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.

Impaired reciprocal social interaction is one of the core features of autism. While its determinants are complex, one biomolecular pathway that clearly influences social behavior is the arginine–vasopressin (AVP) system. The behavioral effects of AVP are mediated through the AVP receptor 1a (AVPR1a), making the AVPR1a gene a reasonable candidate for autism susceptibility. We tested the gene's contribution to autism by screening its exons in 125 independent autistic probands and genotyping two promoter polymorphisms in 65 autism affected sibling pair (ASP) families. While we found no nonconservative coding sequence changes, we did identify evidence of linkage and of linkage disequilibrium. These results were most pronounced in a subset of the ASP families with relatively less severe impairment of language. Thus, though we did not demonstrate a disease-causing variant in the coding sequence, numerous nontraditional disease-causing genetic abnormalities are known to exist that would escape detection by traditional gene screening methods. Given the emerging biological, animal model, and now genetic data, AVPR1a and genes in the AVP system remain strong candidates for involvement in autism susceptibility and deserve continued scrutiny.

Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11–q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5′ introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11–q13.

The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.

Magnetic resonance imaging (MRI) research has suggested that autistic individuals have hypoplasia of cerebellar lobules VI and VII, the pons, and enlargement of the fourth ventricle. Using MRI we measured the mid-sagittal area of these structures in 15 high-functioning autistic males; 15 age- and IQ-comparable male volunteers (control group I); and 15 male volunteers comparable to cases on age and parental socioeconomic status (SES) (control group II). Using ratio measures, cerebellar lobules VI-VII were found to be smaller in autistic subjects than controls in group II but not those in group I. No differences were found after multivariate analysis adjusting for mid-sagittal brain area (MSBA), age, and IQ. The size of the pons and fourth ventricle did not differ between cases and controls, although autistic subjects were noted to have a significantly larger MSBA than subjects in either control group.

Magnetic resonance imaging and a comprehensive cognitive evaluation were carried out in a series of 29 patients with mild to moderate Huntington's disease (HD). A factor analysis of the neuropsychological test scores provided three factors: a memory/speed-of-processing factor, a "frontal" factor, and a response inhibition factor. The memory/speed factor correlated significantly with measures of caudate atrophy, frontal atrophy, and atrophy of the left (but not the right) sylvian cistern. There were no significant correlations between the "frontal" or response inhibition factors and measures of cortical or subcortical brain atrophy. Our findings confirm that subcortical atrophy is significantly correlated with specific cognitive deficits in HD, and demonstrate that cortical atrophy also has important association with the cognitive deficits of patients with HD.

Underrecognition and undertreatment of affective disorders constitute a serious public health problem in this country. The recent availability of improved methods of genetic linkage analysis make the definition of the genetic basis of some types of bipolar affective disorders feasible within the foreseeable future.

Patients with Huntington's Disease (HD) who were without dementia were compared to unilateral stroke patients and controls as previously reported in 1983, to discover if they had a prosodic defect. Subjects were presented tape-recorded speech filtered sentences and asked to indicate the tone of voice as happy, sad or angry (affective prosody), or as a question, command or statement (propositional prosody). HD patients were impaired in comprehension of both types of prosody compared to controls but were not different from stroke patients. A second study compared early HD patients with at-risk siblings and spouse controls on comprehension of affective and propositional prosody, discrimination of both types of prosody, rhythm discrimination and tonal memory (Seashore tests). HD patients were impaired in both comprehension and discrimination of all types of prosody. HD patients were less accurate than at-risk patients on the tonal memory task but not on the rhythm discrimination task. These findings suggest compromise in ability to understand the more subtle prosodic aspects of communication which may contribute to social impairment of HD patients very early in the course of the disease.

The relationship of dopamine receptor binding in the caudate nucleus and the putamen to neurological and neuropsychological functioning was examined in 21 patients with Huntington's disease (HD) and eight individuals at risk of developing Huntington's disease. A significant reduction in relative binding of [11C]3-N-methylspiperone to the dopamine receptor was found in both the caudate and putamen of HD patients. Binding in the caudate was correlated only with tests of rapid coding and set alternation, while binding in the putamen was correlated only with duration of illness. The findings indicate that the well-described atrophic changes in the striatum of Huntington's disease patients are accompanied by receptor alterations. They also support previous animal and human studies indicating that the caudate nucleus plays a larger role in cognition than in motor functions.

CT-scan measurements of cortical and subcortical atrophy were carried out in 34 patients with Huntington's disease (HD). While a significant correlation was observed between parameters of subcortical atrophy (bicaudate ratio, bifrontal ratio and third ventricular ratio) and duration of the disease, there was no significant correlation between these parameters and age. On the other hand, measurements of cortical atrophy (frontal fissure ratio and cortical sulci ratio) correlated significantly with age but not with duration of the disease. When a group of 24 HD patients were compared on CT-scan measurements with a group of 24 age-matched normal controls, significant differences were obtained for all the variables examined, but the bicaudate ratio showed the highest sensitivity and specificity. Even mildly affected patients, with duration of motor symptoms less than 3 years had higher bicaudate ratios than age-matched controls.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder of late onset, characterized by progressive motor disturbance, psychological manifestations, and intellectual deterioration. The HD gene has been genetically mapped by linkage to the DNA marker D4S10 , but the exact physical location of the HD defect has remained uncertain. To delineate critical recombination events revealing the physical position of the HD gene, we have identified restriction fragment length polymorphisms for two recently mapped chromosome 4 loci, RAF2 and D4S62 , and determined the pattern of segregation of these markers in both reference and HD pedigrees. Multipoint linkage analysis of the new markers with D4S10 and HD establishes that the HD gene is located in a very small physical region at the tip of the chromosome, bordered by D4S10 and the telomere. A crossover within the D4S10 locus orients this segment on the chromosome, providing the necessary information for efficient application of directional cloning strategies for progressing toward, and eventually isolating, the HD gene.

Corticotropin-releasing hormone-like immunoreactivity (CRH-IR) was measured in control and Huntington's disease brain tissues obtained postmortem. The concentration of CRH-IR was markedly decreased in the caudate/putamen in Huntington's disease; the concentration of somatostatin-like immunoreactivity measured in the same extracts was significantly increased in the caudate/putamen in Huntington's disease compared with the control group. In contrast to previously reported decreases in CRH-IR in the cerebral cortex in Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy, no significant differences were observed in the concentrations of CRH-IR between controls and Huntington's disease in frontal, parietal, temporal, occipital and cingulate cortex and in globus pallidus.

We studied eye movements in 50 patients with Huntington's disease. Fixation was impaired in 73% of patients; such individuals had difficulty in suppressing saccades toward novel visual stimuli. Impaired initiation of saccades was manifest by increased reaction time (89%) and inability to make a saccade without head movement (89%) or blink (35%). Saccades and quick phases of nystagmus were slowed in 62%. Smooth pursuit was abnormal in 60%, and vergence in 33%. The vestibulo-ocular reflex and the ability to hold eccentric gaze were preserved even late in the disease.

A mildly dyslexic boy of 11 years, with no neurological deficit or history of epileptic seizures, had marked hypersomnia for 2 years, which was most pronounced in the morning hours.