G. Robert DeLong

Timing of Vulnerability of the Brain to Iodine Deficiency in Endemic Cretinism

BACKGROUND Endemic cretinism, caused by severe iodine deficiency during pregnancy, is the worlds most common preventable cause of mental retardation. It can be prevented by iodine treatment before conception, but whether it can be prevented or ameliorated by treatment during pregnancy or after delivery is not known. METHODS In a severely iodine-deficient area of the Xinjiang region of China, we systematically administered iodine to groups of children from birth to three years of age (n = 689) and women at each trimester of pregnancy (n = 295); we then followed the treated children and the babies born to the treated women for two years. We used three independent measures of neural development: the results of the neurologic examination, the head circumference (which correlates with brain weight in the first postnatal year), and indexes of cognitive and motor development. Untreated children one to three years of age, who were studied when first seen, served as control subjects. RESULTS The prevalence of moderate or severe neurologic abnormalities among the 120 infants whose mothers received iodine in the first or second trimester was 2 percent, as compared with 9 percent among the 752 infants who received iodine during the third trimester (through the treatment of their mothers) or after birth (P = 0.008). The prevalence of microcephaly (defined as a head circumference more than 3 SD below U.S. norms) decreased from 27 percent in the untreated children to 11 percent in the treated children (P = 0.006), and the mean (+/- SD) developmental quotient at two years of age increased (90 +/- 14, vs. 75 +/- 18 in the untreated children; P < 0.001). Treatment in the third trimester of pregnancy or after delivery did not improve neurologic status, but head growth and developmental quotients improved slightly. Treatment during the first trimester, which was technically problematic, improved the neurologic outcome. CONCLUSIONS Up to the end of the second trimester, iodine treatment protects the fetal brain from the effects of iodine deficiency. Treatment later in pregnancy or after delivery may improve brain growth and developmental achievement slightly, but it does not improve neurologic status.

Factor Analysis of Restricted and Repetitive Behaviors in Autism Using the Autism Diagnostic Interview-R

The current study examined the factor structure of restricted and repetitive behaviors (RRB) in children with autism. Factor extraction procedures of 12 items from the Autism Diagnostic Interview-Revised (ADI-R) were applied in N = 207 individuals with autism. Two interpretable factors were identified: Factor 1—repetitive sensory motor actions and Factor 2—resistance to change. There was a significant negative correlation between an index of level of adaptive functioning and Factor 1. Intraclass correlations were not significant for either factor in a subset of families with two or more siblings with autism (multiplex). No differences in scores were apparent for either factor when multiplex families and families containing only one affected individual with autism (singleton) were compared. RRB in autism are represented by two distinct factors which may reflect two separate groups within autism. Defining subgroups within autism will allow for reduction of clinical heterogeneity and enhance our ability to dissect the genetic etiology of this complex disorder.

Correlation of Family History with Specific Autistic Subgroups: Asperger's Syndrome and Bipolar Affective Disease.

The etiology of infantile autism is not known. To assess the possible role of familial psychopathology, we investigated a group of autistic subjects subgrouped by level of language functin. Family histories were obtained by the family history method. Neurological status was assessed by neurological diagnostic examination and prenatal and perinatal history. The results showed a high incidence of Aspergers syndrome in family members of high-functioning autistic subjects only. The rate of bipolar affective disorder in family members was 4.2%, higher than in the general population; it was significantly higher in families with Aspergers syndrome, suggesting an etiological link between Aspergers syndrome and manic depression. Positive neurological findings were concentrated in the low-functioning subgroup. These findings imply different etiologies for high- versus low-functioning autism, with high-functioning autism related to familial factors, especially Aspergers syndrome.

Histogenesis of fetal mouse isocortex and hippocampus in reaggregating cell cultures

Abstract Hippocampus and isocortex from brains of fetal mice of gestational age 16 days to newborn (19–20 days postconception) were dissociated with trypsin to produce suspensions of single cells. These were allowed to aggregate in liquid medium in rotating cultures at 36.5°C for 6–8 days. The histogenetic patterns formed in the aggregates were characteristic of the brain region sampled and depended closely on the developmental stage of the tissue at the time of dissociation. For hippocampus, cells dissociated at gestational ages of 16–18 days produced large aggregates with segregation of hippocampal pyramidal cells from other cell populations, but without further organization. Cells dissociated at a very narrow time range about 18.5 days gestation produced in aggregates a remarkable histogenetic pattern closely resembling normal hippocampal architecture, with a characteristic curved pyramidal cell layer of appropriate thickness bounded above and below by cell-sparse zones, and in isolated cases a dentate gyrus and subiculum in their normal relations to the pyramidal layer. The histogenetic events included parallel alignment of elongate hippocampal pyramidal cells and uniform orientation of their apical processes. Cells from fetuses older than 18.5 days mixed randomly in the aggregates, apparently having lost the capacity for self-organization. Thus the orienting mechanism is shown to be operative only at a very specific time in the developmental history of the hippocampus. The histogenetic events occurring in aggregates of cells from different developmental stages correlated closely with the state of histogenetic development in the intact undissociated hippocampus. A similar analysis was performed with dissociated and aggregated cerebral isocortical cells. Cells dissociated at gestational ages between 17.5 and 18.5 days formed spherical aggregates containing an outermost cell-sparse “molecular layer” and a deeper, sharply delimited, concentrically arranged cortical plate composed of young neurons with apical dendrites disposed radially toward the outer surface of the aggregate. Cells dissociated from younger fetuses attained little organization in 7 days in vitro , and cells from older fetuses formed only poor aggregates with randomly mixed cells.

Association Analysis of Chromosome 15 GABAA Receptor Subunit Genes in Autistic Disorder

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p = 0.02 and intron5_687T/C, p = 0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD.

Magnetic resonance imaging evidence of hippocampal sclerosis in progression: a case report.

Summary: A 32‐month‐old child presented in status epilepticus (SE) involving the left side of the body. Fast spin‐echo magnetic resonance imaging (FSE‐MRI) with hippocampal volumetry performed ≤24 h after the seizure showed increased T2 signal of the right hippocampus, but no atrophy. Complex partial seizures (CPS) appeared at age 33 months, and three more episodes of SE occurred between 33 and 37 months of age. Follow‐up FSE‐MRI at 34 and at 45 months of age demonstrated progressive hippocampal atrophy with resolution of the increased T2 signal. Her CPS became intractable and, at age 51 months, she underwent right temporal lobectomy. In the ensuing 5 months, she has had only one major motor seizure. This case demonstrates that acute increased hippocampal T2 signal intensity can occur soon after SE and hippocampal sclerosis (HS) may become evident within months in the setting of recurrent early childhood SE. This observation may support the hypothesis that early childhood SE can lead to HS. Furthermore, this case suggests that years of temporal lobe CPS may not be necessary for development of HS.

Effect on infant mortality of iodination of irrigation water in a severely iodine-deficient area of China

BACKGROUND Hotien county in Xinjiang province, China, is an area of severe iodine deficiency and has a high infantmortality rate. We investigated whether iodine replacement through iodination of the irrigation water would decrease infant mortality. METHODS We added potassium iodate to irrigation water over a 2 to 4 week period beginning in 1992 in certain areas of three townships (Tusala, Long Ru, and Bakechi). Logistic regression analysis was used to compare the odds ratios for infant and neonatal mortality in treated and intreated areas. FINDINGS The median urinary iodine concentration significantly increased in women of child-bearing age from < 10 micrograms/L to 55 micrograms/L. Infant-mortality rates decreased in the treated areas of Long Ru (mean [SD] 58.2 [4.4] per 1000 births to 28.7 [7.1] per 1000 births), Tusala (47.4 [12.4] per 1000 births to 19.1 [1.5] per 1000 births), and Bakechi (106.2 [9.5] per 1000 births to 57.3 [7.3] per 1000 births). Similar results were also seen for neonatal mortality. On regression analysis iodine treatment and time were significant independent predictors of infant mortality. INTERPRETATION Iodine supplementation of irrigation water in areas of severe iodine deficiency decreases neonatal and infant mortality. Iodine replacement has probably been an important factor in the national decrease in infant mortality in China.

Alignment defect of reaggregating cells in cultures of developing brains of reeler mutant mice

Abstract The mechanism of cell alignment and orientation in developing mouse cerebral isocortex and cerebellar cortex was analyzed in reaggregating cell cultures from normal and reeler mutant mice. Isocortical cells dissociated from normal fetuses at 17.5 to 18.5 days of gestation reaggregated over a period of several days in vitro and formed a radially symmetrical pattern in which the young neurons reformed a cortical plate bounded externally by a molecular layer and internally by a cell-poor nerve fiber zone. Cells from reeler littermates formed similar spherical aggregates at about the same rate, but the innermost zone was not recognized and cells within the cortical plate appeared randomly oriented. Cells from younger or older mice did not align into a cortical pattern, and no differences between normal and reeler specimens were discerned. Likewise cerebellar cells dissociated from normal mice at around 4 days after birth reaggregated to form a broad homogeneous internal zone of small cells segregated from a limited number of large, pale-staining neurons; comparable cells from reeler mice 3–4 days old failed to attain any pattern of histological organization. It is shown that the ability to aggregate is a separate process from that of histogenetic self-organization of cells within an aggregate, and that the latter process is affected by a specific genetic mutation known to alter cortical organization. The similarity of patterns of cell alignment in the aggregates to those in vivo probably indicates that cells in the aggregates reproduce the in vivo histogenetic processes. The results argue that specific cell alignment in vivo is not dependent on a preexisting tissue matrix or on the patterned sequential entry of cells into the developing cortical plate. A distinction is made between primary migration and final cell alignment. The reeler genetic locus appears to act directly on cortical cells, rather than at a distance, and probably affects a majority of the cells rather than only the ones initially reaching the cortical plate. The possible genetically dictated properties of cells which could account for the specific alignment in aggregates are discussed.

Effects of fluoxetine treatment in young children with idiopathic autism

Thirty‐seven children, aged between 2 and 7 years, with idiopathic autism underwent an open‐label trial of fluoxetine treatment. All had assessment of diagnosis, developmental status, and family psychiatric history. Independent developmental testing before and after starting fluoxetine permitted quantification of language acquisition in a subgroup. Twenty‐two of the 37 children had a beneficial treatment response sustained during continuing treatment for 13 to 33 months (mean 21 months). Eleven had an excellent response and were able to attend mainstream classrooms. Eleven had a good response though they remained identifiably autistic. Fifteen children had no benefit. Responders showed behavioral, language, cognitive, affective, and social improvements. Responders with adequate testing showed marked increases in language acquisition at every stage of development as compared with (1) pretreatment status, (2) responses to other treatments, (3) ability in non‐language (matching) tasks, and (4) historical controls from the literature. The response to fluoxetine strongly correlated with a family history of major affective disorder. These preliminary findings implicate serotonergic mechanisms in autistic symptomatology and warrant further study with controlled trials.

Neurological signs in congenital iodine-deficiency disorder (endemic cretinism).

Neurological examinations were made of 67 children and adults with congenital iodine‐deficiency disorder (endemic cretinism) in four rural villages in highland Ecuador. There was a distinct and readily identifiable pattern of neurological deficits. These included, to varying degrees: deaf‐mutism or lesser degrees of bilateral hearing‐loss or dysarthria; spasticity, particularly involving the proximal lower extremities; mental deficiency of a characteristic type; and rigidity and bradykinesia. Not all of these elements were found in all cases. Less common features were strabismus, kyphoscoliosis and frontal‐lobe signs. There were exceptional cases with hypotonia. In contrast, cerebellar function was largely spared, as were functions of emotion and attention, vegetative and autonomic functions, social interaction, and probably memory, except in the most severely involved.