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Biomedical subjects

G R DeLong

Publications and source records attributed to G R DeLong.

At least 19 recordsLinked to original sources
PubMed2005

Analysis of the RELN gene as a genetic risk factor for autism.

Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.

5' Untranslated Regions↗
PubMed2004

No association between the APOE gene and autism.

Autism is a neurodevelopmental disorder characterized by stereotypic and repetitive behavior and interests, together with social and communicative deficiencies. The results of several genomic screens suggest the presence of an autism susceptibility locus on chromosome 19p13.2-q13.4. The apolipoprotein E (APOE) gene on chromosome 19 encodes for a protein, apoE, whose different isoforms (E2, E3, E4) influence neuronal growth. APOE participates in lipid transport and metabolism, repair, growth, and maintenance of axons and myelin during neuronal development. The APOE protein competes with the Reelin protein for VLDL/APOER2 receptor binding. Several studies have reported evidence for an association between autism and the Reelin gene. Based on these data we tested for association between APOE and autism using family-based association methods in a data set of 322 autism families. Three promoter, one intronic, and one 3' UTR single nucleotide polymorphisms (SNPs) in the APOE gene (-491a/t, -427c/t, -219g/t, 113c/g, and 5361c/t) as well as the APOE functional polymorphism (E2, E3, E4) were examined and failed to reveal significant evidence that autism is associated with APOE.

Apolipoproteins E↗
PubMed2003

Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes.

Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)--derived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic Interview-Revised--was used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the gamma-aminobutyric acid-receptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits.

Autistic Disorder↗
PubMed2000

Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder.

Autistic disorder (AD) is a neurodevelopmental disorder characterized by abnormalities in behavior, communication, and social interactions and functioning. Recently, Cook et al. reported significant linkage disequilibrium with an AD susceptibility locus and a marker, GABRB3 155CA-2, in the gamma-aminobutyric acid(A) (GABA(A)) receptor beta3-subunit gene on chromosome 15q11-q13. This linkage disequilibrium was detected using a multiallelic version of the transmission/disequilibrium test (TDT) in a sample of nuclear families having at least one child with autistic disorder. In an attempt to replicate this finding we tested for linkage disequilibrium with this marker, as well as with three additional markers in and around the GABA(A) receptor beta3-subunit gene, in an independent, clinically comparable set of AD families. Unlike Cook et al., we failed to detect significant linkage disequilibrium between GABRB3 155CA-2 and AD in our sample. We did, however, find suggestive evidence for linkage disequilibrium with a marker, GABRB3, approximately 60 kb beyond the 3' end of beta3-subunit gene. This finding lends support for previous reports implicating the involvement of genes in this region with AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:43-48, 2000

Autistic Disorder↗
PubMed2000

Genetic studies in autistic disorder and chromosome 15.

Autistic disorder (AD) is a developmental disorder affecting social interactions, communication, and behavior. AD is a disease of complex genetic architecture. It is postulated that several genes contribute to the underlying etiology of AD. Chromosome 15 is of particular interest due to numerous reports of AD in the presence of chromosomal abnormalities, located mainly in the 15q11-q13 region. There are also a number of plausible candidate genes in this area, including the gamma-aminobutyric acidA (GABA(A)) receptor gene complex. We have undertaken a study of this region of chromosome 15 in a data set of 63 multiplex families (with 2 or more AD affected individuals per family). We found evidence in support of linkage to the 15q11-q13 region, as well as evidence of increased recombination in this region. These findings provide further support for the involvement of chromosome 15q11-q13 in the genetic etiology of AD.

Autistic Disorder↗
PubMed2000

Three children with a syndrome of obesity and overgrowth, atypical psychosis, and seizures: a problem in neuropsychopharmacology.

Three children presented with a complex syndrome of atypical psychotic and extremely immature behavior, obesity and overgrowth, borderline retardation, and seizures (prominent in two). Weight overgrowth exceeded height overgrowth and was stratospheric (up to 8 SD above mean). Obesity seemed related to lack of satiety. The cases fit no known condition: hypothalamic damage, Sotos' syndrome, and Prader-Willi syndrome were excluded. Empirical treatment with anticonvulsants (carbamazepine and acetazolamide) together with psychotropic agents (selective serotonin reuptake inhibitors and risperidone) controlled seizures, improved behavior, and stopped weight gain in each patient. We have not found this syndrome previously described. The etiology is unknown: perinatal encephalopathy could be a factor in the two patients with prominent seizures; in the third, familial major affective disorder is implicated. Medication responses suggest a low-serotonin state underlying the lack of satiety, an imbalance of serotonin and noradrenergic modulation in the hypothalamus, and epileptogenic disorders (or affective disorder responsive to anticonvulsants in one case) involving these same systems.

Anticonvulsants↗
PubMed1999

Genetic studies of autistic disorder and chromosome 7.

Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.

Adult↗
PubMed1998

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.

Antidepressive Agents↗
PubMed1997

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.

Adult↗
PubMed1997

The clinical syndrome of early-life bilateral hippocampal sclerosis.

Four infants had bilateral hippocampal sclerosis by magnetic resonance scans, including oblique coronal fast spin echo images of the temporal lobes; [18F]fluorodeoxyglucose-positron emission tomographic scans, done in 2 infants, showed isolated bilateral anterior temporal lobe hypometabolism. All had epilepsy with episodes of status epilepticus. Despite adequate motor and sensory functions, all failed to develop language (or lost attained language), social skills, and complex purposive or adaptive activity, even after epilepsy was controlled. Bilateral hippocampal dysfunction in early life appears to be associated with a profound failure of cognitive capacities, including language learning and learning of complex social and adaptive skills in general. The deficits correspond to the cognitive deficits of severe infantile autism. Hippocampal function, or more generally medial temporal lobe function, appears necessary for language learning in the infant, as well as for complex social and adaptive learning.

Brain Diseases↗
PubMed1996

Intracranial fibromuscular dysplasia in a 5-year-old child.

A 5-year-old girl presenting with acute middle cerebral artery stroke was diagnosed as having intracranial fibromuscular dysplasia by angiographic findings of focal changes in the proximal right middle cerebral artery and pathological dilatation of the right internal carotid artery at the base of the skull, as well as dissection of at least one of the middle cerebral artery branches and nonfilling of two or perhaps three remaining middle cerebral artery segmental branches. Her clinical condition improved after management of the increased intracranial pressure. She did not receive any medication after discharge and had virtually no residual sequelae. Our case documents an unusual location and age of onset of a patient with fibromuscular dysplasia.

Brain Diseases↗
PubMed1994

Timing of vulnerability of the brain to iodine deficiency in endemic cretinism.

BACKGROUND: Endemic cretinism, caused by severe iodine deficiency during pregnancy, is the world's 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.

Brain↗
PubMed1994

Iodination of irrigation water as a method of supplying iodine to a severely iodine-deficient population in Xinjiang, China.

Severe iodine deficiency still occurs in many countries, and causes cretinism and mental impairment. In southern Xinjiang province, China, after usual methods of iodine supplementation had failed, we iodinated irrigation water to increase iodine in soil, crops, animals, and human beings. 5% potassium iodate solution, dripped into an irrigation canal for 12 or 24 days, increased soil iodine 3-fold, and crop and animal iodine 2-fold. Median urinary iodine excretion in children increased from 18 to 49 micrograms/L (two groups of similar age). The cost for iodine was US $0.05 per person per year. Soil iodine remained stable over one winter, and dripping of iodine during the second year (US $0.12 per person per year) resulted in a further 4-fold increase in soil iodine and a 1.8-fold increase in iodine in crops. We conclude that iodination of irrigation water is an advantageous and cost-effective method of supplying iodine in southern Xinjiang, and may be useful in other areas dependent on irrigation.

Agriculture↗
PubMed1994

Neuronal migration disorders: positron emission tomography correlations.

We analyzed the interictal [18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) findings of 17 epileptic patients with neuronal migration disorders (NMDs). Fifteen patients had abnormal PET findings, i.e., focal hypometabolism in 9 patients and displaced metabolic activity of normal gray matter in 6. All 15 patients had magnetic resonance imaging (MRI) abnormalities; however, PET abnormality assisted in the identification of NMDs on MRI in 3 patients. Two patients with negative MRI also had negative PET studies. PET hypometabolism appeared to correlate with severity of neuronal dysgenesis or temporal lobe involvement, or both. Displaced metabolic activity of gray matter is regarded as a unique interictal [18F]fluoro-2-deoxy-D-glucose-PET finding in NMD. This study demonstrates variable metabolic patterns in NMD and that PET may be a useful complement to MRI in the evaluation of NMD.

Adult↗