Search

Objectives:Neurodegenerative diseases (NDDs), such as Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, and Huntington’s disease, inevitably lead to impairments in higher-order cognitive functions, including the perception of emotional cues and decision-making behavior. Such impairments are likely to cause risky daily life behavior, for instance, in traffic. Impaired recognition of emotional expressions, such as fear, is considered a marker of impaired experience of emotions. Lower fear experience can, in turn, be related to risk-taking behavior. The aim of our study was to investigate whether impaired emotion recognition in patients with NDD is indeed related to unsafe decision-making in risky everyday life situations, which has not been investigated yet.Methods:Fifty-one patients with an NDD were included. Emotion recognition was measured with the Facial Expressions of Emotions: Stimuli and Test (FEEST). Risk-taking behavior was measured with driving simulator scenarios and the Action Selection Test (AST). Data from matched healthy controls were used: FEEST (n = 182), AST (n = 36), and driving simulator (n = 18).Results:Compared to healthy controls, patients showed significantly worse emotion recognition, particularly of anger, disgust, fear, and sadness. Furthermore, patients took significantly more risks in the driving simulator rides and the AST. Only poor recognition of fear was related to a higher amount of risky decisions in situations involving a direct danger.Conclusions:To determine whether patients with an NDD are still fit to drive, it is crucial to assess their ability to make safe decisions. Measuring emotion recognition may be a valuable contribution to this judgment.

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published

Objective: To assess the prevalence, severity, and change in health-related problems in a sample of older adults who received individual care and support from Embrace, for the whole sample, per subgroup based on complexity of care needs and frailty, and for those who had at baseline a health-related problem.Design: A pretest-posttest study with assessments at baseline and after 12 months.Setting: Community.Participants: Older adults aged 75 years and older (N=136) who are frail (n=56) or who have complex care needs (n=80).Intervention: Participants received care and support by Embrace, a person-centered and integrated care service for community-living older adults supporting them to age in place. A multidisciplinary team provided care and support, with intensity depending on the older adults' risk profile.Main Outcome Measure: Health-related problems as perceived by older adults and measured with the Geriatric International Classification of Functioning, Disability and Health Core Set.Results: Health-related problems were related to 6 coherent clusters: (1) Mental Functions; (2) Physical Health; (3) Mobility; (4) Personal Care; (5) Nutrition; and (6) Support. The most prevalent and most severe problems at baseline were related to Mental Functions and Mobility. Changes in the prevalence of problems after 12 months varied. Severity scores decreased or remained stable, except for Mobility items which showed a varying changing pattern in participants with complex care needs. Prevalence and severity of problems for those with a problem at baseline decreased after 12 months. Frail participants with a problem had higher baseline severity scores than those with complex care needs experiencing a problem, but differences in changes between individuals who are frail and those with complex care needs were small.Conclusions: The results are encouraging and may indicate that individual, person-centered and integrated care and support from Embrace offers a route to counteracting the decline in physical, cognitive and social functioning associated with aging. (C)2019 by the American Congress of Rehabilitation Medicine

Aims To investigate the accuracy of phenotypic early‐onset ataxia (EOA) recognition among developmental conditions, including developmental coordination disorder (DCD) and hypotonia of central nervous system origin, and the effect of scientifically validated EOA features on changing phenotypic consensus. Method We included 32 children (4–17y) diagnosed with EOA (n=11), DCD (n=10), and central hypotonia (n=11). Three paediatric neurologists independently assessed videotaped motor behaviour phenotypically and quantitatively (using the Scale for Assessment and Rating of Ataxia [SARA]). We determined: (1) phenotypic interobserver agreement and phenotypic homogeneity (percentage of phenotypes with full consensus by all three observers according to the underlying diagnosis); (2) SARA (sub)score profiles; and (3) the effect of three scientifically validated EOA features on phenotypic consensus. Results Phenotypic homogeneity occurred in 8 out of 11, 2 out of 10, and 1 out of 11 patients with EOA, DCD, and central hypotonia respectively. Homogeneous phenotypic discrimination of EOA from DCD and central hypotonia occurred in 16 out of 21 and 22 out of 22 patients respectively. Inhomogeneously discriminated EOA and DCD phenotypes (5 out of 21) revealed overlapping SARA scores with different SARA subscore profiles. After phenotypic reassessment with scientifically validated EOA features, phenotypic homogeneity changed from 16 to 18 patients. Interpretation In contrast to complete distinction between EOA and central hypotonia, the paediatric motor phenotype did not reliably distinguish between EOA and DCD. Reassessment with scientifically validated EOA features could contribute to a higher phenotypic consensus. Early‐onset ataxia (EOA) and central hypotonia motor phenotypes were reliably distinguished.EOA and developmental coordination disorder (DCD) motor phenotypes were not reliably distinguished.The EOA and DCD phenotypes have different profiles of the Scale for Assessment and Rating of Ataxia., Early‐onset ataxia (EOA) and central hypotonia motor phenotypes were reliably distinguished.EOA and developmental coordination disorder (DCD) motor phenotypes were not reliably distinguished.The EOA and DCD phenotypes have different profiles of the Scale for Assessment and Rating of Ataxia. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the http://onlinelibrary.wiley.com/doi/10.1111/dmcn.14355/abstract to view the translations. This article is commented on by Baxter on page https://doi.org/10.1111/dmcn.14376 of this issue.

Functional impairment of spatially distributed brain regions in Parkinson's disease (PD) suggests changes in integrative and segregative network characteristics, for which novel analysis methods are available. To assess underlying structural network differences between PD patients and controls, we employed MRI T1 gray matter segmentation and diffusion MRI tractography to construct connectivity matrices to compare patients and controls with data originating from two different centers. In the Dutch dataset (Data-NL), 14 PD patients, and 15 healthy controls were analyzed, while 19 patients and 18 controls were included in the Canadian dataset (Data-CA). All subjects underwent T1 and diffusion-weighted MRI. Patients were assessed with Part 3 of the Unified Parkinson's Disease Rating Scale (UPDRS). T1 images were segmented using FreeSurfer, while tractography was performed using ExploreDTI. The regions of interest from the FreeSurfer segmentation were combined with the white matter streamline sets resulting from the tractography, to construct connectivity matrices. From these matrices, both global and local efficiencies were calculated, which were compared between the PD and control groups and related to the UPDRS motor scores. The connectivity matrices showed consistent patterns among the four groups, without significant differences between PD patients and control subjects, either in Data-NL or in Data-CA. In Data-NL, however, global and local efficiencies correlated negatively with UPDRS scores at both the whole-brain and the nodal levels [false discovery rate (FDR) 0.05]. At the nodal level, particularly, the posterior parietal cortex showed a negative correlation between UPDRS and local efficiency, while global efficiency correlated negatively with the UPDRS in the sensorimotor cortex. The spatial patterns of negative correlations between UPDRS and parameters for network efficiency seen in Data-NL suggest subtle structural differences in PD that were below sensitivity thresholds in Data-CA. These correlations are in line with previously described functional differences. The methodological approaches to detect such differences are discussed.

INTRODUCTION: In 2011, a homozygous mutation in GOSR2 (c.430G > T; p. Gly144Trp) was reported as a novel cause of Progressive Myoclonus Epilepsy (PME) with early-onset ataxia. Interestingly, the ancestors of patients originate from countries bound to the North Sea, hence the condition was termed North Sea PME (NSPME). Until now, only 20 patients have been reported in literature. Here, we provide a detailed description of clinical and neurophysiological data of seventeen patients.METHODS: We collected clinical and neurophysiological data from the medical records of seventeen NSPME patients (5-46 years). In addition, we conducted an interview focused on factors influencing myoclonus severity.RESULTS: The core clinical features of NSPME are early-onset ataxia, myoclonus and seizures, with additionally areflexia and scoliosis. Factors such as fever, illness, heat, emotions, stress, noise and light (flashes) all exacerbated myoclonic jerks. Epilepsy severity ranged from the absence of or incidental clinical seizures to frequent daily seizures and status epilepticus. Some patients made use of a wheelchair during their first decade, whereas others still walked independently during their third decade. Neurophysiological features suggesting neuromuscular involvement in NSPME were variable, with findings ranging from indicative of sensory neuronopathy and anterior horn cell involvement to an isolated absent H-reflex.CONCLUSION: Although the sequence of symptoms is rather homogeneous, the severity of symptoms and rate of progression varied considerably among individual patients. Common triggers for myoclonus can be identified and myoclonus is difficult to treat; to what extent neuromuscular involvement contributes to the phenotype remains to be further elucidated.

Objectives. To assess the cost-effectiveness of Embrace, an integrated primary care service for older adults.Data Sources. Care and support claims from health care insurers, long-term care administration, and municipalities for enrolled older adults between 2011 and 2013.Study Design. A total of 1,456 older adults, listed with 15 general practitioners practices in the Netherlands, were stratified into risk profiles ("Robust," "Frail,"and "Complex care needs") and randomized to Embrace or care-as-usual groups. Incremental costs were calculated per quality-adjusted life year, per day able to age in place, and per percentage point risk profile improvement.Principal Findings. Total average costs were higher for Embrace compared to careas-usual. Differences in health-associated outcomes were small and not statistically significant. Probabilities that Embrace is cost-effective were below 80 percent, except for "risk profile improvements" within risk profile "Complex care needs."Complete case analysis resulted in smaller differences in total average costs across conditions and differences in health-associated outcomes remained small.Conclusions. According to current standards, Embrace is not considered cost effective after 12 months. However, it could be considered worthwhile in terms of "risk profile improvements"for older adults with "Complex care needs," if society is willing to invest substantially.

Introduction We aimed to uncover the pattern of network-level changes in neuronal function in Spinocerebellar ataxia type 3 (SCA3). Methods 17 genetically-confirmed SCA3 patients and 16 controls underwent structural MRI and static resting-state [18F]‑Fluoro‑deoxyglucose Positron Emission Tomography (FDG-PET) imaging. A SCA3-related pattern (SCA3-RP) was identified using a multivariate method (scaled subprofile model and principal component analysis (SSM PCA)). Participants were evaluated with the Scale for Assessment and Rating of Ataxia (SARA) and with neuropsychological examination including tests for language, executive dysfunction, memory, and information processing speed. The relationships between SCA3-RP expression and clinical scores were explored. Voxel based morphology (VBM) was applied on MRI-T1 images to assess possible correlations between FDG reduction and grey matter atrophy. Results The SCA3-RP disclosed relative hypometabolism of the cerebellum, caudate nucleus and posterior parietal cortex, and relatively increased metabolism in somatosensory areas and the limbic system. This topography, which was not explained by regional atrophy, correlated significantly with ataxia (SARA) scores (ρ = 0.72; P = 0.001). SCA3 patients showed significant deficits in executive function and information processing speed, but only letter fluency correlated with SCA3-RP expression (ρ = 0.51; P = 0.04, uncorrected for multiple comparisons). Conclusion The SCA3 metabolic profile reflects network-level alterations which are primarily associated with the motor features of the disease. Striatum decreases additional to cerebellar hypometabolism underscores an intrinsic extrapyramidal involvement in SCA3. Cerebellar-posterior parietal hypometabolism together with anterior parietal (sensory) cortex hypermetabolism may reflect a shift from impaired feedforward to compensatory feedback processing in higher-order motor control. The demonstrated SCA3-RP provides basic insight in cerebral network changes in this disease., Highlights • A metabolic cerebral pattern could be identified in FDG-PET data of SCA3 patients, which was not explained by regional atrophy. • Striatum decreases in the SCA3-pattern reflect extrapyramidal involvement. • The SCA3-pattern reflects changes in higher-order motor control.

Background: The aim of this study was to examine the stability and relative validity (RV) of the Neuromuscular Disease Impact Profile (NMDIP) using criterion-related groups. In a previous study the NMDIP-scales showed good internal consistency, convergent and discriminant validity. Known-groups analysis showed that the NMDIP discriminates between categories of extent of limitations.Methods: A cross-sectional postal survey study was performed on patients diagnosed with a NMD and registered at the Department of Neurology, University Medical Center Groningen, the Netherlands.Participants were asked to complete the preliminary NMDIP, the Medical Outcome study Short Form Questionnaire (SF-36), the World Health Organization Quality Of Life-abbreviation version (WHOQOL-bref), and two generic domain specific:measures the Groningen Activity Restriction Scale (GARS) and the Impact on Participation and Autonomy Questionnaire (IPAQ). The variables 'Extent of Limitations' and 'Quality of Life' were used to create criterion-related groups. Stability over time was tested using the Wilcoxon Signed Rank Test for paired samples and the intraclass-correlation coefficients for repeated measures. RV was examined by comparing the ability of NMDIP with generic multidimensional health impact measures, and domain specific measures in discriminating between criterion-related subgroups using the Kruskal-Wallis H-test.Results: Response rate was 70% (n = 702). The NMDIP-scales showed sufficient stability over time, and satisfactory or strong RV. In general, the NMDIP scales performed as well as or better than the concurrent measurement instruments.Conclusions: The NMDIP proved to be a valid and reliable disease-targeted measure with a broad scope on physical, psychological and social functioning.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Background Novel population-based integrated care services are being developed to adequately serve the growing number of elderly people. Suitable, reliable and valid measurement instruments are needed to evaluate the quality of care delivered. Objective To develop a measure to evaluate the quality of integrated care from the perspective of elderly people, the Patient Assessment of Integrated Elderly Care (PAIEC), and then to assess its psychometric properties. Methods/Design After the Patient Assessment of Chronic Illness Care was adapted to the PAIEC, a cross-sectional postal-survey study was performed among 223 elderly people who received integrated elderly care and support. We assessed the factor structure, internal consistency, known groups and divergent validity using robust nonparametric tests. Results Mean age of participants was 83 years (standard deviation 4.7), and 69% was female. The original five-factor model was rejected; a good fit was found for a three-factor model, when excluding the item on patients' satisfaction with care. The PAIEC and its subscales showed good internal consistency (ordinal alphas > 0.90). Known-groups validity was supported regarding number of medications, prevalence of chronic conditions and home care received. No differences were found between groups based on sociodemographic aspects. Divergent validity was supported by low correlations (Spearman's rank correlation coefficients

Introduction: Ideally, older adults should receive person-centred care and support that meets their individual needs and wishes, taking all relevant health-related aspects into account. A first step towards that goal is to gain insight into their health-related problems. For that purpose, a person-centred ICF Core Set for community-living older adults, the GeriatrICS, was developed. The objectives of this study were to assess the prevalence and severity of health-related problems in community-living older adults, and to assess the differences between subgroups of older adults: those with complex care needs, frail and robust older adults.Methods: A cross-sectional study was conducted among older adults receiving person-centred and integrated care and support from Embrace, a person-centred and integrated service. Older adults with complex care needs n=163 and frail older adults n=104 were interviewed by case managers, who assessed the older adults using the GeriatrICS. Robust older adults n=274 received a questionnaire version of the GeriatrICS. All older adults had to rate the items on a scale ranging from 0 no problem to 10 complete problem. We examined data per item in terms of prevalence of problems and severity. Differences in prevalence between subgroups was tested using Chi-square tests and differences in severity were tested using Mann-Whitney U tests.Results: Mean age of participants n=541 was 80.7 years SD 4.4, 56% was female, and 51% had a lower educational level.Preliminary analyses showed that, overall, the most prevalent and severe problems were related to the clusters Mobility, Mental Functions and Physical Health. For example, prevalence of Mobility-related problems: Complex care needs 52.0%, Frail 55.6% and Robust 43.6%, and severity: Complex care needs 1.9, Frail 2.4 and Robust 1.0. Although prevalence was comparable among frail older adults and those with complex care needs, results showed a trend in higher severity scores for frail participants. Robust older adults also showed health-related problems e.g. Physical Health: prevalence 33.8%, severity 0.8, but less frequent and less severe compared to participants with complex care needs 45.7%, 1.5 and frail participants 47.1%, 1.8.Discussions and conclusions: We assessed health-related problems due to ageing using the GeriatrICS in a community-sample of older adults. Frail older adults and those with complex care needs showed the highest prevalence of problems, but frail participants experienced them as more severe. Besides, robust older adults already showed health-related problems, indicating the need for prevention.Lessons learned: Prevention of health-related problems in older adults is necessary and should also be targeted at robust older adults.Results suggest that using the GeriatrICS could be a good starting point for the development of person-centred, proactive and preventive care and support programs.Limitations: We may have to deal with common method bias, due to the difference in assessment methods interview by a case manager versus a questionnaire version. However, in both situations, the assessment was self-reported because the older adults had to indicate the severity of their problems.Suggestions for future research: Future studies should examine the concurrent validity of both assessment methods using the GeriatrICS.

Introduction: Ideally, older adults should receive person-centred care and support that meets their individual needs and wishes, taking all relevant health-related problems into account. The International Classification of Functioning, Disability and Health ICF might offer a basis for identification of these problems as it provides a unified language for evaluation of functioning and disability associated with someone’s health status. ICF Core Sets have been developed to describe the spectrum of disabilities of specific patient populations. Therefore, aim of this study was to develop a valid Geriatric ICF Core Set GeriatrICS reflecting all relevant health-related problems of community-living older adults without dementia.Methods: This study consisted of two sub-studies: 1 a written Delphi study to select ICF categories, and 2 assessing content validity in a cross-sectional study. For the Delphi study, a representative panel of experts older adults and non-medical experts on health-related problems due to ageing was constituted. Panel members had to select second-level categories from the ICF-classification relevant to community-living, non-demented older adults 75+, and had to reach consensus on this selection. For the validation study, older adults frail or with complex care needs were visited by a case manager district nurse or social worker who used the initial GeriatrICS as an assessment tool. Older adults had to rate all categories on a scale ranging from 0 no problem to 10 complete problem. Content validity of a category was guaranteed if ≥10% indicated a problem with that category.Results: 41 Delphi panel members obtained consensus in two rounds on 30 ICF-categories. Next, 267 older adults participated in the validation study. All categories met the criterion for content validity except for d530 Toileting. The final GeriatrICS consists of 29 categories: fourteen Body Functions categories, nine Activities and Participation categories and six Environmental Factors categories.Discussions and conclusions: This study resulted in a valid ICF Core Set GeriatrICS including 29 ICF categories representing the most relevant health-related problems among community-living older adults without the diagnosis of dementia. The GeriatrICS included categories from all ICF components, showing that older people’s health is a multidimensional construct. Compared to commonly used, profession-based tools, the GeriatrICS is unique as it is a population-based, cross-domain tool. Therefore, the GeriatrICS is a good starting point for the delivery of person-centred and integrated care. Lessons learned: The GeriatrICS may be used in person-centred and integrated care practice as an assessment tool, in order to tailor care and support to the needs of older adults. Analysis and interpretation of an older adult’s outcomes, and translation into an appropriate care plan, requires highly competent and experienced professionals. Limitations: Older adults with dementia or cognitive impairments may have been included in the validation study since dementia was not an exclusion criterion. Impact on the results is expected to be trivial as case managers were experienced interviewers and a partner or family member participated in the assessment in case of cognitive problems.Suggestions for future research: Future research should investigate the health-related problems of older adults with dementia and robust older adults.

ObjectiveTo evaluate the effects of the population-based, person-centred and integrated care service 'Embrace' at twelve months on three domains comprising health, wellbeing and self-management among community-living older people.MethodsEmbrace supports older adults to age in place. A multidisciplinary team provides care and support, with intensity depending on the older adults' risk profile. A randomised controlled trial was conducted in fifteen general practices in the Netherlands. Older adults (>= 75 years) were included and stratified into three risk profiles: Robust, Frail and Complex care needs, and randomised to Embrace or care as usual (CAU). Outcomes were recorded in three domains. The EuroQol-5D-3L and visual analogue scale, INTERMED for the Elderly Self-Assessment, Groningen Frailty Indicator and Katz-15 were used for the domain 'Health.' The Groningen Well-being Indicator and two quality of life questions measured 'Wellbeing.' The Self-Management Ability Scale and Partners in Health scale for older adults (PIH-OA) were used for 'Self-management.' Primary and secondary outcome measurements differed per risk profile. Data were analysed with multilevel mixed-model techniques using intention-to-treat and complete case analyses, for the whole sample and per risk profile.Results1456 eligible older adults participated (49%) and were randomized to Embrace (n(T0) = 747, n(T1) = 570, mean age 80.6 years (SD 4.5), 54.2% female) and CAU (n(T0) = 709, n (T1) = 561, mean age 80.8 years (SD 4.7), 55.6% female). Embrace participants showed a greater-but clinically irrelevant-improvement in self-management (PIH-OA Knowledge subscale effect size [ES] = 0.14), and a greater-but clinically relevant-deterioration in health (ADL ES = 0.10; physical ADL ES = 0.13) compared to CAU. No differences in change in wellbeing were observed. This picture was also found in the risk profiles. Complete case analyses showed comparable results.ConclusionsThis study found no clear benefits to receiving person-centred and integrated care for twelve months for the domains of health, wellbeing and self-management in community-living older adults.

Myoclonus is a hyperkinetic movement disorder characterized by brief, involuntary muscular jerks. Recognition of myoclonus and determination of the underlying aetiology remains challenging given that both acquired and genetically determined disorders have varied manifestations. The diagnostic work-up in myoclonus is often time-consuming and costly, and a definitive diagnosis is reached in only a minority of patients. On the basis of a systematic literature review up to June 2015, we propose a novel diagnostic eight-step algorithm to help clinicians accurately, efficiently and cost-effectively diagnose myoclonus. The large number of genes implicated in myoclonus and the wide clinical variation of these genetic disorders emphasize the need for novel diagnostic techniques. Therefore, and for the first time, we incorporate next-generation sequencing (NGS) in a diagnostic algorithm for myoclonus. The initial step of the algorithm is to confirm whether the movement disorder phenotype is consistent with, myoclonus, and to define its anatomical subtype. The next steps are aimed at identification of both treatable acquired causes and those genetic causes of myoclonus that require a diagnostic approach other than NGS. Finally, other genetic diseases that could cause myoclonus can be investigated simultaneously by NGS techniques. To facilitate NGS diagnostics, we provide a comprehensive list of genes associated with myoclonus.

Background. The prevalence of multimorbidity (>= 1 disease within an individual) is rapidly increasing. So far, studies on the relationship between vitamin D and morbidity are mainly focusing on effects on single disease domains only, while vitamin D biology is associated with several diseases throughout the human body.Methods. We studied 8,726 participants from the LifeLines Cohort Study (a cross-sectional, population-based cohort study) and used the self-developed composite morbidity score to study the association between vitamin D levels and multimorbidity.Results. Study participants (mean age 45 +/- 13 years, 73% females) had a mean plasma vitamin D level of 59 +/- 22 nmol/L. In participants aged between 50 and 60 years, 58% had >= 2 affected disease domains, while morbidity score increased with age (70-80 years: 82% morbidity score > 1; > 80 years: 89% morbidity score > 1). Each incremental reduction by 1 standard deviation (SD) of vitamin D level was associated with an 8% higher morbidity score (full model OR 0.92, 95% CI 0.88-0.97, P = 0.001). Participants with vitamin D levels 80 nmol/L, OR 1.34, 95% CI 1.07-1.67, P = 0.01).Conclusions. Low levels of vitamin D are associated with higher prevalence of multimorbidity, especially in participants with vitamin D levels

Purpose: The aim of the present study was to develop a valid Geriatric ICF Core Set reflecting relevant health-related problems of community-living older adults without dementia. Methods: A Delphi study was performed in order to reach consensus (70% agreement) on second-level categories from the International Classification of Functioning, Disability and Health (ICF). The Delphi panel comprised 41 older adults, medical and non-medical experts. Content validity of the set was tested in a cross-sectional study including 267 older adults identified as frail or having complex care needs. Results: Consensus was reached for 30 ICF categories in the Delphi study (fourteen Body functions, ten Activities and Participation and six Environmental Factors categories). Content validity of the set was high: the prevalence of all the problems was >10%, except for d530 Toileting. The most frequently reported problems were b710 Mobility of joint functions (70%), b152 Emotional functions (65%) and b455 Exercise tolerance functions (62%). No categories had missing values. Conclusion: The final Geriatric ICF Core Set is a comprehensive and valid set of 29 ICF categories, reflecting the most relevant health-related problems among community-living older adults without dementia. This Core Set may contribute to optimal care provision and support of the older population.Implications for RehabilitationThe Geriatric ICF Core Set may provide a practical tool for gaining an understanding of the relevant health-related problems of community-living older adults without dementia.The Geriatric ICF Core Set may be used in primary care practice as an assessment tool in order to tailor care and support to the needs of older adults.The Geriatric ICF Core Set may be suitable for use in multidisciplinary teams in integrated care settings, since it is based on a broad range of problems in functioning.Professionals should pay special attention to health problems related to mobility and emotional functioning since these are the most prevalent problems in community-living older adults.

Aim: In children, gait and posture assessment provides a crucial marker for the early characterization, surveillance and treatment evaluation of early onset ataxia (EOA). For reliable data entry of studies targeting at gait and posture improvement, uniform quantitative biomarkers are necessary. Until now, the pediatric test construct of gait and posture scores of the Scale for Assessment and Rating of Ataxia sub-scale (SARA) is still unclear. In the present study, we aimed to validate the construct validity and reliability of the pediatric (SARAGAIT/POSTURE) sub-scale. Methods: We included 28 EOA patients [15.5 (6-34) years; median (range)]. For inter-observer reliability, we determined the ICC on EOA SARAGAIT/POSTURE subscores by three independent pediatric neurologists. For convergent validity, we associated SARAGAIT/POSTURE sub-scores with: (1) Ataxic gait Severity Measurement by Klockgether (ASMK; dynamic balance), (2) Pediatric Balance Scale (PBS; static balance), (3) Gross Motor Function Classification Scale -extended and revised version (GMFCSE & R), (4) SARA-kinetic scores (SARAKINETIC; kinetic function of the upper and lower limbs), (5) Archimedes Spiral (AS; kinetic function of the upper limbs), and (6) total SARA scores (SARATOTAL; i.e., summed SARAGAIT/POSTURE, SARAKINETIC, and SARASPEECH sub-scores). For discriminant validity, we investigated whether EOA co-morbidity factors (myopathy and myoclonus) could influence SARAGAIT=POSTURE sub-scores. Results: The inter-observer agreement (ICC) on EOA SARAGAIT/POSTURE sub-scores was high (0.97). SARAGAIT/POSTURE was strongly correlated with the other ataxia and functional scales [ASMK (rs = -0.819; p < 0.001); PBS (rs = -0.943; p < 0.001); GMFCS-E & R (rs = -0.862; p < 0.001); SARAKINETIC (rs = 0.726; p < 0.001); AS (rs = 0.609; p = 0.002); and SARATOTAL (rs = 0.935; p < 0.001)]. Comorbid myopathy influenced SARAGAIT/POSTURE scores by concurrent muscle weakness, whereas comorbid myoclonus predominantly influenced SARAKINETIC scores. Conclusion: In young EOA patients, separate SARAGAIT/POSTURE parameters reveal a good inter-observer agreement and convergent validity, implicating the reliability of the scale. In perspective of incomplete discriminant validity, it is advisable to interpret SARAGAIT/POSTURE scores for comorbid muscle weakness.

The clinical diagnosis of Huntington's disease (HD) is based on the motor symptoms, although these can be preceded by cognitive and behavioral changes. Biomarker studies have shown that structural imaging modalities are useful biomarkers of HD onset, while functional imaging measures have been studied less often for this purpose. Our aim was to investigate the combined value of 18-fluorodesoxyglucose (FDG)-PET and cognitive measures as biomarkers of HD onset. Twenty-two premanifest mutation carriers of HD (PMCs) and 11 healthy controls were assessed twice with FDG-PET scan, neurological and neuropsychological assessments over a 2-year interval. Seventeen PMCs had an additional third neurological evaluation, 10 years after baseline. Disease load was defined as the probability of motor onset within 5 years. Metabolism in putamen, caudate and pallidum of PMCs was significantly lower than that of controls, at both assessments. Almost half of the PMCs had converted to manifest HD 10 years later and all converters had low average or abnormal putaminal metabolism at 2 year follow-up. In contrast, all PMCs with normal putaminal metabolism at 2 year follow-up remained premanifest during the following 8 years. Furthermore, glucose metabolism of putamen explained a substantial part of the variance in disease load. A composite score of psychomotor tests contributed significantly to the prediction model as well, while cognitive performance was comparable for PMCs and controls. We conclude that in future clinical trials a combination of psychomotor tests and putaminal glucose metabolism may be used to identify PMCs close to motor onset of HD.

This review summarizes the long-term consequences of the posterior reversible encephalopathy syndrome (PRES) that have been described in the obstetric literature (eclampsia and preeclampsia) and compares these with data from the nonobstetric literature. Preeclampsia is characterized by new-onset hypertension and proteinuria after the 20th week of pregnancy. Neurological symptoms include headache; visual deficits; confusion; seizures; and, in the most severe cases, intracranial hemorrhage. Eclampsia is an acute cerebral complication of preeclampsia, defined as the occurrence of tonic-clonic seizures in pregnant or recently postpartum women. With severe preeclampsia, in conjunction with neurological symptoms, or eclampsia, neuroimaging changes consistent with PRES can be seen. Posterior reversible encephalopathy syndrome is a specific clinicoradiological syndrome presenting with headaches, visual impairment, seizures, and altered mental status. Characteristic neuroimaging features are consistent with cerebral edema predominantly in the parietal and occipital lobes. In addition to preeclampsia/eclampsia, PRES has been associated with various conditions in the nonobstetric population, that is, severe hypertension, transplantation, or autoimmune disease, in combination with immunosuppressive therapy or high-dose chemotherapy for various malignant conditions. Long-term sequelae of both preeclampsia/eclampsia and other PRES-related conditions are poorly described. After eclampsia or preeclampsia, nonspecific white matter lesions may be found on magnetic resonance imaging, which may or may not be related to the PRES episode. Previously (pre)eclamptic women report cognitive failures; however, no neurocognitive impairment has been shown so far. Various nonobstetric PRES-related conditions have been described with long-term neuroimaging abnormalities as well as cognitive problems, epilepsy, or visual impairment. Although no firm conclusions can be drawn because of the heterogeneity of reported cases, some general comments can be made. Because most persistent long-term problems are present in the nonobstetric population, the main determinant for these long-term problems may be the underlying condition that gave rise to the PRES episode. In addition, most reports suggest that late diagnosis or inadequate therapy may contribute, emphasizing the need for early recognition, adequate treatment, follow-up, and support.

Background: Ramsay Hunt syndrome (progressive myoclonus ataxia) is a descriptive diagnosis characterized by myoclonus, ataxia, and infrequent seizures. Often the etiology cannot be determined. Recently, a mutation in the GOSR2 gene (c.430G>T, p.Gly144Trp) was reported in 6 patients with childhood-onset progressive ataxia and myoclonus. Methods: We evaluated 5 patients with cortical myoclonus, ataxia, and areflexia. Results: All 5 patients had the same homozygous mutation in GOSR2. Here we present their clinical and neurophysiological data. Our patients (aged 7-26 years) all originated from the northern Netherlands and showed a remarkably homogeneous phenotype. Myoclonus and ataxia were relentlessly progressive over the years. Electromyography revealed signs of sensory neuronopathy or anterior horn cell involvement, or both, in all patients with absent reflexes. Conclusions: Based on the presented phenotype, we would advise movement disorder specialists to consider mutation analysis of GOSR2 in patients with Ramsay Hunt syndrome, especially when they also have areflexia. (Less)

Introduction: Health care systems are challenged by the changing demands for care and support of older adults. Integrated care models may provide a solution for these transformations. Embrace is a recently developed population-based, person-centered, and integrated care service for community-living older adults. It was implemented in the Netherlands in 2012. Currently, 2600 older adults from 29 general practitioner (GP) practices are participating. We evaluated the effects of Embrace regarding patient outcomes and experiences, quality of care, and service use and costs using Mixed Methods Research.Theory/Methods: Intervention. Embrace combines the Chronic Care Model with risk profiles based on a population health management model. A multidisciplinary Elderly Care Team – consisting of a GP, an elderly care physician, and two case managers (district nurse and social worker) – provide care and support. The intensity level, focus, and individual or group approach of the care and support depends on an older adults’ risk profile.Design. We used different measurement instruments, e.g. the specifically developed GeriatrICS (a geriatric core set based on the ICF) and the Patient Assessment of Integrated Elderly Care (PAIEC), to assess the effects of Embrace after twelve months using Mixed Methods. A Randomized Clinical Trial and cost-effectiveness study was conducted to assess the effectiveness of Embrace on patient outcomes for older adults, their perceived quality of care, and service use and costs. Qualitative studies were performed to determine the experiences of older adults and professionals with Embrace. One group pre-post studies were conducted to evaluate professionals’ perceived quality of care, effects of Embrace on health-related problems, and goal attainment scores. Furthermore, the long term effects of Embrace will be assessed.Results: (Patient outcomes and experiences) The RCT showed no clear advantages of Embrace regarding the domains health, well-being, and self-management. The qualitative study showed that older adults felt safe and secure and had the confidence to remain living at home. The preliminary findings of the pre-post study indicated that the number and severity of perceived health-related problems decreased.Quality of care. Results of the RCT showed that older adults in the Embrace group reported greater improvement in quality of care compared to care as usual (CAU). In addition, professionals reported a significant increase in the level of integrated care. A qualitative study showed that case managers identified problems early, took preventive actions, and felt more competent to meet their clients’ needs.Service use and costs. Findings of the cost-effectiveness study will be available in May 2016.Discussion: Embrace care and support has several advantages compared to CAU. Quality of care improved, older adults felt safe, secure, and in control, case managers felt that they were able to connect fragmented and discontinuous elderly care, and the number and severity of perceived health-related problems decreased. Embrace yielded greatest improvement in the “Frail” risk profile, a subgroup of older adults “at risk” of poor health outcomes with no immediate need for professional care yet. This specific group is usually not eligible for integrated care services even though these could be increasingly effective for their health outcomes in the long run.Lessons learned: Complex interventions such as Embrace require a multimethod evaluation to obtain a complete overview of the effects. Focusing only on a RCT would lead to limited conclusions. Furthermore, commonly used measurement instruments for health and well-being may not have been sufficiently sensitive to change to detect advantages of Embrace in clinical practice. This may explain why we only found effects using the specifically developed measurement instruments (GeriatrICS and PAEIC).Limitations: A limitation of this study is that we randomized participating older adults within the GP practices. This may have led to some contamination of CAU via the members of the Elderly Care Team. In addition, we had no control groups for the studies on professionals’ perspectives on quality of care and on older adults’ health-related problems.Future research: Future research should focus on the long-term effects of Embrace and on evaluating the process of care provision. Furthermore, the effects of Embrace in other geographical areas and in other cultures with different healthcare systems should be explored.Conclusion: Mixed Methods Research showed that receiving care and support by Embrace for twelve months resulted in several advantages compared to care as usual.

Contains fulltext : 108770.pdf (Publisher’s version ) (Closed access) We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (

Although the combined presence of ataxia and pyramidal features has a long differential, the presence of a true spastic-ataxia as the predominant clinical syndrome has a rather limited differential diagnosis. Autosomal recessive ataxia of Charlevoix-Saguenay, late-onset Friedreich ataxia, and hereditary spastic paraplegia type 7 are examples of genetic diseases with such a prominent spastic-ataxic syndrome as the clinical hallmark. We review the various causes of spastic-ataxic syndromes with a focus on the genetic disorders, and provide a clinical framework, based on age at onset, mode of inheritance, and additional clinical features and neuroimaging signs, that could serve the diagnostic workup. Neurology (R) 2012;79:1507-1514

Introduction: Embrace1 is a population-based, person-centred, and integrated care service for community-living older adults that combines the Chronic Care Model with risk profiles based on a population health management model. A multidisciplinary Elderly Care Team organizes and evaluates care and support, with intensity depending on an older adult’s risk profile. Embrace has been implemented since 2012 and showed positive outcomes after 12 months regarding patient outcomes, quality of care, and costs. Aim of this study was to assess the long-term outcomes, overall and by risk profile.Methods: We performed a longitudinal study on patient outcomes, quality of care, and costs, with evaluation of change after 12, 24, and 36 months compared to baseline.Results: In total, 1308 older adults participated in the study mean age 80.7 years SD 4.6, 55% female, 57% low educational level. The risk profile distribution changed after 12 and 24 months, with an increase in frail participants Robust 66% vs 39% after 24 months, Frail 17% vs 41%, Complex care needs 18% vs 20%.Overall, general health EQ-VAS remained stable across measurement moments. Quality of life ‘compared to the year before’ SF-36 was stable after 12 months, and decreased after 24 months p=0.026, ES=0.12 and 36 months p0.001, ES=0.61.Discussion and conclusion: Overall, long-term outcomes of Embrace for the older adults are beneficial, particularly for older adults with complex care needs. It seems that Embrace has halted the declining trends in general health and well-being associated with ageing, as well as the related costs increase.Lessons learned: Implementation of Embrace among frail older adults can be improved.Limitations: The lack of a control group.Suggestions for future research: Further research should focus on preventive en proactive support programs for older adults.Reference:1- Spoorenberg SLW, Uittenbroek RJ, Middel B, Kremer HPH, Reijneveld SA, Wynia K. Embrace, a model for integrated elderly care: study protocol of a randomized controlled trial on the effectiveness regarding patient outcomes, service use, costs, and quality of care. BMC Geriatr. 2013;13:62.

A novel TECTA mutation (c.5331G>A) was identified affecting α-tectorin just N-terminally of the zona pellucida domain in a Dutch family with nonsyndromic autosomal dominant sensorineural hearing impairment. The present mutation is clearly associated with a flat-threshold type of hearing impairment. Intriguingly, our results demonstrated that the present TECTA mutation had a significant protective effect against presbyacusis. Substantial protection against presbyacusis is a novel finding in a family with autosomal dominant hearing impairment.

BackgroundIntegrated care models aim to solve the problem of fragmented and poorly coordinated care in current healthcare systems. These models aim to be patient-centered by providing continuous and coordinated care and by considering the needs and preferences of patients. The objective of this study was to evaluate the opinions and experiences of community-living older adults with regard to integrated care and support, along with the extent to which it meets their health and social needs.MethodsSemi-structured interviews were conducted with 23 older adults receiving integrated care and support through "Embrace," an integrated care model for community-living older adults that is based on the Chronic Care Model and a population health management model. Embrace is currently fully operational in the northern region of the Netherlands. Data analysis was based on the grounded theory approach.ResultsResponses of participants concerned two focus areas: 1) Experiences with aging, with the themes "Struggling with health," "Increasing dependency," "Decreasing social interaction," "Loss of control," and "Fears;" and 2) Experiences with Embrace, with the themes "Relationship with the case manager," "Interactions," and "Feeling in control, safe, and secure". The prospect of becoming dependent and losing control was a key concept in the lives of the older adults interviewed. Embrace reinforced the participants' ability to stay in control, even if they were dependent on others. Furthermore, participants felt safe and secure, in contrast to the fears of increasing dependency within the standard care system.ConclusionThe results indicate that integrated care and support provided through Embrace met the health and social needs of older adults, who were coping with the consequences of aging.

Contains fulltext : 51320.pdf (Publisher’s version ) (Closed access) PURPOSE: To prospectively investigate whether quantitative magnetic resonance (MR) parameters, including magnetization transfer ratio (MTR), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and MR spectroscopic metabolite concentrations, allow for discrimination between different types of pathologic conditions that underlie signal intensity abnormalities in white matter. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Forty-one patients (19 male, 22 female; mean age, 15.4 years) and 41 control subjects (25 male, 16 female; mean age, 11.3 years) were included. Twelve patients had a hypomyelinating disorder; 14, a demyelinating disorder; five, a disorder characterized by myelin vacuolation; and 10, a disorder characterized by cystic degeneration. Regions of interest were selected within the parietal white matter and were transferred to the corresponding sections of the generated ADC, FA, and MTR maps to extract quantitative measurements. Linear discriminant analysis and univariate analysis of covariance were used for statistical evaluation. RESULTS: Linear discriminant analysis showed that 95% of patients were correctly classified by using total creatine, choline-containing compounds, myo-inositol, MTR, and ADC. In the hypomyelination group, all MR parameters were close to normal, with the exception of elevated total creatine (P = .03) and myo-inositol (P < .001) levels and decreased MTR values (P < .001). In the demyelination group, the levels of choline-containing compounds (P = .02) and myo-inositol (P < .001) were highly elevated. In the myelin vacuolation and cystic degeneration groups, high ADC values (P < .001) and variable decreases in all MR spectroscopic metabolites were seen. MTR was significantly reduced (P < .001) in the cystic degeneration group. CONCLUSION: Quantitative MR techniques can be used to discriminate between different types of white matter disorders and to classify white matter lesions of unknown origin with respect to underlying pathologic conditions.

We read with interest the Article by Silvia Romano and colleagues, describing a novel and potentially important application of riluzole in patients with spinocerebellar ataxia or Friedreich’s ataxia. The investigators noted that riluzole significantly improved ataxia at 3 months and 12 months. This improvement was assessed as at least a one-point reduction in the Scale for Assessment and Rating of Ataxia (SARA), a rating scale with summed scores of up to a maximum of 40 points in the domains of gait, kinetics, and speech. A posthoc analysis showed improvement in the patients’ quality of life (on the SF-36 scale). In absence of an ideal biomarker for ataxia, Romano and colleagues predefined a one-point reduction in the SARA score as a cutoff for improvement in ataxia. The chosen cutoff suggests that the smallest difference in any of the three SARA domains would represent an improvement in ataxia. We challenge this assumption. First, any selected cutoff should exceed the effects of interobserver and intraobserver variability. Because of the inclusion of heterogeneous patients in Romano and colleagues’ trial, a high variation in SARA scores (2·0–29·5) would induce an increase in the margin of error. Thus, although we noted high interobserver and intraobserver agreements on SARA scores (intraclass correlation coefficient of 0·91–0·98 and 0·96–0·98, respectively), the investigators’ chosen cutoff is highly likely to refer to the margin of error. Second, as indicated by Durr, potentially confounding effects on SARA scores should be taken into account, especially for the comparison of two small and heterogeneous treatment groups. In previous reports, we have shown that SARA scores are not only aff ected by ataxia, but also by age of the child (in terms of observer variability and absolute scores), and by muscle force (in Friedreich’s ataxia). Although we are interested in the potentially positive eff ect of riluzole treatment, the interpretation of the SARA score outcomes are open to question. Until biomarkers for ataxia progression are available, consideration of the SARA construct is important to prevent overinterpretation. The Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS), is now doing a SARA validation study in children to provide increased uniformity for the interpretation of longitudinal ataxia trajectories, from childhood to adulthood.

A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. A nucleotide substitution was identified in the splice acceptor site of intron 7, leading to skipping of exon 8 in part of the transcripts. The mutation was found in 18 individuals. Sensorineural hearing impairment was non-syndromic and symmetric. In early life, presumably congenitally, hearing impairment amounted to 30 dB in the high frequencies. Progression was most pronounced at 1 kHz (1.8 dB/year). Speech recognition was relatively good with a phoneme score of about 50% at the age of 70. Onset age was 37 years, and recognition deteriorated by 1.3% per year. The recognition score deteriorated by 1.0% per decibel threshold increase from a mean pure-tone average (PTA at 1, 2 and 4 kHz) of 63 dB onwards. Vestibular function was generally normal. The second mutation identified in the DFNA5 gene results in hearing impairment, similar to that in the original DFNA5 family in terms of pure-tone thresholds, but with more favourable speech recognition.

Item does not contain fulltext We present a five-generation family with a novel phenotype of autosomal dominant nemaline myopathy not linked to the three genes known to be causative for nemaline myopathy (alpha-tropomyosin-3, nebulin, and alpha-actin). Although there was muscle weakness in the neck flexors and proximal muscles of the limbs, as found in other families, facial, ankle dorsiflexor and respiratory muscles were normal. The most remarkable clinical feature was a peculiar kind of slowness in movement not reported previously in nemaline myopathy.

Item does not contain fulltext IMPORTANCE: ANO10 mutations have been reported to cause a novel form of autosomal recessive cerebellar ataxia (ARCA). Our objective was to report 9 ataxic patients carrying 8 novel ANO10 mutations to improve the delineation of this form of ARCA and provide genotype-phenotype correlation. OBSERVATIONS: The ANO10 gene has been sequenced in 186 consecutive patients with ARCA. The detailed phenotype of patients with ANO10 mutations was investigated and compared with the 12 previously reported cases. The mean age at onset was 33 years (range, 17-43 years), and the disease progression was slow. Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity. No patient in our series had peripheral neuropathy. Magnetic resonance imaging of the brains of our patients revealed marked cerebellar atrophy. The most frequent mutation, a mononucleotide expansion from a polyA repeat tract (c.132dupA) that causes protein truncation, was never observed in homozygosity. Only 2 truncating mutations were reported in homozygosity, one of which (c.1150-1151del) was associated with juvenile or adolescent onset and mental retardation, whereas we show that the presence of at least 1 missense or in-frame mutation is associated with adult onset and slow progression. CONCLUSIONS AND RELEVANCE: An ANO10 mutation is responsible for ARCA that is mainly characterized by cerebellar atrophy and lack of peripheral neuropathy. We therefore suggest naming this entity autosomal recessive cerebellar ataxia type 3 (ARCA3).

Item does not contain fulltext

Although SPG11 is the most common complicated hereditary spastic paraplegia, our knowledge of the long-term prognosis and life expectancy is limited. We therefore studied the disease course of all patients with a proven SPG11 mutation as tested in our laboratory, the single Dutch laboratory providing SPG11 mutation analysis, between 1 January 2009 and 1 January 2011. We identified nine different SPG11 mutations, four of which are novel, in nine index patients. Eighteen SPG11 patients from these nine families were studied by means of a retrospective chart analysis and additional interview/examination. Ages at onset were between 4 months and 14 years; 39% started with learning difficulties rather than gait impairment. Brain magnetic resonance imaging showed a thin corpus callosum and typical periventricular white matter changes in the frontal horn region (known as the 'ears-of the lynx'-sign) in all. Most patients became wheelchair bound after a disease duration of 1 to 2 decades. End-stage disease consisted of loss of spontaneous speech, severe dysphagia, spastic tetraplegia with peripheral nerve involvement and contractures. Several patients died of complications between ages 30 and 48 years, 3-4 decades after onset of gait impairment. Other relevant features during the disease were urinary and fecal incontinence, obesity and psychosis. Our study of 18 Dutch SPG11-patients shows the potential serious long-term consequences of SPG11 including a possibly restricted life span. © 2013 Macmillan Publishers Limited.

Item does not contain fulltext SPG8 is a rare autosomal dominant hereditary spastic paraplegia (AD-HSP), with only six SPG8 families described so far. Our purpose was to screen for KIAA0196 (SPG8) mutations in AD-HSP patients and to investigate their phenotype. Extensive family investigation was performed after positive KIAA0196 mutation analysis, which was part of an on-going mutation screening effort in AD-HSP patients. A novel pathogenic KIAA0196 mutation p.(Gly696Ala) was identified in two AD-HSP patients, who subsequently were shown to belong to a single large Dutch pedigree with more than 10 affected family members. The phenotype consisted of a pure HSP with ages at onset between 20 and 60 years, distally reduced vibration sense in the legs in all, and urinary urgency in seven out of 10 patients. Frequent features were exercise- or emotion-induced increase of spasticity and gait problems and chronic nonspecific lower back and joint pains. We have identified a fourth pathogenic KIAA0196 mutation in a Dutch HSP-family, the seventh family worldwide, with a less severe clinical course than described before.

Item does not contain fulltext SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.

Sirs: The diagnosis of a patient with an early-onset cerebellar ataxia still remains a neurological challenge. Although this clinical syndrome merits careful and intensive evaluation, it frequently turns out to be a disappointing effort, for both patient and physician, in terms of understanding the underlying pathogenesis. The differential diagnosis is extensive and encompasses mostly metabolic and molecular-genetic disorders or yet unexplained syndromal diagnoses, most in a presumably autosomal recessive mode of inheritance. However, structural, neoplastic, and infectious posterior fossa lesions, some of which are potentially treatable, should be considered as well. Here, we describe a patient who presented with an early-onset progressive spinocerebellar syndrome, which was found to be caused by a central nervous system (CNS) localisation of Langerhans’ cell histiocytosis (LCH). This neurological syndrome was the presenting manifestation of the disease. A 23-year-old male was referred to our outpatient clinic because of progressive cerebellar ataxia. His medical history revealed a chronic bronchitis. He had always been clumsy in primary school sports. However, at the age of 8 years he noticed double vision in all directions. Four years later, gait difficulties and disturbances in fine motor tasks gradually evolved. The gait instability resulted in a suspension from his high school because of suspected drug abuse. Symptoms turned out to be progressive, and speech and swallowing difficulties developed subsequently. At the age of 18 years he lost the ability to run. From the age of 22 years, the severe gait disorder necessitated the use of a wheelchair outdoors. His parents were non-consanguineous and the family history was non-contributory. He started smoking cigarettes 4 years before referral and had a cumulative consumption of 5 pack years. Neurological examination revealed slight euphoria, normal cognitive functions, normal optic discs, saccadic intrusions and gazeevoked nystagmus in ocular pursuit, slowing of saccades, horizontal diplopia, cerebellar dysarthria, slowing of rapidly alternating tongue movements, impaired finger tapping, severe gait ataxia, moderately severe limb ataxia, absence of Romberg’s sign, no sensory abnormalities, and brisk tendon reflexes, without pathological reflexes. Scoliosis and skin abnormalities were absent. Laboratory examination, including vitamin E, ceruloplasmin, alpha-fetoprotein levels, lysosomal enzymes, lipid profile, organic acids, aminoacids, long-chain fatty acids, urinary bile alcohols, purines/pyrimidines, and angiotensin-converting enzyme, was without abnormalities. Mutationanalysis of the X25 gene failed to detect GAA-repeat expansions, making Friedreich’s ataxia highly unlikely. In addition, no abnormalities were found in the cerebrospinal fluid analysis, on electromyography or in nerve conduction studies, brainstem auditory evoked potentials, muscle biopsy, and ophthalmologic evaluation. During admission, polydypsia was observed and, in combination with a high-normal sodium level (146 mmol/L), diabetes insipidus was suspected. A thirst provocation test confirmed this diagnosis. Furthermore, endocrine evaluation revealed the presence of subclinical ACTH and growth hormone deficiency. Cranial magnetic resonance imaging (MRI) indicated a thickened, contrast-enhanced infundibulum; atrophy of the cerebellar vermis (Fig. 1a); and, on the T2-weighted images, asymmetrically distributed patchy areas of relative hyperintensity in the pons (Fig. 1b) that showed no enhancement after the administration of gadolinium. At this stage, the combination of a progressive spinocerebellar ataxia and diabetes insipidus, together with the findings on neuroimaging, left only a few differential diagnostic possibilities, including LCH, neurosarcoidosis, and a low-grade glioma. High Resolution computed tomography (HRCT) of the thoracic cavity showed discrete reticular interstitial opacities, predominantly affecting the apical zones. A bronchoalveolar lavage (BAL) showed five percent CD1 a and S100 immunopositive (Langerhans’) cells. A diagnosis of Langerhans’ cell histiocytosis with pulmonary and CNS involvement was made. Skeletal bone scintigraphy and radiographs, iliac crest bone marrow aspirate, and abdominal CT did not demonstrate other LCH localisations. The patient was treated with cranial radiation (20 Gray in 10 fractions), but despite this treatment the clinical course remained slowly progressive. Repeat neuroimaging showed identical non-progressive fossa posterior abnormalities. The diabetes insipidus was LETTER TO THE EDITORS

Item does not contain fulltext Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, but no genotype-phenotype correlations have been found so far. From a total of almost 800 patients referred for testing, we identified 60 patients with mutations in the SPG7 gene. We identified 14 previously unreported mutations and detected a high recurrence rate of several earlier reported mutations. We were able to collect detailed clinical data for 49 patients, who were ranked based on a pure versus complex phenotype, ataxia versus no ataxia and missense versus null mutations. A generally complex phenotype occurred in 69% of all patients and was associated with a younger age at onset (trend with P = 0.07). Ataxia was observed in 57% of all patients. We found that null mutations were associated with the co-occurrence of cerebellar ataxia (trend with P = 0.06). The c.1409 G > A (p.Arg470Gln) mutation, which was found homozygously in two sibs, was associated with a specific complex phenotype that included predominant visual loss due to optical nerve atrophy. Neuropathology in one of these cases showed severe degeneration of the optic system, with less severe degeneration of the ascending tracts of the spinal cord and cerebellum. Other disease features encountered in this cohort included cervical dystonia, vertical gaze palsy, ptosis and severe intellectual disability. In this large Dutch cohort, we seem to have identified the first genotype-phenotype correlation in spastic paraplegia type 7 by observing an association between the cerebellar phenotype of spastic paraplegia type 7 and SPG7 null alleles. An overlapping phenotypic presentation with its biological counterpart AFG3L2, which when mutated causes spinocerebellar ataxia type 28, is apparent and possibly suggests that abnormal levels of the SPG7 protein impact the function of the mitochondrial ATPases associated with diverse cellular activities-protease complex (formed by SPG7 and AFG3L2) in the cerebellum. In addition, a missense mutation in exon 10 resulted in predominant optical nerve atrophy, which might suggest deleterious interactions of this SPG7 variant with its substrate OPA1, the mutated gene product in optic atrophy type 1. Functional studies are required to further investigate these interactions.

Description of the audiometric and vestibular characteristics of a Dutch family with Muckle-Wells syndrome (MWS). Examination of all family members consisted of pure tone audiometry, otoscopy and genetic analysis. In addition, a selected group underwent speech audiometry, vestibulo-ocular examination, acoustic reflex testing and tests assessing loudness scaling, gap detection, difference limen for frequency and speech perception in noise. Linear regression analyses were performed on the audiometric data. Six clinically affected family members participated in this study and all were carriers of a p.Tyr859His mutation in the NLPR3 gene. Most affected family members reported bilateral, slowly progressive hearing impairment since childhood. Hearing impairment started at the high frequencies and the low- and mid-frequency threshold values deteriorated with advancing age. Annual threshold deterioration (ATD) ranged from 1.3 to 1.9 dB/year with the highest values at the lower frequencies. Longitudinal linear regression analysis demonstrated significant progression for a number of frequencies in five individuals. Speech recognition scores were clearly affected. However, these individuals tended to have higher speech recognition scores than presbyacusis patients at similar PTA 1,2,4 kHz levels. The loudness growth curves were steeper than those found in individuals with normal hearing, except for one family member (individual IV:6). Suprathreshold measurements, such as difference limen for frequency (DL f ), gap detection and particularly speech perception in noise were within the normal range or at least close to data obtained in two groups of patients with a so-called conductive type of hearing loss, situated in the cochlea. Hearing impairment in MWS is variable and shows resemblance to previously described intra-cochlear conductive hearing impairment. This could be helpful in elucidating the pathogenesis of hearing impairment in MWS. Other associated symptoms of MWS were mild and nonspecific in the present family. Therefore, even without any obvious syndromic features, MWS can be the cause of sensorineural hearing impairment, especially when combined with (mild) skin rash and musculoskeletal symptoms. An early diagnosis of MWS is essential to prevent irreversible damage from amyloidosis. The effect of IL-1β inhibitors on hearing impairment is more controversial, but an early start of treatment seems to be essential. Therefore, our results are of importance in patient care and counselling.

Objective Investigation of the audiometric characteristics of a large Dutch DFNX4 family with a p.Glu72X mutation in the SMPX gene. Patients and methods Sixty family members participated in this study and examination consisted of medical history, otoscopy, pure tone and speech audiometry. Linkage and mutation analysis revealed a pathogenic mutation in the SMPX gene. Results All 25 mutation carriers exhibited hearing impairment, except one woman aged 25 years. The men ( n = 10) showed more severe hearing impairment than the women ( n = 14) and already at a younger age. The age of onset according to history was 2–10 years (mean: 3.3 years) in men and 3–48 years (mean: 26.4 years) in women. In the men, severe threshold deterioration mainly occurred during the first two decades of life, especially at the higher frequencies. The women showed milder threshold deterioration and more pronounced across-subjects and individual inter-aural variation, especially at 2–8 kHz. Longitudinal linear regression analysis demonstrated significant progression of at least two frequencies in five individuals (3 men and 2 women). The speech recognition scores of the mutation carriers with hearing impairment were decreased at relatively young ages compared to a reference group of patients with only presbycusis, especially in men. However, all these patients tended to have better speech recognition scores than the presbycusis patients at matching PTA 1,2,4 kHz levels. Conclusion This study demonstrates the phenotypic heterogeneity in this large family with an X-linked pattern of inherited sensorineural hearing impairment. The men showed more severe hearing impairment at a younger age with more pronounced progression during the first two decades of life, while women demonstrated less severe hearing impairment with more gradual progression and a wider variation in age of onset, degree of hearing impairment and inter-aural asymmetry in thresholds.

Contains fulltext : 88378.pdf (author's version ) (Open Access) BACKGROUND: In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form. OBJECTIVE: To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4). METHODS: SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed. RESULTS: 151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype. CONCLUSIONS: Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed. 01 oktober 2010

Because the medical literature on hereditary spastic paraplegia (HSP) is dominated by descriptions of adult case series, there is less emphasis on the genetic evaluation in suspected pediatric cases of HSP. The differential diagnosis of progressive spastic paraplegia strongly depends on the age at onset, as well as the accompanying clinical features, possible abnormalities on MRI, and family history. In order to develop a rational diagnostic strategy for pediatric HSP cases, we performed a literature search focusing on presenting signs and symptoms, age at onset, and genotype. We present a case of a young boy with a REEP1 (SPG31) mutation. A 4-year-old boy presented with progressive walking difficulties from the time he started walking at the age of 12 to 13 months. His family history was significant for minimal gait abnormalities with onset after age 35, occurring in the patient's mother, maternal grandfather, and maternal aunt; none of them had ever sought medical attention. Neurologic examination revealed a mildly spastic gait and marked lower limb hyperreflexia with bilateral Babinski signs present. Vibration perception was reduced at the ankles. Neurologic examination of the patient's mother and maternal aunt revealed subtle gait abnormalities with bilateral Babinski signs present. MRI of the brain and spinal cord and general metabolic screening revealed no abnormalities. Diagnostic genetic testing in both the patient and his mother revealed a pathogenic mutation (c.417 + 1 G>T) in REEP1 (SPG31) which causes a pure HSP. Mutations in ATL1 (SPG3A) and SPAST (SPG4) had previously been excluded. HSP is a genetically and clinically heterogeneous group of disorders in which the main clinical feature is progressive lower limb spasticity secondary to pyramidal tract dysfunction. HSP is classified as pure if neurologic signs are limited to the lower limbs (although urinary urgency and mild impairment of vibration perception in the distal lower …

Editor—Noonan syndrome (NS) is an autosomal dominant developmental disorder in which the cardinal features include short stature, typical facies with hypertelorism, ptosis, downward slanting palpebral fissures, and low set, posteriorly rotated ears. In addition, there is a notable cardiac involvement seen in these patients, principally pulmonary valve stenosis and hypertrophic obstructive cardiomyopathy.1 2 The frequency of NS has been estimated to be between 1:1000-1:2500 live births.2 3 Using linkage analysis in a large three generation pedigree, we have previously mapped a gene for NS to an interval of more than 6 cM on 12q24 flanked by the markers D12S1637 and NOS1 .4 5 A similar analysis in smaller two generation families showed genetic heterogeneity for this disorder.4 Despite the relatively high incidence of NS, there appears to be a distinct lack of large families suitable for linkage analysis, possibly resulting from an increase of infertility in males.6 However, the location of the NS gene has recently been further refined to a 5 cM interval through the identification of additional recombinants in one additional large NS family.7 No chromosome rearrangements associated with the disease have so far been discovered. In view of this, one approach currently being used to identify the underlying gene responsible for this disorder is examination of candidate genes from within this large region of chromosome 12. We present below the examination of four candidate genes, the precise localisation of three of which, epidermal growth factor receptor pathway substrate-8 ( EPS8 ), decorin ( DCN ), and myosin light chain 2 ( MYL2 ), had not previously been accurately determined. The fourth, ribosomal protein L6 ( RPL6 ) was known to lie within the NS interval on 12q24.8 PCR was used to produce gene specific products for FISH (see below) and to produce exonic fragments for SSCP …

Contains fulltext : 57313.pdf (Publisher’s version ) (Closed access) Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, recurrent fever attacks, and death in early childhood, and hyper-immunoglobulin D (hyper-IgD) syndrome, with recurrent fever attacks without neurologic symptoms, are caused by a functional deficiency of mevalonate kinase. In a systematic review of known mevalonate kinase-deficient patients, the authors identified five adults with phenotypic overlap between these two syndromes, which argues for a continuous spectrum of disease. Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic fever attacks.