Gene-positive Individuals Research Articles

Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease.

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population.

Individuals' experiences in genetic counseling and predictive testing for familial amyotrophic lateral sclerosis.

As clinical genetic testing in the amyotrophic lateral sclerosis (ALS) diagnostic setting increases, the identification of at-risk family members has also expanded. No practice guidelines specifically for predictive genetic testing exist, and few studies about the psychological impacts of testing in this subgroup have occurred, limiting the ability to tailor recommendations and counseling in this community. We surveyed asymptomatic individuals at risk for inheriting an ALS-associated gene mutation. The 80-question survey was designed using a combination of validated measures (General Anxiety Disorder; FACToR; Decision Regret Scale) and original items. Ninety participants completed the survey, including those who completed predictive genetic testing (N = 42) and those who did not (N = 48). Gene positive individuals experienced greater negativity, uncertainty, and overall psychological impairment (p = 0.002; p < 0.001; p = 0.001). Individuals who had not undergone testing reported thinking about their risk multiple times per day and experiencing more decisional regret than those who tested (p = 0.006). In terms of decision-making, being prepared for potential clinical drug trials was a more important potential benefit among those who underwent testing (p = 0.026). Participants valuing preparedness for clinical drug trials supports the concept that genetic testing for ALS will increase as research in gene-targeted therapeutics progresses. This study describes factors relevant to the genetic testing decision-making process and adaptation to results from the perspective of at-risk individuals, which can ultimately guide genetic counseling practice in this population.

Prognostic enrichment for early-stage Huntington’s disease: An explainable machine learning approach for clinical trial

BackgroundIn Huntington’s disease clinical trials, recruitment and stratification approaches primarily rely on genetic load, cognitive and motor assessment scores. They focus less on in vivo brain imaging markers, which reflect neuropathology well before clinical diagnosis. Machine learning methods offer a degree of sophistication which could significantly improve prognosis and stratification by leveraging multimodal biomarkers from large datasets. Such models specifically tailored to HD gene expansion carriers could further enhance the efficacy of the stratification process. ObjectivesTo improve stratification of Huntington’s disease individuals for clinical trials. MethodsWe used data from 451 gene positive individuals with Huntington’s disease (both premanifest and diagnosed) from previously published cohorts (PREDICT, TRACK, TrackON, and IMAGE). We applied whole-brain parcellation to longitudinal brain scans and measured the rate of lateral ventricular enlargement, over 3 years, which was used as the target variable for our prognostic random forest regression models. The models were trained on various combinations of features at baseline, including genetic load, cognitive and motor assessment score biomarkers, as well as brain imaging-derived features. Furthermore, a simplified stratification model was developed to classify individuals into two homogenous groups (low risk and high risk) based on their anticipated rate of ventricular enlargement. ResultsThe predictive accuracy of the prognostic models substantially improved by integrating brain imaging features alongside genetic load, cognitive and motor biomarkers: a 24 % reduction in the cross-validated mean absolute error, yielding an error of 530 mm3/year. The stratification model had a cross-validated accuracy of 81 % in differentiating between moderate and fast progressors (precision = 83 %, recall = 80 %). ConclusionsThis study validated the effectiveness of machine learning in differentiating between low- and high-risk individuals based on the rate of ventricular enlargement. The models were exclusively trained using features from HD individuals, which offers a more disease-specific, simplified, and accurate approach for prognostic enrichment compared to relying on features extracted from healthy control groups, as done in previous studies. The proposed method has the potential to enhance clinical utility by: i) enabling more targeted recruitment of individuals for clinical trials, ii) improving post-hoc evaluation of individuals, and iii) ultimately leading to better outcomes for individuals through personalized treatment selection.

Are you angry? Neural basis of impaired facial expression recognition in pre-manifest Huntington's

IntroductionEarly non-motor symptoms in Huntington's disease (HD), including visual perceptual difficulties, can have profound negative impacts on quality of life. In particular, deficits in emotion recognition may contribute to misinterpretation of social cues, and may adversely affect interpersonal relationships, work relationships and/or general well-being. This may be particularly salient during the pre-manifest period, a period prior to the onset of motor symptoms. We sought to evaluate impairments in emotion recognition in gene-positive individuals who did not meet criterial for a diagnosis of HD; we also sought to determine associations between emotion recognition processing and altered cortico-striatal circuitry. MethodsWe used a standardized battery to evaluate performance on a facial expression recognition task in a cohort of motor pre-manifest HD (Pre-HD) individuals (N = 21). Functional MRI (fMRI) was then used to assess the face processing network in a subset (N = 15). ResultsWe found significantly decreased response accuracy to certain facial expressions, particularly of negative emotions (p < 0.001) in Pre-HDs. When Pre-HDs viewed faces with different emotions, activation within the Superior Temporal Sulcus (fSTS) was reduced compared to controls; in contrast, the level of evoked response within other face-selective cortical regions was comparable. ConclusionEarly deficits in emotion recognition in Pre-HD appear to be associated with alterations in the fSTS response, a distinctly different pathway from that involved in face perception and provide support for early cognitive and behavioral interventions.

Differential tractography as a dynamic imaging biomarker: A methodological pilot study for Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Due to its diverse manifestations, the scientific community has long recognized the need for sensitive, objective, individualized, and dynamic disease assessment tools. We examined the feasibility of Differential Tractography as a biomarker to evaluate correlation of symptom severity and of HD progression at the individual level. Differential tractography is a novel tractography modality that maps pathways with axonal injury characterized by a decrease of anisotropic diffusion pattern. We recruited sixteen patients scanned at 0-, 6-, and 12-month intervals by diffusion MRI scans for differential tractography assessment and correlated its volumetric findings with the Unified Huntington’s Disease Rating Scale (UHDRS). Deterministic fiber tracking algorithm was applied. Longitudinal data was modeled using the generalized estimating equation (GEE) model and correlated with UHDRS scores, in addition to Spearman correlation for cross-sectional data. Our results show that volumes of affected pathways revealed by differential tractography significantly correlated with UHDRS scores in longitudinal data (p-value < 0.001), and chronological changes in differential tractography also correlated with the changes in UHDRS (p-value < 0.001). This technique opens new clinical avenues as a clinical translational tool to evaluate presymptomatic and symptomatic gene positive individuals. Our results provide support that differential tractography has the potential to be used as a dynamic imaging biomarker to assess at the individual level in a non-invasive manner, disease progression in HD. Critically important, differential tractography proves to be a quantitative tool for following degeneration in presymptomatic patients, with potential applications in clinical trials.

Huntington's Disease Gene Hunters: An Expanding Tale.

Huntington's Disease Gene Hunters: An Expanding Tale.

Exercise Dose Associated With Military Service: Implications for the Clinical Management of Inherited Risk for Arrhythmogenic Right Ventricular Cardiomyopathy.

High levels of aerobic exercise in individuals who have a gene mutation associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) are associated with clinical disease progression. Guidelines consequently restrict patients from competitive athletics. However, there is minimal literature to guide the safe dosing of physical activity outside of the setting of competitive athletics. Patients may be physically active pursuant to a variety of careers, including military service. This study aimed to define a therapeutic window for exercise for ARVC gene-positive individuals that are compatible with continuing military service and general health while maintaining a level of exercise below that which risks disease progression. Using standard metabolic equations, we calculated the minimum VO2 max (amount of oxygen utilized at peak exercise capacity) required to pass the physical fitness tests for each branch. We then developed a sample exercise prescription to maintain this level of fitness. We compared the prescribed exercise load with the physical activity levels associated with non-inferior clinical outcomes in ARVC gene-positive individuals. Additionally, we determined the physical activity exposure sustained by service members based on self-report data and compared these values with the upper limit of safe exercise exposure. Based on a review of the currently available literature, aerobic exercise exposure less than 700 to 1,100 MET-hours/year (metabolic equivalent-hours per year) is not associated with inferior clinical outcomes for gene-positive individuals. A military service member needs 600 to 700 MET-hours/year to minimally pass the physical fitness test. However, many military members are exercising in excess of this minimum, with typical exposures between 900 and 2,400 MET-hours/year. A therapeutic window of aerobic exercise may exist for ARVC gene-positive individuals which would allow continuation of military service while maintaining levels of exercise restriction associated with non-inferior clinical outcomes.

Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype

BackgroundPathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. Methods120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. ResultsNovel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle. ConclusionsACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations.

34 Hour QT analysis in the prediction of genotype positivity in suspected LQTS: a study in both proband and family screening populations

Introduction LQTS is an inheritable condition with a suspected prevalence on 1/2000 and has a risk of sudden cardiac death due to ventricular arrhythmia if untreated. 24 hour QT analysis is a method of averaging QT measurements obtained via holter monitoring over a 24 hour period. The utility of 24 hour QT analysis to predict genotype positivity has not been widely studied. Methods 28 probands with genetic testing results and 107 first degree relatives of genotyped LQTS patients were included in the analysis. Retrospective review of the medical charts of all patients was performed. Parameters analysed included corrected QT (QTc) interval on 12 lead ECG, 24 hour ambulatory ECG, the QTc after 4 minutes of recovery post exercise stress testing (EST), and the Schwartz score based on clinical and ECG criteria. All these parameters were then compared to the results of subsequent genetic testing. Results 28 probands were analysed with 7 returning a positive gene test and 21 returning a negative gene test. Gene positive individuals had significantly greater QTc by resting ECG (p = 0.047), 24 hour ECG (p = 0.005) and after 4 minutes recovery post EST (p = 0.001) (independent t-test). Using standard cut offs (450 ms for males and 460 ms for females) the association between clinically positive resting ECG and positive genotype was not statistically significant (p = 0.17). Schwartz score >3.5 showed no significant difference between gene positive and gene negative groups (p = 0.33). 24 hour QTc (p = 0.029) was significantly associated with positive genotype and QTc at 4 minutes recovery post EST showed a trend toward significance (p = 0.069). Of 107 first degree relatives of LQTS cases there were 50% gene positive cases. There were statistically significant differences between gene positive and gene negative family members in QTc (p 3.5 was 98% specific for genotype positive LQTS but this test had a very low sensitivity of 29%. The most sensitive test was 24 hour QTc with a cut off of 450 ms for males and 460 ms for females with a sensitivity of 69% and specificity of 83%. Conclusions Family screening and prevention of sudden cardiac death is central to the management of LQTS. Current individual clinical testing methods are not sufficiently sensitive to diagnose LQTS alone and must be used in combination to assess the risk of LQTS. 24 hour QT analysis is the most sensitive method of predicting positive genotype in both probands and family members of affected individuals.

Functional Brain Correlates of Neuropsychiatric Symptoms in Presymptomatic Huntington's Disease: The IMAGE-HD Study.

Neuropsychiatric disturbances are common in Huntington's Disease (HD) and have been observed in gene-positive individuals several years prior to the onset of motor symptoms. The neural mechanism underpinning the development of neuropsychiatric problems in HD remain unclear. To investigate whether neural activity during working memory is associated with neuropsychiatric symptoms in premanifest Huntington's Disease. functional magnetic resonance imaging (fMRI) data from Pre-HD far from onset (pre-HDfar, n = 18), pre-HD close to onset (pre-HDclose, n = 17), and controls (n = 32) were analysed. Correlations were performed between fMRI activity in three regions of interest [bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC)] and neuropsychiatric scores. In the pre-HDclose group, increased symptoms of obsessive compulsion and depression were associated with decreased blood-oxygen-level-dependent (BOLD) fMRI activity in the right DLPFC and ACC during 1-BACK and 2-BACK working memory conditions. In the pre-HDfar group increased symptoms of depression was associated with decreased right DLPFC BOLD fMRI activity during 2-BACK working memory only. The findings suggest that association between neuropsychiatric function and fMRI activity is more readily detectable at higher working memory loads, and becomes more pronounced in those closer to onset.

The impact of occipital lobe cortical thickness on cognitive task performance: An investigation in Huntington's Disease

BackgroundThe occipital lobe is an important visual processing region of the brain. Following consistent findings of early neural changes in the occipital lobe in Huntington's Disease (HD), we examined cortical thickness across four occipital regions in premanifest (preHD) and early HD groups compared with controls. Associations between cortical thickness in gene positive individuals and performance on six cognitive tasks, each with a visual component, were examined. In addition, the association between cortical thickness in gene positive participants and one non-visual motor task was also examined for comparison. MethodsCortical thickness was determined using FreeSurfer on T1-weighted 3T MR datasets from controls (N=97), preHD (N=109) and HD (N=69) from the TRACK-HD study. Regression models were fitted to assess between-group differences in cortical thickness, and relationships between performance on the cognitive tasks, the motor task and occipital thickness were examined in a subset of gene-positive participants (N=141). ResultsThickness of the occipital cortex in preHD and early HD participants was reduced compared with controls. Regionally-specific associations between reduced cortical thickness and poorer performance were found for five of the six cognitive tasks, with the strongest associations in lateral occipital and lingual regions. No associations were found with the cuneus. The non-visual motor task was not associated with thickness of any region. ConclusionsThe heterogeneous pattern of associations found in the present study suggests that occipital thickness negatively impacts cognition, but only in regions that are linked to relatively advanced visual processing (e.g., lateral occipital, lingual regions), rather than in basic visual processing regions such as the cuneus. Our results show, for the first time, the functional implications of occipital atrophy highlighted in recent studies in HD.

E17 Diffusion Weighted Imaging Study Of Prefrontal Cortex White Matter In Prodromal Huntington Disease

<h3>Background</h3> There is considerable interest in finding reliable indicators of Huntington’s disease (HD) progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion-weighted imaging (DWI) may provide a reliable marker of disease progression by characterising diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connexions and documented role in executive function. <h3>Aims</h3> The primary goal is to assess alterations in the white matter tracts of HD gene-positive individuals using DWI and examine its association with motor, cognitive, psychiatric, demographic and genetic variables. <h3>Methods</h3> Imaging and clinical data were collected from 15 PREDICT-HD sites. This study uses DWI to characterise diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. A streamline-specific alteration was assessed in four major PFC WM tracts: forceps minor (FM), anterior thalamic radiations (ATR), inferior fronto-occipital fasciculi (IFO), uncinate fasciculi (UNC). <h3>Results</h3> Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. White matter alterations in FM, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. <h3>Conclusions</h3> The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression with increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals. Our tract study also suggests that long-range tracts that are essential for cross-region information that shows early vulnerability in HD and may help to explain cognitive problems in the prodromal stage. <h3>Funding</h3> National Institutes for Health, National Institute of Neurological Disorders and Stroke 040068, and CHDI Foundation, Inc. <h3>Reference</h3> Matsui JT, Vaidya JG, Johnson HJ, <i>et al</i>. Diffusion weighted imaging of prefrontal cortex in prodromal huntington’s disease. <i>Human Brain Mapping</i>2013;1–12:doi:10.1002/hbm.22273

A07 Critical consideration of the criteria for the motor diagnosis of huntington disease

Background Huntington disease (HD) is a fatal inherited disorder with typical onset in adulthood. In research studies of HD, it is necessary to characterise the progression of participants in order to validly interpret results. Aims A distinction is often made between gene-positive individuals who are displaying hallmark motor signs (manifest HD) and gene-positive individuals who are not (pre-manifest HD). The conventional threshold for this distinction is the highest rating on the Diagnostic Criterion Level (DCL) scale of the Unified Huntington Disease Rating Scale (UHDRS), which constitutes the motor examiner9s confidence level of ≥99% for an unequivocal movement disorder (DCL=4). Methods A study was undertaken to investigate the empirical support for the use of the DCL for manifest HD classification, and alternatives including cutoffs based on the Total Motor Score (TMS) of the UHDRS. Because a gold standard classification does not exist, extreme case/control differences and extreme of the control distribution were used as a guide to selecting cutoffs. Results The results show that the conventional DCL criteria is too stringent in the sense that (1) cutoffs based on the TMS and the lower DCL confidence level of 90%–99% (DCL=3) both provide a very strong distinction between cases and controls, and (2) the conventional criterion tends to be assigned well after the accelerated deterioration trajectory characteristic of late-stage HD has already commenced. Conclusion The results suggest that alternate criteria, especially the intersection of DCL ≥3 and TMS cutoffs, might be considered in HD research.

Huntingtonʼs disease

This review highlights the recent advances in Huntington's disease, with particular focus on clinical characterization of prodromal Huntington's disease, as well as the growing literature regarding pathophysiological mechanisms and their relevance to potential therapeutic targets. Clinical and neuroradiological abnormalities can be demonstrated in gene-positive individuals prior to the onset of manifest Huntington's disease, even as far as 15 years before the disease onset. Although some measures show promise as potential markers of disease progression, further longitudinal studies are required. Several molecular pathways have been implicated in the process of neurodegeneration involved in Huntington's disease and provide potential therapeutic targets. With predictive testing allowing the identification of gene-positive individuals prior to disease onset, the prodromal stage of Huntington's disease provides an ideal period for the use of disease-modifying therapy. A quantifiable and reliable biomarker for monitoring disease progression is crucial for clinical studies of neuroprotection, and this remains an area of active research. Understanding of the underlying pathophysiological mechanisms continues to grow, based mainly on cellular and animal models of Huntington's disease.

Tapping in Huntington disease

The development of therapeutics aimed at delaying the onset or slowing progression of neurodegenerative diseases has been elusive. This is largely related to the challenges of identifying a homogenous cohort, the long time horizons associated with disease onset and progression, and the ability to identify outcome measures that reflect the underlying neuropathology of disease. Huntington disease (HD) is a prototypical adult-onset neurodegenerative disease that allows one to identify with 100% certainty a homogenous population years before the onset of clinical symptoms and therefore represents an ideal disease to explore therapeutic strategies aimed at delaying the onset of illness. However, even in HD, the ability to determine accurately whether a treatment has a meaningful effect on delaying disease onset remains challenging due to the low incidence of onset over relatively short study periods and the difficulty of measuring clinical signs in a population that is not yet ill. In this issue of Neurology ®, Bechtel et al.1 describe a quantitative motor task that links function and structure and distinguishes healthy controls from gene-positive individuals prior to disease onset through early stages of manifest HD. These findings suggest a path forward to designing therapeutic trials aimed at showing an effect on delaying onset in preHD or in …

The profile of KIR3DL1 and KIR3DS1 alleles in an African American population resembles that found in African populations

KIR3DL1 and KIR3DS1 allele frequencies were determined by DNA sequencing of the complete coding regions from 100 random unrelated African Americans. Alleles 3DL1*01501 (29 individuals) and 3DL1*01502 (23 individuals) were most frequently observed in addition to 21 other known alleles and 7 new alleles: KIR3DL1*01503, *03102, *064, *065, *066, *067, and *068. Two of the new alleles (KIR3DL1*064, *065) created additional variants of the chimeric KIR3DL1/KIR3DL2 gene. KIR3DS1*01301 (94% of the gene positive individuals) and KIR3DS1*049N (11%) were identified in the 18 individuals carrying this gene. Three individuals appeared to carry a killer cell immunoglobulin-like receptor haplotype with KIR3DL1/S1 duplication. The profile of alleles resembles that found in African populations but also shows signs of admixture.

Onset and Progression of Pathologic Atrophy in Huntington Disease: A Longitudinal MR Imaging Study

Longitudinal MR imaging measures provide an opportunity to track progression in HD before the emergence of clinical symptoms. This may prove useful in assessing disease-modifying treatments. We investigated how caudate and global volumes change as HD progresses from premanifest to early disease. Forty HD gene-positive individuals and 19 controls underwent serial volumetric MR imaging (baseline, 12 and 27 months; 2 or 3 scans per person). At baseline, 3 patients with HD were premanifest but developed overt motor features during the study, and 37 had early HD. All had dates of motor onset recorded. Caudates, lateral ventricles, and TIVs were measured using semiautomated procedures. Linear mixed models were used to investigate differences between HD and controls in relation to motor onset, controlling for TIV, sex, and age. Extrapolating backwards in time, we found that differences in caudate and ventricular volumes between patients with HD and controls were evident 14 and 5 years, respectively, before motor onset (P < .05). At onset, caudate volume was 2.58 mL smaller than that in controls (P < .0001); ventricular volume was 9.27 mL larger (P < .0001). HD caudate atrophy rates were linear, showed low variability between subjects, and were approximately 10-fold higher than those in controls (P < .001). HD ventricular enlargement rates were variable between subjects, were approximately 4-fold higher than those in controls at onset (P < .001), and accelerated with disease duration (P = .02). We provide evidence of acceleration of global atrophy in HD with disproportionate caudate involvement. Both caudate and global measures may be of use as early markers of HD pathology.

In contrast to other stimulatory natural killer cell immunoglobulin-like receptor loci, several KIR2DS5 alleles predominate in African Americans

The five two-domain stimulatory KIR genes carried by 100 random African Americans were characterized by DNA sequencing of genomic DNA covering the majority of coding exons. The frequency of individual loci was similar to that found in European Americans, with the exception of a reduced frequency for KIR2DS1 in African Americans. New alleles were identified at the KIR2DS1 ( *008), KIR2DS2 ( *006), KIR2DS3 ( *00104, *00105, *00106, *004), KIR2DS4 ( *00103, *00104, *009, *011, *012, *013), and KIR2DS5 ( *006, *007, *00801, *00802, *009) loci. The distribution of alleles at each locus was similar to that found in a European American population except for KIR2DS5. KIR2DS5 exhibits a single allele in European Americans; the same allele is found at a reduced frequency (41% of gene-positive individuals), accompanied by KIR2DS5*006 (18%), KIR2DS5*007 (26%), and six other alleles (25%), in African Americans.

Brain-specific Proteins Decline in the Cerebrospinal Fluid of Humans with Huntington Disease

We integrated five sets of proteomics data profiling the constituents of cerebrospinal fluid (CSF) derived from Huntington disease (HD)-affected and -unaffected individuals with genomics data profiling various human and mouse tissues, including the human HD brain. Based on an integrated analysis, we found that brain-specific proteins are 1.8 times more likely to be observed in CSF than in plasma, that brain-specific proteins tend to decrease in HD CSF compared with unaffected CSF, and that 81% of brain-specific proteins have quantitative changes concordant with transcriptional changes identified in different regions of HD brain. The proteins found to increase in HD CSF tend to be liver-associated. These protein changes are consistent with neurodegeneration, microgliosis, and astrocytosis known to occur in HD. We also discuss concordance between laboratories and find that ratios of individual proteins can vary greatly, but the overall trends with respect to brain or liver specificity were consistent. Concordance is highest between the two laboratories observing the largest numbers of proteins.

MR‐spectroscopic findings in juvenile‐onset Huntington's disease

Seven HD gene positive individuals under the age of 21 years are described with clinical examination and proton-MR-spectroscopy ((1)H-MRS) profiles of the putamen. Despite clinical variability, the predominate (1)H-MRS abnormality is elevated glutamate, expressed well beyond the confines of the basal ganglia, and low striatal creatine.