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PubMed2002

Mitochondrial transduction of ocular teratogenesis during methylmercury exposure.

BACKGROUND: The purpose of the present study was to investigate the correlation between MeHg developmental toxicity and mitochondrial 16S ribosomal RNA (16S rRNA) expression in the embryonic forebrain and pharmacological intervention with PK11195, a ligand for the mitochondrial peripheral-type benzodiazepine receptor (Bzrp). METHODS: Pregnant CD-1 mice were dosed with methylmercury (II) chloride (MeHg) with or without 4 mg/kg PK11195 on Day 9 of gestation. Fetuses were examined on Day 9 (RT-PCR), Day 15 (histology), and Day 17 (teratology). RESULTS: MeHg (10 mg/kg) induced microcephaly, microphthalmia and cleft palate. The mean incidences of malformed fetuses were 47.7% with MeHg (P < 0.001) and 19.2% with PK11195 co-treatment (P < 0.01 for rescue). Cleft palates were 12.8% and 1.5%, respectively. An estimate of neurocranial circumference revealed a small (5%) but highly significant (P < 0.001) reduction that was rescued in a subset of co-treated fetuses (P < 0.05). RT-PCR analysis of the Day 9 forebrain revealed inhibition of 16S rRNA expression 3.0 hr after 5 mg/kg MeHg exposure (P < 0.001). This effect was rescued with PK11195 (P < 0.001). Preliminary findings revealed a similar response-rescue in cultured embryos exposed to 1 microM Hg(II) when exogenous 5-aminolevulinic acid (ALA) was added. Protoporphyrin-IX (PP9), the penultimate precursor to heme and an endogenous ligand of the Bzrp, increased in a manner that was ALA-dependent and PK11195-sensitive. CONCLUSION: At least some teratological effects of Hg appear linked with late steps in the heme biosynthesis pathway through the Bzrp. PK11195, a ligand for these mitochondrial receptors, significantly lessens the risk of microphthalmia, microcephaly, and cleft palate in Hg-poisoned embryos.

Abnormalities, Drug-Induced↗

PubMed1989

Bendectin and human congenital malformations.

The relationship between Bendectin exposure during the first trimester of pregnancy and the occurrence of congenital malformations was prospectively studied in 31,564 newborns registered in the Northern California Kaiser Permanente Birth Defects Study. The odds ratio for any major malformation and Bendectin use was 1.0 (95% confidence interval 0.8-1.4). There were 58 categories of congenital malformations; three of them were statistically associated with Bendectin exposure (microcephaly--odds ratio = 5.3, 95% confidence interval = 1.8-15.6; congenital cataract--odds ratio = 5.3, 95% confidence interval = 1.2-24.3; lung malformations (ICD-8 codes 484.4-484.8)--odds ratio = 4.6, 95% confidence interval = 1.9-10.9). This is exactly the number of associations that would be expected by chance. An independent study (the Collaborative Perinatal Project) was used to determine whether vomiting during pregnancy in the absence of Bendectin use was associated with these three malformations. Two of the three (microcephaly and cataract) had strong positive associations with vomiting in the absence of Bendectin use. We conclude that there is no increase in the overall rate of major malformations after exposure to Bendectin and that the three associations found between Bendectin and individual malformations are unlikely to be causal.

Abnormalities, Drug-Induced↗

PubMed1994

Methanol-induced neural tube defects in mice: pathogenesis during neurulation.

A spectrum of cephalic neural tube defects was observed in near-term (gestation day [GD] 17) mouse fetuses following maternal inhalation of methanol at a high concentration (15,000 ppm) for 6 hr/day during neurulation (GD 7-9). Dysraphism, chiefly exencephaly, occurred in 15% of fetuses, usually in association with reduction or absence of multiple bones in the craniofacial skeleton and ocular anomalies (prematurely open eyelids, cataracts, retinal folds). Measurements of cerebrocortical width in grossly normal, methanol-exposed fetuses revealed significant semiquantitative differences in the thicknesses of the frontal cortex and its constituent layers (neuroepithelium, intermediate cortex/subventricular plate, and cortical layer 1) as well as apparent increases in subventricular plate cellularity relative to controls. Subsequently, the early morphogenesis of these neural changes was investigated in neurulating mouse embryos to define tissue-specific patterns of methanol-induced damage that lead to cephalic axial dysraphism. Following daily 6-hr maternal inhalations of 15,000 ppm methanol during GD 7-8, the cephalic neural fold margins were swollen, blunted, and poorly elevated on GD 8.5 and 9 relative to controls. Histopathology of exposed GD 8.5 embryos revealed microcephaly in association with reductions in the cell density and mitotic index of at least 47% in the cranial mesoderm. The mitotic index in the embryonic neuroepithelium was also reduced by 55%, and groups of neural crest cells were displaced to the neural folds dorsal to the foregut (relative to the more ventral location in the facial regions of control embryos). When examined on GD 9.5 and 10.5, maternal methanol exposure (15,000 ppm for 6 hr/day) during GD 7-9 resulted in stunting, delayed rotation, and microcephaly in over 90% of the affected embryos. Persistent patency of the anterior neuropore and prosencephalic hypoplasia were seen in > 40% and up to 90% of embryos, respectively. Shallow optic vesicles, stunted branchial arches, scoliosis, and hydropericardium were also observed. Many 10.5-day-old embryos were edematous. Occult dysraphism, recognized grossly by abnormally narrow cephalic conformation and histopathologically by the absence of mesoderm in the mesencephalon, was present in at least 21% of methanol-exposed embryos on GD 9.5 and 10.5. Nile blue vital dye staining of methanol-exposed embryos revealed no difference in dye accumulation between control and treated embryos on GD 8.5, 9.0, or 9.5. There were no apparent dysmorphogenic effects in control embryos at any stage of development.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

Maternal phenylketonuria: an international study.

Maternal phenylketonuria (PKU) syndrome results in multiple congenital anomalies in the offspring, usually consisting of microcephaly, intrauterine growth retardation, dysmorphology, and congenital heart disease. Pregnancies treated preconceptionally with a phenylalanine-restricted diet and control of maternal blood phenylalanine levels within the recommended range result in normal offspring. However, in this 15-year study, several significant factors resulted in microcephaly in 27% of the offspring, and 7% exhibited serious congenital heart disease. These results occurred chiefly in women with mean IQ scores of 83 associated with low socioeconomic status and decreased educational achievement. Another important factor associated with suboptimal control of blood phenylalanine levels during pregnancy was the fact that most pregnancies were not carefully planned and occurred in women off dietary treatment with phenylalanine-restricted products. These results indicate that greater effort must be developed to assist women with PKU in remaining on diet during their reproductive years. It appears that continued adherence to the diet, resulting in normal maternal intelligence, is an important contribution to improved fetal development.

Female↗

PubMed1982

Four cases of hyperphenylalaninaemia: studies during pregnancy and of the offspring produced.

Four cases of variant hyperphenylalaninaemia during pregnancy are presented. Babies born to mothers with blood phenylalanine concentrations of 4-8 mg/dl were normal and did not exhibit significant microcephaly, although one did have a major congenital anomaly (exstrophy of the bladder). The mother with blood phenylalanine concentrations of 6-12 mg/dl during pregnancy delivered three of four infants with mild microcephaly but normal intellectual function. The data suggest that phenylalanine concentrations of 4-8 mg/dl are reasonable and desirable during pregnancy in hyperphenylalaninaemic women. Furthermore, the data do not support or refute the justification hypothesis of Bessman et al.

Adult↗

PubMed1990

A disease with immune deficiency, skin abscesses, pancytopenia, abnormal bone marrow karyotype, and increased sister chromatid exchanges: an autosomal recessive chromosome instability syndrome?

A 19-year-old girl is described with microcephaly, short stature, mental retardation, pigmentation of the skin, and recurrent skin abscesses over the whole body. Her elder brother and sister both showed growth and developmental retardation, microcephaly, and anemia. Both died during childhood. Their parents were first cousins. Laboratory studies of the proband revealed hyperchromic erythrocytes with an increased HbF content, thrombocytopenia, an impaired mitogenic response of the PHA-stimulated lymphocytes, and partial impairment of humoral and cellular immunity. She developed pancytopenia in the terminal stage of the disease. Cytogenetic studies of the bone marrow revealed 46,XX, 15p+, -18, +mar karyotype, increased chromosomal aberrations and sister chromatid exchanges, in cultured lymphocytes and skin fibroblasts. She died at age 20. Thus, the disorder in the patient was deduced as an unclassified chromosomal breakage syndrome with an apparently autosomal recessive inheritance.

Abscess↗

PubMed1989

Partial monosomy 5p and partial trisomy 5q due to paternal pericentric inversion 5(p15.1q35.1).

A male infant with karyotype 46,XY,rec(5),dup q,inv(5)(p15.1 q35.1)pat is presented. The proband showed growth and developmental retardation, complex cardiovascular abnormalities, inguinal hernia and microcephaly in addition to facial appearance and cat-like cry characteristic of the cri-du-chat syndrome. Growth and developmental retardation, and microcephaly noted in this patient were markedly more serious than those observed in patients either with partial monosomy 5p or with partial trisomy 5q alone.

Abnormalities, Multiple↗

PubMed1994

Familial mitochondrial encephalopathy with fetal ultrasonographic ventriculomegaly and intracerebral calcifications.

In two sibs antenatal ultrasonography revealed identical intracranial calcification, ventricular widening and microcephaly. The first pregnancy was artificially terminated at 19 weeks. Post-mortem examination of the brain revealed destructive calcification and extracerebral neuronal heterotopia. The second sib went to term but died 48 h after birth from irreversible lactic acidosis. Autopsy showed extensive encephalopathy with cavitation and calcification in the cerebral hemispheres, polymicrogyria, multiple neuronal heterotopia, partial callosal dysgenesis, and severe Leigh syndrome, together forming a continuum of early and late brain disruption. Mitochondrial respiratory chain abnormalities, mainly affecting complexes I and IV, and deficiency of pyruvate dehydrogenase complex were detected in skeletal muscle and in liver. A normal functioning of the respiratory chain was found in the fibroblasts. Analysis of mtDNA from muscle, liver and blood revealed normal amounts of intact mtDNA without any of the known point mutations associated with MELAS, MERRF or Leigh syndromes. The early fetal disruption and necrotic changes in the brains of sibs indicate a specific genetically determined disorder which affects neuronal migration, a finding not previously associated with respiratory chain disorders. The present disorder may mimic antenatal congenital infectious encephalopathy because of the combined finding of microcephaly and destructive intracerebral calcification.

Brain↗

PubMed1997

Disordered migration and loss of virus-infected neuronal cells in developing mouse brains infected with murine cytomegalovirus.

Microcephaly is the most prominent symptom of the developmental brain abnormalities induced by congenital cytomegalovirus (CMV) infection. To investigate the effect of CMV infection on neuronal migration in developing brains, mouse embryos on one side of uteri received, on day 15.5 of gestation (E15.5), an injection of murine CMV (MCMV) into the cerebral ventricles, and the embryos on the other side of the uteri were injected with minimum essential medium (MEM). Labeling with 5-bromo-2-deoxyuridine (BrdU) was accomplished by intraperitoneal injection of BrdU 6 h later. Disturbance of the neuronal migration and loss of neurons were observed postnatally in the brains of MCMV-infected mice, which were identified by immunohistochemical staining of viral antigen. Double staining of BrdU-labeled and viral antigen-positive cells in brains on the 7th postnatal day showed that the migration of BrdU-single-labeled cells, mainly localized in cerebral layers II-III, mostly preceded that of the viral antigen-positive cells. However, about 7.5% of the cells observed were double-labeled, especially in the layers III-IV, and a few double-stained cells were markedly disturbed in migration. In the brains of offspring labeled with BrdU 72 h after infection with MCMV on E15.5, most of the double-stained cells were seen around the ventricular and subventricular zones. These findings suggest that a disturbance of neuronal migration in addition to neuronal loss may play a crucial role in the development of microcephaly in congenital CMV infection in humans.

Animals↗

PubMed2006

A novel missense mutation in the L1CAM gene in a boy with L1 disease.

A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.

Abnormalities, Multiple↗

PubMed1985

Nocturnal sleep in mentally retarded infants with cerebral palsy.

Sleep EEG patterns in 23 mentally retarded children with cerebral palsy (CP) (from 4 months to 5 years of age) and 39 reference mentally retarded children of no abnormality with the exception of psychomotor retardation (from 4 months to 12 years of age) were studied throughout nocturnal sleep, and the following results were obtained. Eleven CP cases and 30 reference cases evidenced normal sleep patterns that could be classified into 6 stages. Twelve other cases in CP and 9 reference cases showed some abnormal sleep EEG patterns as follows: (i) in CP cases absence of EEG patterns characteristic of wakefulness, NREM sleep and REM sleep without spindles (n = 3); porencephaly with microcephaly (n = 1) and cytomegalovirus infection (n = 2), no characteristic EEG patterns of stages 1-4 without spindles (n = 2); cardiac arrest (n = 1) and agenesis of corpus callosum with lissencephaly (n = 1), absence of REM sleep (n = 1); kernicterus, spindles with an extremely low incidence (n = 5); perinatal anoxia (n = 2), kernicterus (n = 1), Lesch-Nyhan syndrome (n = 1) and cerebral palsy due to unknown etiologies (n = 1), and extreme spindles (n = 1); cerebral palsy due to unknown etiologies, (ii) in reference cases no spindles (n = 2), spindles with an extremely low incidence (n = 6), and extreme spindles (n = 1). Short sleep and long waking times during the night were noted in 4 out of 23 CP subjects; kernicterus (n = 2), agenesis of corpus callosum with lissencephaly (n = 1), and porencephaly with microcephaly (n = 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗

PubMed1990

Morphometrical and microdensitometrical studies on peptide- and tyrosine hydroxylase-like immunoreactivities in the forebrain of rats prenatally exposed to methylazoxymethanol acetate.

Methylazoxymethanol acetate (MAM Ac) injected into pregnant rats at a dose of 25 mg/kg at gestational day 15 causes microcephaly due to an atrophy of various telencephalic areas, mainly neocortex, hippocampus and basal ganglia. Previous studies demonstrated alterations in various neurochemical markers of classical transmitter systems in these regions. The present paper deals with changes in peptide and tyrosine hydroxylase (TH)-containing neurons in MAM Ac-induced microcephaly using immunocytochemistry coupled with computer-assisted morphometry and microdensitometry. No change in the number of vasoactive intestinal polypeptide (VIP)-immunoreactive neurons in the neocortex and neuropeptide Y (NPY)-immunoreactive neurons in the nucleus caudatus-putamen was found whereas cholecystokinin (CCK)-and NPY-immunoreactive neurons in the neocortex and CCK- and VIP-immunoreactive neurons in the hippocampus were decreased. The reduction of the latter peptide containing neuronal populations led to a maintained density of cells in MAM Ac-exposed rats, due to the parallel reduction of the overall mass of these regions. TH immunoreactivity was found to be unchanged in the basal ganglia, and increased in the cerebral cortex in agreement with previous reports on noradrenaline cortical system after MAM Ac exposure. The present results show a heterogenous vulnerability of different peptide immunoreactive neuronal populations to MAM Ac exposure. The sparing of VIP- and NPY-immunoreactive neurons may be due to their late development in the neocortex and striatum, respectively. The hypothesis is introduced that cortical VIP interneurons can develop independent of marked alterations in the intrinsic circuitry of the cortical region.

Animals↗

PubMed2004

Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects.

OBJECTIVE: Impaired neurodevelopmental outcome represents a major morbidity for survivors of infant heart surgery for congenital heart defects. Previous studies in these neonates have reported preoperative microcephaly, periventricular leukomalacia, and other findings. The hypothesis of this study is that preoperative cerebral blood flow is substantially diminished and might relate to preoperative neurologic conditions. METHODS: Preoperative brain magnetic resonance imaging was performed. Cerebral blood flow measurements in infants with congenital heart defects were obtained by using a novel noninvasive magnetic resonance imaging technique, pulsed arterial spin-label perfusion magnetic resonance imaging. Cerebral blood flow was measured before the operation under standard ventilation and repeated after increased carbon dioxide. RESULTS: A total of 25 term infants were studied. The average age at the time of the operation was 4.4 +/- 4.6 days. Congenital heart defects varied widely. Microcephaly occurred in 24% (6/25). Baseline cerebral blood flow was 19.7 +/- 9.2 mL . 100 g -1 . min -1 (8.0-42.2 mL . 100 g -1 . min -1 ). Five patients had cerebral blood flow measurements of less than 10 mL . 100 g -1 . min -1 . Mean hypercarbic cerebral blood flow increased to 40.1 +/- 20.3 mL . 100 g -1 . min -1 (11.4-94.0 mL . 100 g -1 . min -1 , P < .001). Pairwise analyses found that low hemoglobin levels were associated with higher baseline cerebral blood flow values ( P = .04). Periventricular leukomalacia occurred in 28% (7/25) and was associated with decreased baseline cerebral blood flow values ( P = .05) and a smaller change in cerebral blood flow with hypercarbia ( P = .003). CONCLUSIONS: Structural brain abnormalities are common in these neonates before surgical intervention. Preoperative cerebral blood flow for this cohort was low and drastically reduced in some patients. Low cerebral blood flow values were associated with periventricular leukomalacia. Carbon dioxide reactivity was preserved but might be compromised by some aspects of the cardiac anatomy. The full spectrum of cerebral blood flow measurements with this technique in congenital heart defects and their long-term significance require continued investigation.

Brain↗

PubMed2006

Human brain evolution and the "Neuroevolutionary Time-depth Principle:" Implications for the Reclassification of fear-circuitry-related traits in DSM-V and for studying resilience to warzone-related posttraumatic stress disorder.

The DSM-III, DSM-IV, DSM-IV-TR and ICD-10 have judiciously minimized discussion of etiologies to distance clinical psychiatry from Freudian psychoanalysis. With this goal mostly achieved, discussion of etiological factors should be reintroduced into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). A research agenda for the DSM-V advocated the "development of a pathophysiologically based classification system". The author critically reviews the neuroevolutionary literature on stress-induced and fear circuitry disorders and related amygdala-driven, species-atypical fear behaviors of clinical severity in adult humans. Over 30 empirically testable/falsifiable predictions are presented. It is noted that in DSM-IV-TR and ICD-10, the classification of stress and fear circuitry disorders is neither mode-of-acquisition-based nor brain-evolution-based. For example, snake phobia (innate) and dog phobia (overconsolidational) are clustered together. Similarly, research on blood-injection-injury-type-specific phobia clusters two fears different in their innateness: 1) an arguably ontogenetic memory-trace-overconsolidation-based fear (hospital phobia) and 2) a hardwired (innate) fear of the sight of one's blood or a sharp object penetrating one's skin. Genetic architecture-charting of fear-circuitry-related traits has been challenging. Various, non-phenotype-based architectures can serve as targets for research. In this article, the author will propose one such alternative genetic architecture. This article was inspired by the following: A) Nesse's "Smoke-Detector Principle", B) the increasing suspicion that the "smooth" rather than "lumpy" distribution of complex psychiatric phenotypes (including fear-circuitry disorders) may in some cases be accounted for by oligogenic (and not necessarily polygenic) transmission, and C) insights from the initial sequence of the chimpanzee genome and comparison with the human genome by the Chimpanzee Sequencing and Analysis Consortium published in late 2005. Neuroevolutionary insights relevant to fear circuitry symptoms that primarily emerge overconsolidationally (especially Combat related Posttraumatic Stress Disorder) are presented. Also introduced is a human-evolution-based principle for clustering innate fear traits. The "Neuroevolutionary Time-depth Principle" of innate fears proposed in this article may be useful in the development of a neuroevolution-based taxonomic re-clustering of stress-triggered and fear-circuitry disorders in DSM-V. Four broad clusters of evolved fear circuits are proposed based on their time-depths: 1) Mesozoic (mammalian-wide) circuits hardwired by wild-type alleles driven to fixation by Mesozoic selective sweeps; 2) Cenozoic (simian-wide) circuits relevant to many specific phobias; 3) mid Paleolithic and upper Paleolithic (Homo sapiens-specific) circuits (arguably resulting mostly from mate-choice-driven stabilizing selection); 4) Neolithic circuits (arguably mostly related to stabilizing selection driven by gene-culture co-evolution). More importantly, the author presents evolutionary perspectives on warzone-related PTSD, Combat-Stress Reaction, Combat-related Stress, Operational-Stress, and other deployment-stress-induced symptoms. The Neuroevolutionary Time-depth Principle presented in this article may help explain the dissimilar stress-resilience levels following different types of acute threat to survival of oneself or one's progency (aka DSM-III and DSM-V PTSD Criterion-A events). PTSD rates following exposure to lethal inter-group violence (combat, warzone exposure or intentionally caused disasters such as terrorism) are usually 5-10 times higher than rates following large-scale natural disasters such as forest fires, floods, hurricanes, volcanic eruptions, and earthquakes. The author predicts that both intentionally-caused large-scale bioevent-disasters, as well as natural bioevents such as SARS and avian flu pandemics will be an exception and are likely to be followed by PTSD rates approaching those that follow warzone exposure. During bioevents, Amygdala-driven and locus-coeruleus-driven epidemic pseudosomatic symptoms may be an order of magnitude more common than infection-caused cytokine-driven symptoms. Implications for the red cross and FEMA are discussed. It is also argued that hospital phobia as well as dog phobia, bird phobia and bat phobia require re-taxonomization in DSM-V in a new "overconsolidational disorders" category anchored around PTSD. The overconsolidational spectrum category may be conceptualized as straddling the fear circuitry spectrum disorders and the affective spectrum disorders categories, and may be a category for which Pitman's secondary prevention propranolol regimen may be specifically indicated as a "morning after pill" intervention. Predictions are presented regarding obsessive-compulsive disorder (OCD) (e.g., female-pattern hoarding vs. male-pattern hoarding) and "culture-bound" acute anxiety symptoms (taijin-kyofusho, koro, shuk yang, shook yong, suo yang, rok-joo, jinjinia-bemar, karoshi, gwarosa, Voodoo death). Also discussed are insights relevant to pseudoneurological symptoms and to the forthcoming Dissociative-Conversive disorders category in DSM-V, including what the author terms fright-triggered acute pseudo-localized symptoms (i.e., pseudoparalysis, pseudocerebellar imbalance, psychogenic blindness, pseudoseizures, and epidemic sociogenic illness). Speculations based on studies of the human abnormal-spindle-like, microcephaly-associated (ASPM) gene, the microcephaly primary autosomal recessive (MCPH) gene, and the forkhead box p2 (FOXP2) gene are made and incorporated into what is termed "The pre-FOXP2 Hypothesis of Blood-Injection-Injury Phobia." Finally, the author argues for a non-reductionistic fusion of "distal (evolutionary) neurobiology" with clinical "proximal neurobiology," utilizing neurological heuristics. It is noted that the value of re-clustering fear traits based on behavioral ethology, human-phylogenomics-derived endophenotypes and on ontogenomics (gene-environment interactions) can be confirmed or disconfirmed using epidemiological or twin studies and psychiatric genomics.

Animals↗

PubMed1985

Bilateral cystic nephroblastomas and multiple malformations with trisomy 8 mosaicism.

The case of a 16-month-old female infant with bilateral cystic nephroblastomas, Dandy-Walker syndrome, microcephaly, bilateral cataracts, and cerebellar heterotopia is reported. The patient's older sister, who had had bilateral cystic nephroblastomas, botryoid sarcoma involving the vagina and urinary bladder, microcephaly, arhinencephaly, and bilateral cataracts, was described in a previous report. Chromosomal study in the present case confirmed trisomy 8 mosaicism (rate of mosaicism, 16 per cent). The familial occurrence and the chromosomal disorder suggest a syndrome involving genetic abnormalities.

Abnormalities, Multiple↗

PubMed1999

Merosin-positive congenital muscular dystrophy in two siblings with cataract and slight mental retardation.

We report on two siblings that have been followed for 14 years, with merosin-positive congenital muscular dystrophy (CMD), cataract, retinitis pigmentosa, dysversion of the optic disc, but no cerebral anomalies, except for microcephaly and slight mental retardation (MR). The younger child had three generalized seizures easily controlled by anticonvulsant therapy. Both children presented hypotonia from birth, delayed psychomotor development, generalized muscular weakness, and atrophy and joint contractures of knees and ankles. The course of the disease, apparently static during the first 10 years of life, became progressive during the second decade with loss of deambulation by the age of 13. Creatine kinase was increased in both children. Bilateral cataract was diagnosed at 6-months of age. In spite of the occurrence of microcephaly, MR was slight and the siblings acquired reading and writing skills after the aged 10. Head magnetic resonance imaging showed normal results in both siblings. The classification of these cases within the broad spectrum of CMD is difficult since most of the known muscle-eye-brain syndromes generally show severe MR and brain anomalies. We consider these cases as corresponding to the rarer syndromes of merosin-positive CMD with associated features such as cataract and MR that were particularly emphasized during the 50th ENMC International Workshop on CMD [Dubowitz V. Workshop report: 50th ENMC International workshop on congenital muscular dystrophy. Neuromusc Disord 1997;7:539-547]. Further genetic, pathological, neuroradiological, and immunocytochemical studies will be necessary for better elucidation of the classification and pathogenesis of CMD.

Adolescent↗

PubMed2002

A peptide agonist of the neural cell adhesion molecule (NCAM), C3, protects against developmental defects induced by a teratogen pyrimethamine.

The neural cell adhesion molecule, NCAM, not only plays an important role in neuronal migration, differentiation and formation of connections in the developing nervous system, but also in the condensation of the mesodermal mesenchyme of the limb bud. Therefore, NCAM may be regarded as a target molecule for preventive strategies aimed at minimizing the effects of teratogens affecting the prenatal development of the nervous system and the skeleton. Treatment of fetuses with the teratogen pyrimethamine results in a reduced body weight, microcephaly and malformations of the hind limbs and forelimbs, e.g. micromelia, brachydactyly and adactyly. We here show that a peptide agonist of NCAM, C3, partly prevented the defects induced by this treatment. Although intra-amniotic administration of C3 at gestational day 14 had no effect on the pyrimethamine-induced reduction in body weight, it rescued the deficit in brain weight (microcephaly), partly reversed a decrease in thickness of the cortical plate, and significantly reduced the number of malformed fetuses. In vitro, C3 promoted survival of PC12-E2 cells treated with pyrimethamine. Since C3 is a peptide mimetic of NCAM, our data strongly suggest that stimulating of NCAM results in neuroprotection in vivo and in vitro.

Abnormalities, Multiple↗

PubMed2003

Clinical spectrum associated with cerebellar hypoplasia.

We reviewed 45 children with cerebellar hypoplasia on magnetic resonance imaging to identify clinical features associated with cerebellar hypoplasia. We then studied children presenting with any likely associated clinical feature of cerebellar hypoplasia previously observed or reported. Two hundred fifty-one children, with one or more of these features, exhibited no cerebellar hypoplasia on imaging. We compared the children with cerebellar hypoplasia with those without cerebellar hypoplasia. Logistic regression and Pearson's chi(2) test were used. Of the 45 children with cerebellar hypoplasia, 39 exhibited developmental delay; 24, speech delay; 25, seizures; nine, microcephaly; 22, hypotonia; 22, ataxia and impaired coordination; four, abnormal movements (tremor or titubation); 13, hypertonia; eight, autistic features; and 18, ocular signs (nystagmus, strabismus, and abnormal ocular movements). Statistically significant clinical features of children with cerebellar hypoplasia compared with those without were development and speech delay, microcephaly, abnormal movements, ataxia and impaired coordination, autistic features, hypotonia, and ocular signs. The regression combination of speech delay, ataxia, hypotonia, autistic features, and ocular signs correctly predicted 86% of those with cerebellar hypoplasia. Main clinical features of cerebellar hypoplasia are developmental or speech delay, autistic features, ataxia, hypotonia, and ocular signs.

Cerebellar Diseases↗