Sandra Close Kirkwood

Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington’s disease

We compared oculomotor control among individuals in the early stages of Huntingtons disease (HD), with that of individuals who are presymptomatic HD gene carriers (PSGC) and nongene carriers (NGC). The oculomotor testing paradigm included both traditional tests and a novel experimental procedure to assess visual scanning. Traditional tests elicited saccades, pursuit and optokinetic nystagmus (OKN). HD patients demonstrated marked delay in the initiation of volitional saccades (anti-saccade and memory-guided saccades), a reduced number of correct volitional saccades, reduced velocity of saccades, and a decreased OKN gain. We also studied visual scanning while the participants completed the Digit Symbol Subscale of the Wechsler Adult Intelligence Survey-Revised (WAIS-R). The HD participants demonstrated an abnormal gaze strategy, which may be associated with attention and/or planning deficits. Differences between the PSGC and NGC groups were only observed for two measures: PSGC had a decreased number of memory-guided saccades and a subtle delay in the initiation of volitional saccades. Our results suggest that oculomotor measures are a sensitive biomarker in the early stage of HD and demonstrate that the combination of more traditional oculomotor tests with visual scanning tests is useful in the evaluation of visual performance.

Evaluation of psychological symptoms among presymptomatic HD gene carriers as measured by selected MMPI scales

Individuals at-risk for Huntington disease (HD), both HD gene carriers and nongene carriers, were recruited to determine whether psychological changes are detectable among clinically presymptomatic individuals who carry the HD allele. Each participant underwent genotyping to determine HD gene carrier status and a clinical assessment that included a quantified neurological examination and an abbreviated Minnesota Multiphasic Personality Inventory (MMPI): the Hypochondriasis, Depression, Psychasthenia, Neuroticism, Cynical Hostility, and Irritability Scales and the Harris Subscales of Depression. The results of the MMPI were evaluated for differences between nongene carriers (NGC) (n = 363), presymptomatic gene carriers (PSGC) (n = 149), and those with manifest HD (MHD) (n = 26). The overall multiple analysis of variance was not significant, indicating that there was no overall difference among the three groups. However, when subscales of the MMPI were examined individually, participants with manifest HD scored higher on the Psychasthenia scale (MHD vs. PSGC, P = 0.005; MHD vs. NGC, P = 0.03) and the Harris Depression subscale, Brooding (MHD vs. PSGC, P=0.0005; MHD vs. NGC, P = 0.003). No significant correlation was found between the number of trinucleotide repeats on the disease-producing allele and any of the MMPI scales for the gene carriers, MHD or PSGC. These results verify the presence of psychological symptoms in the early phases of MHD but not in PSGC. Thus, further study of the behavioral and mood symptoms thought to accompany HD using measures designed specifically to detect depressive symptoms and changes in behavior specific to HD is warranted to delineate the timing of onset of the psychological symptoms.

Linkage of type II and type III cystinuria to 19q13.1: Codominant inheritance of two cystinuric alleles at 19q13.1 produces an extreme stone-forming phenotype

Cystinuria, a renal tubule disease affecting urinary cystine excretion with or without kidney stone formation, previously was mapped to chromosome region 2p.21. Mutations in the gene SLC3A1 or NBAT, the reported candidate gene for cystinuria at 2p.21, have been demonstrated in individuals with the autosomal recessive Type I cystinuria phenotype. Recently, the Type III cystinuria phenotype was mapped to chromosome region 19q13.1. Here we report a kindred of 39 persons in two families of cystinurics, Types II and III, that support linkage to 19q13.1 and exclude 2p.21. Based on a dominant model of inheritance, two-point analysis of the entire pedigree produced a maximum lod score (Z(max)) of 3.82 at marker D19S425. Multipoint analysis yielded a lod score of 4.96 at this marker, and a resultant lod score of 5.90 using a codominant model of inheritance. Furthermore, a candidate gene interval of 8.9 cM, flanked by markers D19S225 and D19S223, was obtained using multipoint and haplotype analyses. Thus, this kindred demonstrates the linkage of Type II cystinuria to 19q13.1 and confirms the linkage of Type III cystinuria at 19q13.1 while excluding the marker D19S225 that was previously included in the critical interval.

Relationship of Family History Scores for Stroke and Hypertension to Quantitative Measures of White-Matter Hyperintensities and Stroke Volume in Elderly Males

White-matter hyperintensities (WMHI) are frequently associated with cerebrovascular risk factors in the elderly, particularly hypertension, and have been interpreted as a subclinical form of ischemic brain damage. WMHI, clinical stroke and blood pressures show significant genetic influences. The objective of this study was to determine whether a relationship exists between family history of stroke and/or hypertension in first degree relatives and WMHI in the elderly. WMHI and stroke (CVA) volumes were quantified from brain MRI performed on 414 white, male twins born between 1917 and 1927 (average age 72.3 ± 2.9 years). WMHI, adjusted for age and head size, was significantly correlated with the family history score (r = 0.21, p < 0.001). Dividing the family history scores into quintiles revealed significant differences in WMHI by quintile mean (p < 0.05). Subjects in the highest quintile of family history score had the highest mean WMHI. Recalculation of the family history score, by only counting relatives reported to have had a clinical stroke as a positive event, revealed a nonsignificant correlation with WMHI, but the correlation of the family history score with MRI CVA volume was significant (p < 0.05). Stepwise multivariate analysis including ApoE status, current smoking status, smoking packyear history, Doppler ankle/arm blood pressure ratios, current and long term hypertensive status and current systolic and diastolic pressures indicated that the stroke/hypertension family history score was the single best predictor (p < 0.01) of WMHI volumes. Family history was not an independent predictor of CVA volume.

Visual function in Huntington's disease patients and presymptomatic gene carriers.

Disturbances of visual cognition, visuomotor performance, and visual memory have been described frequently in Huntingtons disease (HD). Early stage visual abnormalities could contribute to these deficits. We evaluated visual processing in 20 control subjects who were non‐gene carriers at risk for HD, nine presymptomatic gene‐positive subjects, and eight subjects with a recent diagnosis of Huntingtons disease. Visual perceptual tests of contrast sensitivity and motion discrimination were used to probe early stage visual processing. Extraocular movements were evaluated in a neurologic examination, and the Digit Symbol test was used to test visual motor performance. Contrast sensitivity did not differ among the three groups. Motion discrimination was impaired in HD subjects but not in the presymptomatic gene carriers when compared to gene noncarriers. Among gene carriers, impaired motion discrimination performance was associated with poorer Digit Symbol performance and extraocular abnormalities. These findings suggest that the early stages of HD are associated with disturbances of motion perception as well as disruptions of visual motor and ocular motor performance.

Identification of genes for complex disease using longitudinal phenotypes.

Using the simulated data set from Genetic Analysis Workshop 13, we explored the advantages of using longitudinal data in genetic analyses. The weighted average of the longitudinal data for each of seven quantitative phenotypes were computed and analyzed. Genome screen results were then compared for these longitudinal phenotypes and the results obtained using two cross-sectional designs: data collected near a single age (45 years) and data collected at a single time point. Significant linkage was obtained for nine regions (LOD scores ranging from 5.5 to 34.6) for six of the phenotypes. Using cross-sectional data, LOD scores were slightly lower for the same chromosomal regions, with two regions becoming nonsignificant and one additional region being identified. The magnitude of the LOD score was highly correlated with the heritability of each phenotype as well as the proportion of phenotypic variance due to that locus. There were no false-positive linkage results using the longitudinal data and three false-positive findings using the cross-sectional data. The three false positive results appear to be due to the kurtosis in the trait distribution, even after removing extreme outliers. Our analyses demonstrated that the use of simple longitudinal phenotypes was a powerful means to detect genes of major to moderate effect on trait variability. In only one instance was the power and heritability of the trait increased by using data from one examination. Power to detect linkage can be improved by identifying the most heritable phenotype, ensuring normality of the trait distribution and maximizing the information utilized through novel longitudinal designs for genetic analysis.

Parametric linkage analysis and disequilibrium methods to identify loci for complex disease.

A two‐step process was used to find loci contributing to the qualitative disease phenotype in the Genetic Analysis Workshop (GAW) 12 simulated data. The first step used parametric linkage analysis with a limited number of dominant and recessive models to detect linkage to chromosomal regions. Subsequently, a subset of the simulated biallelic sequence polymorphisms was used for transmission/disequilibrium tests and to build haplotypes to fine map the disease‐predisposing polymorphism(s). A haplotype, strongly associated with the disease phenotype whose proximal end was within 39 base pairs of the functional allele for simulated major gene 6, was identified in the isolated population.