Houston, Tex. PARTICIPANTS: Ninety-six girls fulfilling criteria for Rett syndrome; comparison group with standard growth curves. SELECTION PROCEDURE: Consecutive entries into the Rett Syndrome Program Project. INTERVENTION: None. MEASUREMENTS/MAIN RESULTS: Height, weight, and fronto-occipital head circumference data were grouped into intervals. Group medians were then generated. Regression lines were fitted through the median points and plotted on standard growth charts. Deceleration of growth velocities began at age 3 months and persisted through age 18 years. CONCLUSIONS: Early deceleration of head growth, followed by deceleration of weight and height measurements, appears to be a growth pattern characteristic of Rett syndrome. This pattern of growth may provide the earliest clinical indicator for the diagnosis of Rett syndrome.

The neuropathology of the Rett syndrome.

The neuropathology of the Rett syndrome is summarized utilizing a format of clinical pathological correlations, describing the pathology at specific anatomic sites which could correlate with the well defined clinical signs and symptoms in the Rett syndrome; decreased head and body size, autism, gait dysfunction, spasticity, movement and breathing disorder. Published reports of altered morphology in the cerebral cortex, basal ganglia, substantia nigra, cerebellum, spinal cord, muscle, nerve, pituitary gland and somatic organs are supplemented by the author's observations. These include studies of dendritic morphology employing Scholl analysis of Golgi preparation, and quantitation of cerebellar Purkinje cells. The possible pathoetiology of the Rett syndrome is considered, particularly, in relation to the ultrastructural demonstration of altered mitochondria and accumulations of lipidic bodies in several tissues.