The Neuropsychiatry of Huntington Disease-Like 2: A Comparison with Huntington's Disease.

BACKGROUND: Huntington Disease-Like 2 (HDL2) is a rare autosomal dominant disorder caused by an abnormal CAG/CTG triplet repeat expansion on chromosome 16q24. The symptoms of progressive decline in motor, cognitive and psychiatric functioning are similar to those of Huntington's disease (HD). The psychiatric features of the HDL2 have been poorly characterized. OBJECTIVE: To describe the neuropsychiatric features of HDL2 and compare them with those of HD. METHODS: A blinded cross-sectional design was used to compare the behavioural component of the Unified Huntington's Disease Rating Scale (UHDRS) in participants with HDL2 (n = 15) and HD (n = 13) with African ancestry. RESULTS: HDL2 patients presented with psychiatric symptoms involving mood disturbances and behavioural changes that were not significantly different from those in the HD group. Duration of disease and motor performance correlated (p < 0.001) with the Functional Capacity score and the Independence score of the UHDRS. HD patients reported movement dysfunction as the first symptom more frequently than HDL2 Patients (p < 0.001). CONCLUSION: The psychiatric phenotype of HDL2 is similar to that of HD and linked to motor decline and disease duration. Psychiatric symptoms seem more severe for HDL2 patients in the early stages of the disease.

Conviver com a incerteza relacionada com a doença neurodegenerativa hereditária: um estudo etnográfico / Living with uncertainty related to hereditary neurodegenerative disease: an ethnographical study

Introduction and Objectives: Familial Amyloidotic Polyneuropathy is an autosomal dominant disease and threatens the life of the gene carrier by extracellular deposition of transtirretin in the peripheral nervous system. This paper aims to describe how people living with Familial Amyloidotic Polyneuropathy experience the transition and uncertainty arising from the knowledge of the outcome of the pre-symptomatic genetic test. Methodology: focused ethnography study conducted in the community of Vila do Conde and Póvoa de Varzim. Data collection was performed through ethnographic interview to 31 patients. The collected data were verbatim transcribed and analyzed according to the qualitative data analysis procedures. Results and Discussion: Data have been narrowed into four categories that illustrate how people with Familial Amyloidotic Polyneuropathy, on the one hand, feel and live the uncertainty of the disease, and on the other hand explain the resources and conditions they must have to deal with this uncertainty. Thus, we have as categories, perform the presymptomatic test, personal conditions for transition, community conditions for transition and conditions of society for transition. The management of disease uncertainty is mediated by previous knowledge about a certain health condition, because it affects several generations of the same family, previous knowledge about the risk condition contributes to the acceptance of health status. Conclusions: It is important that nurses promote strategies that increase social and family support and assume as credible authorities in caring for people living with Andrade's disease, becoming facilitators of their personal growth and uncertainty management

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Twenty Years of a Pre-Symptomatic Testing Protocol for Late-Onset Neurological Diseases in Portugal.

INTRODUCTION: The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other hereditary ataxias, to Huntington's disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene. The aim of this study was to describe the profile of the population seeking pre-symptomatic testing, while also reflecting on the experience of conducting the protocol of multidisciplinary sessions since 1996. MATERIAL AND METHODS: We conducted a retrospective study and collected data from clinical records of consultands who requested pre-symptomatic testing at our centre in Porto (Portugal) during the first twenty years of practice (1996 - 2015). RESULTS: A total of 1446 records were reviewed. The most common reason for testing was to reduce uncertainty (41.7%). The rate of withdrawals before results disclosure was lower (16%) than reported in other international experiences with pre-symptomatic testing, while 45% of the consultands dropped out the protocol after learning the test results (73.5% of them were non-carriers). As far as the mutation carriers were concerned, 29.6% adhered to the protocol a year after test disclosure. Consultands that had learned about presymptomatic testing through healthcare professionals tended to adhere more to pre-symptomatic testing consultations. DISCUSSION: The profile of Portuguese consultands at risk for late-onset neurological diseases is similar to those reported in other international programs. The largest group in this data set was the one comprising the subjects at risk for familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene, and it is likely that therapeutic options for this condition may have influenced this result. Adherence to pre-symptomatic testing may change in the future since effective therapies are available (or given the fact that people think effective treatments are imminent). CONCLUSION: This study reflects the first comprehensive description of a Portuguese experience with pre-symptomatic testing for late onset neurological diseases. The development of innovative approaches to improve the consultands' experience with pre-symptomatic testing and their engagement in genetic departments is still a challenge in Portuguese genetics healthcare departments. A better coordination among primary care and genetics healthcare services is needed.

Introdução: Em 1995 foi iniciado em Portugal um protocolo nacional para o aconselhamento genético e teste pré-sintomático de doenças neurológicas de início tardio. Inicialmente, foi disponibilizado para indivíduos adultos em risco para a doença de Machado-Joseph e posteriormente estendido a outras ataxias hereditárias, doença de Huntington e polineuropatia amiloidótica familiar ATTR Val30Met. O objetivo deste estudo é descrever o perfil dos consultandos envolvidos no teste pré-sintomático desde 1996, e refletir no protocolo de sessões multidisciplinares. Material e Métodos: Realizámos um estudo retrospetivo com recolha de dados dos processos clínicos dos utentes que solicitaram teste pré-sintomático ao longo dos primeiros 20 anos do Centro de Genética Preditiva e Preventiva (1996 - 2015), localizado no Porto, Portugal. Resultados: Analisámos um total de 1446 processos clínicos; a principal motivação para a realização do teste pré-sintomático foi o alívio da incerteza (41,7%). A taxa de abandono do protocolo antes da comunicação dos resultados do pré-sintomático (16% dos casos) foi mais baixa do que em outras experiências internacionais; 45% dos consultandos abandonaram o protocolo depois de saberem o resultado do teste pré-sintomático (73,5% dos quais eram não-portadores). 29,6% de consultandos portadores continuaram envolvidos no protocolo um ano após saberem o resultado do teste pré-sintomático. Os consultandos encaminhados para o protocolo através de outros profissionais de saúde revelaram maior adesão ao protocolo. Discussão: O perfil sociodemográfico dos consultandos no Centro de Genética Preditiva e Preventiva é similar ao reportado noutras experiências internacionais. Os consultandos em risco para polineuropatia amiloidótica familiar ATTR Val30Met representaram o maior grupo nos nossos dados, sendo provável que as opções terapêuticas disponíveis para esta doença tenham influenciado este resultado. A adesão ao teste pré-sintomático poderá alterar-se no futuro quando terapias eficazes estiverem disponíveis (ou as pessoas as percepcionem como estando iminentes). Conclusão: Este trabalho constitui a descrição mais completa até ao momento publicada acerca da realização de teste pré-sintomático em Portugal. O desenvolvimento de abordagens com vista à melhoria da experiência dos consultandos com os testes pré-sintomáticos e ao seu envolvimento nos serviços de genética é um desafio atual, assim como a melhor articulação dos mesmos com os cuidados de saúde primários.

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model.

Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.

Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1.

Polyglutamine diseases are dominantly inherited neurodegenerative diseases caused by an expansion of a CAG trinucleotide repeat encoding a glutamine tract in the respective disease-causing proteins. Extensive studies have been performed to unravel disease pathogenesis and to develop therapeutics. Here, we report on several lines of evidence demonstrating that Nemo-like kinase (NLK) is a key molecule modulating disease toxicity in spinocerebellar ataxia type 1 (SCA1), a disease caused by a polyglutamine expansion in the protein ATAXIN1 (ATXN1). Specifically, we show that NLK, a serine/threonine kinase that interacts with ATXN1, modulates disease phenotypes of polyglutamine-expanded ATXN1 in a Drosophila model of SCA1. Importantly, the effect of NLK on SCA1 pathology is dependent upon NLK's enzymatic activity. Consistent with this, reduced Nlk expression suppresses the behavioral and neuropathological phenotypes in SCA1 knock-in mice. These data clearly indicate that either reducing NLK enzymatic activity or decreasing NLK expression levels can have beneficial effects against the toxicity induced by polyglutamine-expanded ATXN1.

The neuropsychiatric manifestations of Huntington's disease-like 2.

Huntington's disease-like 2 (HDL2) is a rare neuropsychiatric disorder that resembles HD but results from a distinct mutation. The authors present a patient with HDL2, hospitalized for psychiatric management, and they review the neuropsychiatric manifestations of this disorder. Depression, irritability/aggression, and frontal lobe personality changes are common presentations of HDL2 and are comparable to classic HD. Patients with HDL2 may differ from those with HD in having a lower incidence of obsessive-compulsive acts, known suicides, antisocial acts, and changes in sexuality. Clinicians should be aware of the psychiatric presentations of this disorder, when to obtain genetic testing, and how to manage problematic behaviors.

Presymptomatic testing for neurogenetic diseases in Brazil: assessing who seeks and who follows through with testing.

Diagnostic tests are available to detect several mutations related to adult-onset, autosomal dominant, neurodegenerative diseases. We aimed to describe our experience in a presymptomatic testing program run by the Brazilian Public Health System from 1999 to 2009. A total of 184 individuals were eligible for presymptomatic testing due to a risk for spinocerebellar ataxia (SCA) - SCA3 (80%), Huntington's disease (11.9%), familial amyloidotic neuropathy (4.3%), SCA1, SCA2, SCA6, or SCA7. Most were women (70%), married (54%), and had children prior to presymptomatic testing (67%). Their mean age at entrance was 34 (SD = 11 years). Educational level was above the average Brazilian standard. After receipt of genetic counseling, 100 individuals (54%) decided to undergo testing; of these, 51 were carriers. Since no individual returned for post-test psychological evaluation, we conducted a subsequent survey, unrelated to test disclosures. We contacted 57 individuals of whom 31 agreed to participate (24 had been tested, 7 had not). Several ascertainment concerns relating to these numerous losses prevented us from generalizing our results from this second survey. We concluded that: decision-making regarding presymptomatic testing seems to be genuinely autonomous, since after genetic counseling half the individuals who asked for presymptomatic testing decided in favor and half decided against it; general characteristics of Brazilians who sought presymptomatic testing were similar to many European samples studied previously; and individuals at risk for SCA3 may be at greater risk of depression. Although no clear-cut reason emerged for rejection of follow-up psychological sessions after presymptomatic testing, this finding suggests adjustments to our presymptomatic testing program are necessary.

Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aß is induced by pyroglutamate-Aß formation.

Posttranslational amyloid-ß (Aß) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified Aß species, pyroglutamate-amyloid-ß (pE3-Aß), has been described as a major constituent of Aß deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated Aß species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-Aß aggregates rapidly and is known to seed additional Aß aggregation. To directly investigate pE3-Aß toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human Aß. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating Aß and pE3-Aß deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3-Aß neurotoxicity, this phenotype was not found in heterozygous animals but in homozygous TBA2.1 or double-heterozygous TBA2.1/2.2 animals only. A significant amount of pE3-Aß formation was shown to be QC-dependent, because crossbreeding of TBA2.1 with QC knock-out, but not isoQC knock-out, mice significantly reduced pE3-Aß levels. Hence, lowering the rate of QC-dependent posttranslational pE3-Aß formation can, in turn, lower the amount of neurotoxic Aß species in AD.

A low symptomatic form of neurodegeneration in younger carriers of the FMR1 premutation, manifesting typical radiological changes.

Fragile X-associated tremor/ataxia (FXTAS) is a late onset disorder caused by a premutation in the FMR1 gene, in which neurological symptoms are associated with white matter (wm) changes, especially within the middle cerebellar peduncles (MCP sign), seen on magnetic resonance images (MRIs). We report a discrepancy between obvious radiological presentations and minimal clinical involvement in two younger male premutation carriers. These carriers, aged 52 and 39 years, showed distinct MCP sign, but reported no neurological symptoms. If this discrepancy represents the initial stage of FXTAS, our findings suggest the possibility of early diagnosis from MRI scans.

Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation.

Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Abeta plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.

Maturity of judgement in decision making for predictive testing for nontreatable adult-onset neurogenetic conditions: a case against predictive testing of minors.

International guidelines developed to minimize harm from predictive testing for adult-onset, nontreatable neurogenetic conditions such as Huntington disease (HD) state that such testing should not be available to minors. Some authors have proposed that predictive testing for these conditions should be available to minors at the request of parents and/or of younger adolescents themselves. They highlight the lack of empirical evidence that predictive testing of minors causes harm and suggest that refusing to test minors may be detrimental. The current study focuses on the context of predictive test requests by adolescents younger than 18 years, and presents arguments and evidence that the risk of potential harm from testing such young people is sufficiently high to justify continued caution in this area. A study based on a model of psychosocial maturity found that the 3 factors involved in maturity of judgement in decision making - responsibility, temperance and perspective - continue to develop into late adolescence. There is also evidence that the prefrontal areas of the brain, which are involved in executive functions such as decision making, are not fully developed until early adulthood. Combined with evidence of adverse long-term effects, from research with adults who have undergone predictive testing, these findings constitute grounds for retaining a minimum age of 18 years for predictive testing for nontreatable conditions. Further research on assessment of maturity will assist with reaching a consensus on this issue.

Lessons from fragile X regarding neurobiology, autism, and neurodegeneration.

The fragile X mental retardation 1 gene (FMR1) mutation causes two disorders: fragile X syndrome (FXS) in those with the full mutation and the fragile X-associated tremor/ataxia syndrome (FXTAS) in some older individuals with the premutation. FXS is caused by a deficiency of the FMR1 protein (FMRP) leading to dysregulation of many genes that create a phenotype with ADHD, anxiety, and autism. FXTAS is caused by the elevation of FMR1-mRNA to levels 2 to 8 times normal in the premutation. This causes an RNA gain of function toxicity leading to brain atrophy, white matter disease, neuronal and astrocytic inclusion formation, and subsequent ataxia, intention tremor, peripheral neuropathy, and cognitive decline. The neurobiology and pathophysiology of FXS and FXTAS are described in detail.

[Predictive testing: presymptomatic diagnosis in neurogenetic disorders]. / Les tests présymptomatiques en neurogénétique.

Presymptomatic testing is available since 15 years for Huntington disease and it is now possible for a number of other neurogenetic disorders, mostly neurodegenerative disorders. The possibility of determining the genetic status of an at-risk person for the disorder which run in his family raises questions because of the absence of preventive and curative treatments in most instances. In addition, being carrier does not tell you when the disease will start and how it will evolve, impairing the possibilities of planning the future. A pluridisciplinary approach to predictive testing with care before, during and after the test taking into account the medical, social and psychological aspects of the disease is good practice. At the present time, only a minority of at-risk individuals request presymptomatic testing and almost 50 % do not pursue until the results. The consequences of the test may be harmful, more frequently after an unfavorable than after a favorable result. Although the motivations and the outcome in terms of request for prenatal testing after a carrier result are different in Huntington's disease and spinocerebellar ataxias, our experience underlines the benefit of pluridisciplinary care and of time for decision taking. For other disorders like familial Alzheimer's disease, or familial Creutzfeldt-Jakob disease, the experience in presymptomatic testing is still limited but the situation seems similar to Huntington's disease because of the presence of dementia. It will be interesting to study the motivations and the outcome of the tests in disorders like autosomal dominant spastic paraplegias which usually do not reduce the life expectancy. Nevertheless, the overall situation might change greatly when efficient treatments will become available in these disorders.

[Treatment of patients with neuromuscular disease in a warm climate]. / Behandling i varmt klima for pasienter med nevromuskulaere sykdommer.

BACKGROUND: Several patient groups request treatment in a warm climate, in spite of the fact that the effects of such treatment are undocumented. MATERIAL AND METHODS: 47 children and 40 adults with neuromuscular diseases were recruited, stratified according to sex, use or non-use of electric wheelchair, primary myopathy or hereditary neuropathy, and randomised into two adult and two children groups. The patients were treated in a rehabilitation centre, either on Lanzarote or in Norway. All patients were monitored with physical tests and questionnaires at the start of the study, at the end of the treatment period, after three months (all groups) and after six months (adults only). RESULTS: No significant differences in effect between the groups were found. In the warm climate, the adult patient group showed a statistically significant improvement regarding pain, quality of life, depression, and results of physical tests at the end of treatment. After three months, the improvement in physical tests was still present. Among adult patients treated in Norway, improvement in physical tests was statistically significant after three months, but not at the end of the treatment period. INTERPRETATION: This study did not show a statistically significant difference between patients with various neuromuscular diseases treated in a warm climate compared to similar patients treated in Norway.

Quality of life in hereditary neuromuscular diseases.

OBJECTIVE: The aim of the study is to evaluate different aspects in the quality of life (QoL) in a group of patients affected by hereditary neuromuscular disease. MATERIAL AND METHODS: Forty-five consecutive outpatients (mean age 49.46 +/- 17.07 years, range 19-80 years) with hereditary neuromuscular disease underwent the Brooke scale and functional independent measure to assess the functional status, the Sickness Impact Profile (SIP) and Psychological General Well-Being Index (PGWBI), as a measure of the QoL. RESULTS AND CONCLUSIONS: All patients had a poor QoL assessment with SIP. The higher disability level was not related to a worse QoL perception with the exception of the physical area. Females and patients above 49 years showed the worst QoL profile. The discomfort linked to the emotional and affective sphere, assessed with PGWBI, appeared low in the study sample. Therefore psychosocial aspects and economical and environmental factors may influence the QoL.

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.

The psychological complexity of predictive testing for late onset neurogenetic diseases and hereditary cancers: implications for multidisciplinary counselling and for genetic education.

Increasing knowledge about the human genome has resulted in the availability of a steadily increasing number of predictive DNA-tests for two major categories of diseases: neurogenetic diseases and hereditary cancers. The psychological complexity of predictive testing for these late onset diseases requires careful consideration. It is the main aim of the present paper to describe this psychological complexity, which necessitates an adequate and systematic multidisciplinary approach, including psychological counselling, as well as ongoing education of professionals and of the general public. Predictive testing for neurogenetic diseases--in an adequate counselling context--so far elicits optimism regarding the short- and mid-term impact of the predictive test result. The psychosocial impact has been most widely studied for Huntington's disease. Longitudinal studies are of the utmost importance in evaluating the long-term impact of predictive testing for neurogenetic diseases on the tested person and his/her family. Given the more recent experience with predictive DNA-testing for hereditary cancers, fewer published scientific data are available. Longitudinal research on the mid- and long-term psychological impact of the predictive test result is essential. Decision making regarding health surveillance or preventive surgery after being detected as a carrier of one of the relevant mutations should receive special attention. Tailoring the professional approach--inside and outside genetic centres--to the families' needs is a continuous challenge. Even if a continuous effort is made, several important questions remain unanswered, last but not least the question regarding the best strategy to guarantee that the availability of predictive genetic testing results in a reduction of suffering caused by genetic disease and in an improvement of the quality of life of families confronted with genetic disease.

Redefinition: coping with normal results from predictive gene testing for neurodegenerative disorders.

The purpose of this qualitative study was to describe the psychosocial impact and coping processes of normal (negative) results from predictive testing for an inherited neurodegenerative disease. Ten adults with normal results of predictive testing for the Huntington disease (HD) or the Pallido-Ponto-Nigral Degeneration (PPND) gene mutation participated in semi-structured interviews 1 month after receiving results, and seven of these participants were interviewed 6 months later. The major theme of Redefinition was derived using Knafl and Webster's analysis method (1988). People who received normal gene results experienced loss of former beliefs about themselves and developed new self definitions, relationships with family, and roles in society. This coping process evolved from a personal focus at 1 month to a broader future perspective at 6 months after testing. Identifying components of the redefinition process may be an important consideration in planning interventions to promote coping with normal gene results in persons within at-risk families.