Cerebellar ataxia-neuropathy-vestibular areflexia-syndrome.

CANVAS including its clinical components of cerebellar ataxia, sensory neuropathy and vestibular areflexia is presented in this review. An intronic biallelic pentanucleotide expansion in RFC1 is the genetic cause of CANVAS. Several patients diagnosed with isolated "idiopathic" neurological or otological conditions might have a CANVAS spectrum disorder. The number of CANVAS patients may well increase considerably in the near future, making it important to consider the diagnostic set-up and infrastructure for counselling, treatment and follow-up in the Danish healthcare system.

Relationship between cerebrospinal fluid biomarkers of inflammation and tissue damage in primary progressive multiple sclerosis.

BACKGROUND AND OBJECTIVES: It is unclear to what extent intrathecal inflammation contributes to the pathogenesis in primary progressive multiple sclerosis (PPMS). We conducted an exploratory study to investigate the degree of intrathecal inflammation and its association with biomarkers of disease activity and severity in patients with PPMS. METHODS: We included patients with PPMS who participated in a randomized controlled trial conducted at the Danish Multiple Sclerosis Center, patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls. We analyzed concentrations of a panel of cytokines in CSF using electrochemiluminescence assays. We then explored the relationship between cytokines found in increased CSF concentrations in patients with PPMS (compared with healthy controls) with CSF concentrations of neurofilament light chain (NFL) and myelin basic protein (MBP), IgG-index, and magnetic resonance imaging (MRI) metrics (volume, magnetization transfer ratio and diffusion tensor imaging) from lesions, normal-appearing white matter, and cortical grey matter. RESULTS: We included 59 patients with PPMS, 40 patients with RRMS, and 21 healthy controls. In patients with PPMS, CSF concentrations of CC chemokine ligand 3 (CCL-3), CXC chemokine ligand 8 (CXCL-8), CXCL-10, interleukin (IL)-10, IL-15, and vascular endothelial growth factor (VEGF)-A were increased compared with healthy controls and comparable with CSF concentrations in patients with RRMS. In addition, patients with PPMS had increased CSF concentrations of IL-12p40, IL-17A, tumor necrosis factor (TNF)-α, and lymphotoxin (LT)-α compared with healthy controls, but concentrations of these cytokines were even higher in patients with RRMS. For the remaining seven cytokines (CCL22, interferon-γ, IL-5, IL-7, IL-16, IL-22, IL-27), we found no difference between patients with PPMS and healthy controls. CSF concentrations of NFL and MBP correlated weakly with concentrations of IL-15, while the remaining proinflammatory cytokines were not associated with CSF concentrations of NFL or MBP. The IgG-index correlated with four cytokines (IL-10, IL-12p40, TNF-α, and LT-α). We did not observe any significant associations between MRI metrics and CSF biomarkers of inflammation. DISCUSSION: In this exploratory study, we found few and weak associations between intrathecal inflammation and the extent of neuroaxonal damage and demyelination, and no associations between intrathecal inflammation and MRI metrics, in patients with PPMS. Our findings suggest that, for patients with PPMS, these measures of intrathecal inflammation are not associated with the extent of neuroaxonal injury, demyelination, and disease severity, and these processes may therefore have less relevance in PPMS than in relapsing forms of MS.

Decreased CSF oxytocin relates to measures of social cognitive impairment in Huntington's disease patients.

OBJECTIVE: Huntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition. METHODS: We recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay. RESULTS: We found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002). CONCLUSIONS: This is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

Impairments of social cognition significantly predict the progression of functional decline in Huntington's disease: A 6-year follow-up study.

This study sought to investigate if there was a significant difference between the Huntington's Disease gene expansion carriers who were impaired on the cognitive domains, social cognition and executive functions. Also, it was investigated which of the cognitive domains could predict the decrease in total functional capacity over a 6-year follow-up period. Premanifest and motor-manifest Huntington's Disease gene expansion carriers (N = 98), were examined with a neurological and neuropsychological examination at Time 1 (year 2012-2013). Regression-based normative data was used to classify impairments on the two cognitive domains. Follow-up participants (N = 80) had their functional capacity reexamined at Time 2 (year 2018-2020), to examine which cognitive domain could predict the decrease in functional capacity over the 6-year follow-up. More than 50% of the participants were impaired on the domain of social cognition. These participants were significantly different from the participants who were impaired on executive functions. The motor function and impairments on social cognition significantly predicted the decline in functional capacity. The Emotion Hexagon test was the only significant social cognitive task, that predicted the decline in functional capacity. Social cognition includes unique and separate functions in Huntington's Disease, unaffected by executive functions. This study emphasizes the importance of regular assessment of social cognition in Huntington's Disease and the clinical relevance of impaired social cognitive function.

Endophenotypical drift in Huntington's disease: a 5-year follow-up study.

BACKGROUND: Huntington's disease (HD) is clinically characterized by progressing motor, cognitive and psychiatric symptoms presenting as varying phenotypes within these three major symptom domains. The disease is caused by an expanded CAG repeat tract in the huntingtin gene and the pathomechanism leading to these endophenotypes is assumed to be neurodegenerative. In 2012/2013 we recruited 107 HD gene expansion carriers (HDGECs) and examined the frequency of the three cardinal symptoms and in 2017/2018 we followed up 74 HDGECs from the same cohort to describe the symptom trajectories and individual drift between the endophenotypes as well as potential predictors of progression and remission. RESULTS: We found higher age to reduce the probability of improving on psychiatric symptoms; increasing disease burden score ((CAG-35.5) * age) to increase the risk of developing cognitive impairment; increasing disease burden score and shorter education to increase the risk of motor onset while lower disease burden score and higher Mini Mental State Examination increased the probability of remaining asymptomatic. We found 23.5% (N = 8) to improve from their psychiatric symptoms. CONCLUSIONS: There is no clear pattern in the development of or drift between endophenotypes. In contrast to motor and cognitive symptoms we find that psychiatric symptoms may resolve and thereby not entirely be caused by neurodegeneration. The probability of improving from psychiatric symptoms is higher in younger age and advocates for a potential importance of early treatment.

Hybrid 2-[18F] FDG PET/MRI in premanifest Huntington's disease gene-expansion carriers: The significance of partial volume correction.

BACKGROUND: Huntington's disease (HD) is an inherited, progressive neurodegenerative disease that has no cure. Striatal atrophy and hypometabolism has been described in HD as far as 15 years before clinical onset and therefore structural and functional imaging biomarkers are the most applied biomarker modalities which call for these to be exact; however, most studies are not considering the partial volume effect and thereby tend to overestimate metabolic reductions, which may bias imaging outcome measures of interventions. OBJECTIVE: Evaluation of partial volume effects in a cohort of premanifest HD gene-expansion carriers (HDGECs). METHODS: 21 HDGECs and 17 controls had a hybrid 2-[18F]FDG PET/MRI scan performed. Volume measurements and striatal metabolism, both corrected and uncorrected for partial volume effect were correlated to an estimate of disease burden, the CAG age product scaled (CAPS). RESULTS: We found significantly reduced striatal metabolism in HDGECs, but not in striatal volume. There was a negative correlation between the CAPS and striatal metabolism, both corrected and uncorrected for the partial volume effect. The partial volume effect was largest in the smallest structures and increased the difference in metabolism between the HDGEC with high and low CAPS scores. Statistical parametric mapping confirmed the results. CONCLUSIONS: A hybrid 2-[18F]FDG PET/MRI scan provides simultaneous information on structure and metabolism. Using this approach for the first time on HDGECs, we highlight the importance of partial volume effect correction in order not to underestimate the standardized uptake value and thereby the risk of overestimating the metabolic effect on the striatal structures, which potentially could bias studies determining imaging outcome measures of interventions in HDGECs and probably also symptomatic HD.

Cognitive Screening Tests in Huntington Gene Mutation Carriers: Examining the Validity of the Mini-Mental State Examination and the Montreal Cognitive Assessment.

BACKGROUND: Due to high prevalence of cognitive impairment in Huntington's disease (HD) gene mutation carriers, even before onset of motor symptoms, cognitive screening is important for the optimal management of patients. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are widely used, but the validity for HD has only been evaluated in few studies with important limitations. OBJECTIVE: To evaluate the discriminative validity of the MMSE and the MoCA for the assessment of cognitive dysfunction in HD gene mutation carriers, independently of motor manifestation and furthermore, to report estimated probabilities for cognitive impairment with different score ranges on the MMSE and the MoCA. METHODS: 106 pre-motor-manifest and motor-manifest HD gene mutation carriers and 40 non-HD gene mutation carriers were administered the MMSE, the MoCA, and an extensive neuropsychological battery with operationalized criteria for cognitive impairment. The same physician and the same neuropsychologist performed all examinations; blinded to one another. RESULTS: The area under the receiver operating characteristic (ROC) curve was 0.70 for the MMSE and 0.82 for the MoCA. The latter correctly diagnosed 82% of the cognitively impaired and not-impaired HD gene mutation carriers and non-HD gene mutation carriers, whereas the MMSE only diagnosed 73% correctly. CONCLUSIONS: The MMSE and the MoCA can both be used as cognitive screening tests in HD gene mutation carriers, but both have important limitations. Our results indicate that the MoCA is a better cognitive screening test for HD than the MMSE. In addition, our study provides estimated probabilities for cognitive impairment with different score ranges, which may be used as clinical guidelines in the interpretation of results from the two tests.

Early Intrathecal T Helper 17.1 Cell Activity in Huntington Disease.

OBJECTIVE: Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. No disease-modifying therapy exists for the treatment of patients with HD. The purpose of this study was therefore to investigate early disease mechanisms that potentially could be used as a target therapeutically. METHODS: Lymphocyte activity in cerebrospinal fluid (CSF) from 4 cohorts of HTT gene expansion carriers (n = 121 in total) and controls was analyzed by techniques based on flow cytometry and enzyme-linked immunosorbent assays. RESULTS: The data of this study provide evidence of immune abnormalities before motor onset of disease. In CSF of HTT gene expansion carriers, we found increased levels of proinflammatory cytokines, including IL-17, and increased consumption of the lymphocyte growth factor IL-7 before motor onset of HD. In concordance, we observed an increased prevalence of IL-17-producing Th17.1 cells in the CSF of HTT gene expansion carriers, predominantly in pre-motor manifest individuals. The frequency of intrathecal Th17.1 cells correlated negatively with progression of HD and the level of neurodegeneration, suggesting a role of Th17.1 cells in the early disease stage. We also observed a skewing in the balance between proinflammatory and regulatory T cells potentially favoring a proinflammatory intrathecal environment in HTT gene expansion carriers. INTERPRETATION: These data suggest that Th17.1 cells are implicated in the earliest pathogenic phases of HD and suggest that treatment to dampen T -cell-driven inflammation before motor onset might be of benefit in HTT gene expansion carriers. ANN NEUROL 2020;87:246-255.

Defining active progressive multiple sclerosis.

BACKGROUND: It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). OBJECTIVE: To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. METHODS: Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24). RESULTS: Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. CONCLUSION: Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.

SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy.

The spinocerebellar ataxias (SCA) are a group of rare inherited neurodegenerative diseases characterized by slowly progressive cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The disorders are predominantly inherited in an autosomal dominant manner. Mutations in the gene AFG3L2 that encodes a subunit of the mitochondrial m-AAA protease have previously been shown to cause spinocerebellar ataxia type 28 (SCA28). Here, we present the clinical phenotypes of three patients from a family with autosomal dominant cerebellar ataxia and show by molecular genetics and in silico modelling that this is caused by a novel missense mutation in the AFG3L2 gene. Furthermore, we show, for the first time, fluorodeoxyglucose-positron emission tomography (FDG-PET) scans of the brain and selective type I fiber atrophy of skeletal muscle of SCA28 patients indicating non-nervous-system involvement in SCA28 as well.

Personality traits in Huntington's disease: An exploratory study of gene expansion carriers and non-carriers.

Huntington's disease (HD) is associated with risk for developing psychiatric symptoms. Vulnerability or resilience to psychiatric symptoms may be associated with personality traits. This exploratory study, aimed to investigate personality traits in a large cohort of HD carriers and at risk gene-expansion negative individuals (HD non-carriers), exploring whether carrying the HD gene or growing up in an HD family influences personality traits. Forty-seven HD carriers, Thirty-nine HD non-carriers, and 121 healthy controls answered the Danish version of the revised NEO personality inventory. Comparisons between HD carriers and HD non-carriers were mostly non-significant but the combined group of HD carriers and non-carriers showed significantly higher scores on the facets: "hostility," "assertiveness," and "activity" and on the trait "Conscientiousness" relative to controls, "Conscientiousness" have been associated with resilience to psychiatric symptoms. Twelve HD carriers and non-carriers were classified as depressed and showed significantly lower scores on "Extraversion" and "Conscientiousness" and significantly higher scores on "Neuroticism," which are associated with vulnerability to psychiatric symptoms. Our findings suggest that, there is no direct effect of the HD gene on personality traits, but that personality assessment may be relevant to use when identifying individuals from HD families who are vulnerable to develop psychiatric symptoms. © 2016 Wiley Periodicals, Inc.

Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease.

OBJECTIVE: To investigate CSF biomarkers of neuroinflammation and neurodegeneration in Huntington disease (HD) gene-expansion carriers compared to controls and to investigate these biomarkers in association with clinical HD rating scales and disease burden score. METHODS: We collected CSF from 32 premanifest and 48 manifest HD gene-expansion carriers and 24 gene-expansion negative at-risk controls. We examined biomarkers of neuroinflammation (matrix metalloproteinase 9, C-X-C motif chemokine 13, terminal complement complex, chitinase-3-like-protein 1 [CHI3L1], and osteopontin [OPN]) and neurodegeneration (microtubule-associated protein tau, neurofilament light polypeptide [NFL], and myelin basic protein [MBP]). The study was approved by the Ethics Committee of the Capital Region of Denmark (H2-2011-085) and written informed consent was obtained from each participant before enrollment. RESULTS: NFL was the only biomarker that increased in premanifest stages and no evidence of early involvement of neuroinflammation in HD was found. However, we found that the biomarkers for neurodegeneration, MBP and tau, increased during the disease course in manifest HD gene-expansion carriers and were associated with an increase of the neuroinflammation biomarkers CHI3L1 and OPN. Tau was also increased in all gene-expansion carriers with psychiatric symptoms compared to gene-expansion carriers without psychiatric symptoms. CONCLUSIONS: Neuroinflammation, which seems not to be an early event in our cohort, may be secondary to neurodegeneration in late HD. NFL is a possible disease burden correlate in HD, reflecting neuronal loss even before motor symptom onset, and may be useful as a dynamic biomarker in intervention studies.

Liver function in Huntington's disease assessed by blood biochemical analyses in a clinical setting.

Huntington's disease (HD) is a dominantly inherited, progressive neurological disorder caused by a CAG repeat elongation in the huntingtin gene. In addition to motor-, psychiatric- and cognitive dysfunction, peripheral disease manifestations in the form of metabolic changes and cellular dysfunction are seen. Blood levels of a wide range of hormones, metabolites and proteins have been analyzed in HD patients, identifying several changes associated with the disease. However, a comprehensive panel of liver function tests (LFT) has not been performed. We investigated a cohort of manifest and premanifest HD gene-expansion carriers and controls, using a clinically applied panel of LFTs. Here, we demonstrate that the level of alkaline phosphatase is increased in manifest HD gene-expansion carriers compared to premanifest HD gene-expansion carriers and correlate with increased disease severity indicated by the Unified Huntington's disease rating scale-Total Functional Capacity Score (UHDRS-TFC). For gamma-glutamyl transferase, elevated levels were more frequent in the manifest groups than in both the HD gene-expansion negative controls and premanifest HD gene-expansion carriers. Finally, the manifest HD gene-expansion carriers displayed moderate increases in total cholesterol and blood glucose relative to the premanifest HD gene-expansion carriers, as well as increased C-reactive protein relative to HD gene-expansion negative controls. Our results show that LFT values are elevated more frequently in manifest compared to premanifest HD gene-expansion carriers and controls. The majority of the manifest HD gene-expansion carriers receive medication, and it is possible that this can influence the liver function tests performed in this study.

Social Cognition, Executive Functions and Self-Report of Psychological Distress in Huntington's Disease.

OBJECTIVE: Huntington's disease (HD) is characterized by motor symptoms, psychiatric symptoms and cognitive impairment in, inter alia, executive functions and social cognition. The aim of this study was to investigate the relationship between subjective feeling of psychological distress using a self-report questionnaire and performances on tests of executive functions and social cognition in a large consecutive cohort of HD patients. METHOD: 50 manifest HD patients were tested in social cognition and executive functions and each answered a self-report questionnaire about current status of perceived psychological distress (the Symptom Checklist-90-Revised (SCL-90-R)). Correlation analyses of test performance and SCL-90-R scores were made as well as stepwise linear regression analyses with the SCL-90-R GSI score and test performances as dependent variables. RESULTS: We found that less psychological distress was significantly associated with worse performances on social cognitive tests (mean absolute correlation .34) and that there were no significant correlations between perceived psychological distress and performance on tests of executive functions. The correlations between perceived psychological distress and performance on social cognitive tests remained significant after controlling for age, Unified Huntington's Disease Rating Scale-99 total motor score and performance on tests of executive functions. CONCLUSIONS: Based on previous findings that insight and apathy are closely connected and may be mediated by overlapping neuroanatomical networks involving the prefrontal cortex and frontostriatal circuits, we speculate that apathy/and or impaired insight may offer an explanation for the correlation between self-report of psychological distress and performance on social cognitive tests in this study.

Do I misconstrue? Sarcasm detection, emotion recognition, and theory of mind in Huntington disease.

OBJECTIVE: Emotion recognition has been widely studied in Huntington disease (HD), but only a few studies have investigated more complex social cognition and, when so, exclusively in manifest HD. The present study sought to investigate social-cognitive functions in a large, consecutive cohort of premanifest and manifest HD gene expansion carriers using tests assessing sarcasm detection, theory of mind (ToM), and emotion recognition. METHOD: Fifty manifest, 50 premanifest HD gene expansion carriers, and 39 at risk gene expansion negative healthy controls were included. All participants were tested with sarcasm detection, ToM, and emotion recognition tasks. Between-group comparisons of test performances and correlation analyses of test performances and disease burden scores were made. RESULTS: Group comparisons showed significant differences in performances on the social-cognitive tests between manifest HD gene expansion carriers and healthy controls, but differences in performances between premanifest HD gene expansion carriers and healthy controls were not statistically significant. Correlation analysis showed that the worse test performances were associated with higher disease burden scores in all HD gene expansion carriers. CONCLUSION: Our findings support a theory of impaired social-cognitive functions in the early stages of HD. Test performances decreased with increasing disease burden in all HD gene expansion carriers, suggesting that social-cognitive tests may be useful for tracking disease progression. Simple emotion recognition tasks are just as sensitive for measuring social-cognitive deficits as more complex measures, but knowledge of the quality of social-cognitive impairments in HD can be of great importance to both patients and caregivers.

Assessing impairment of executive function and psychomotor speed in premanifest and manifest Huntington's disease gene-expansion carriers.

Executive functions (EF) and psychomotor speed (PMS) has been widely studied in Huntington's disease (HD). Most studies have focused on finding markers of disease progression by comparing group means at different disease stages. Our aim was to investigate performances on nine measures of EF and PMS in a group of premanifest and manifest HD-gene expansion carriers and to investigate which measures were most sensitive for assessment of individual patients by analyzing frequencies of impaired performances relative to healthy controls. We recruited HD gene-expansion carriers, 48 manifest and 50 premanifest and as controls 39 healthy gene-expansion negative individuals. All participants underwent neurological examination and neuropsychological testing with nine cognitive measures. The frequency of impairment was investigated using cutoff scores. In group comparisons the manifest HD gene-expansion carriers scored significantly worse than controls on all tests and in classification of individual scores the majority of scores were classified as probably impaired (10th percentile) or impaired (5th percentile) with Symbol Digit Modalities Test (SDMT) being the most frequently impaired. Group comparisons of premanifest HD gene-expansion carriers and healthy controls showed significant differences on SDMT and Alternating fluency tests. Nevertheless the frequencies of probably impaired and impaired scores on individual tests were markedly higher for Alternating and Lexical fluency tests than for SDMT. We found distinct group differences in frequency of impairment on measures of EF and PMS in manifest and premanifest HD gene-expansion carriers. Our results indicate to what degree these measures can be expected to be clinically impaired.

A clinical classification acknowledging neuropsychiatric and cognitive impairment in Huntington's disease.

BACKGROUND: Involuntary movements, neuropsychiatric symptoms, and cognitive impairment are all part of the symptom triad in Huntington's disease (HD). Despite the fact that neuropsychiatric symptoms and cognitive decline may be early manifestations of HD, the clinical diagnosis is conventionally based on the presence of involuntary movements and a positive genetic test for the HD CAG repeat expansion. After investigating the frequencies of the triad manifestations in a large outpatient clinical cohort of HD gene-expansion carriers, we propose a new clinical classification. METHODS: In this cross-sectional study, 107 gene-expansion carriers from a Danish outpatient clinic were recruited. All participants underwent neurological examination, psychiatric evaluation and neuropsychological testing. Participants were categorised according to motor symptoms, neuropsychiatric symptoms, the use of psychotropic medication, and cognitive impairment. RESULTS: Among the motor manifest HD gene-expansion carriers, 51.8% presented with the full symptom triad, 25.0% were defined as cognitively impaired in addition to motor symptoms, and 14.3% had neuropsychiatric symptoms along with motor symptoms. Only 8.9% had isolated motor symptoms. Among gene-expansion carriers without motor symptoms, 39.2% had neuropsychiatric symptoms, were cognitively impaired, or had a combination of the two. CONCLUSION: This is the first study to report the frequencies of both motor symptoms, cognitive impairment, and neuropsychiatric symptoms in HD gene-expansion carriers in a national outpatient HD clinical cohort. We found that almost 40% of the gene-expansion carriers without motor symptoms had either neuropsychiatric symptoms, cognitive impairment or both, emphasising that these patients are not premanifest in psychiatric and cognitive terms, suggesting that the current clinical classification is neither necessarily suitable nor helpful for this patient group. Some premanifest gene-expansion carriers may have psychiatric and/or cognitive symptoms caused by reactive stress or other pathology than HD. Acknowledging this fact we, however, suggest classifying all HD gene-expansion carriers into three clinical categories: premanifest, non-motor manifest, and motor manifest.

Reduction in mitochondrial DNA copy number in peripheral leukocytes after onset of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by movement disorder, cognitive symptoms and psychiatric symptoms with predominantly adult-onset. The mutant huntingtin protein leads to mitochondrial dysfunction in blood leukocytes. This discovery led to the investigation of the mitochondrial DNA (mtDNA) copy number relative to nuclear DNA (nDNA) in leukocytes from carriers of the HD mutation compared to healthy individuals. We found significantly reduced mtDNA/nDNA in HD mutation carriers compared to controls. A longitudinal study of archive DNA sample pairs from HD patients revealed a biphasic pattern of increasing mtDNA/nDNA before onset of motor symptoms and decreasing mtDNA/nDNA after.

Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2.

The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective genes leading to pathogenic expansions of polyglutamine stretches in the encoded proteins. In general, unstable CAG repeats have an uninterrupted CAG repeat, whereas stable CAG repeats are either short or interrupted by CAA codons, which - like CAG codons - code for glutamine. Here we report on an infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded CAG repeat in the SCA2 locus. Surprisingly, the expanded allele of the father was an interrupted CAG repeat sequence. Furthermore, analyses of single spermatozoa showed a high frequency of paternal germ-line repeat sequence instability of the expanded SCA2 locus.