A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases
Introduction
Predictive genetic testing and molecular genetic diagnosis have taken an ever-increasing role in clinical practice and translational research for the neurodegenerative diseases over the last two decades. The hope underlying genetic advancements is that accurate and early identification of disease or genetic risk will reduce morbidity and mortality through screening, observation, and early treatment or prevention. Up to now, the identification of genes responsible for adult neurodegenerative disorders has helped elucidate molecular mechanisms underlying the etiology and pathogenesis of these disorders (see Fig. 1 from Bertram and Tanzi, 2005). Such discoveries have begun to impact biomarker development and drug discovery, but have not yet led to improved treatments or prevention. Twenty years after the discovery of the Huntington disease (HD) gene, in the absence of disease-modifying treatments, we felt it was important to reexamine the human reaction to genetic testing – how individuals and families respond to the sometimes life-altering information. In this review, we discuss the current state of health-related quality of life (HRQOL) measurements in neurodegenerative diseases and the importance of these self-report or “patient reported outcomes” for all clinical research. Next, we address HRQOL following predictive genetic testing in some neurodegenerative diseases: HD, Alzheimer disease (AD), Parkinson's disease (PD), Dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), prion diseases, hereditary ataxias, Dentatorubral-pallidoluysian atrophy (DRPLA) and Wilson's disease (WD). Predictive genetic testing reflects knowledge of location and number of mutations associated with a condition. In some disorders, a mutation will be family specific, limiting the potential for predictive testing to biologic relatives of a person with a known mutation. Furthermore, some neurodegenerative disorders are genetically heterogenous, with rare cases being inherited in an autosomal dominant fashion in which a mutation may or may not be identified within the family (Table 1 for an overview). After a brief report of available direct-to-consumer (DTC) genetic tests, we address the juxtaposition of earlier disease identification with assumed reluctance toward predictive genetic testing. The discussion includes directions for research and practice.
Section snippets
Background
With the advent of amniocentesis in the 1970s came a steady stream of discourse regarding ethical guidelines for disclosure of genetic information and communication of risk (Ethical Principles, 1979, Screening, 1983, Powledge and Fletcher, 1979). Developments in genetic testing and increased public awareness of inherited disease stimulated the formation of committees to examine the ethics of health policy worldwide. For example, The United States Secretary of Health and Human Services chartered
HRQOL overview
Expanded definitions of health and functioning, such as that of the World Health Organizations’ (WHO) International Classification of Functioning, Disability and Health (WHO, 2010), have challenged traditional outcomes and encouraged consideration of contextual factors on a person's well-being, in addition to the impact of health. The WHO defines health as a condition of total well-being, inclusive of multiple domains of well-being and not only the lack of disease. WHO has developed the
Huntington disease
Characterized as an inherited disease in its seminal publication over 140 years ago (Huntington, 1872), HD patients, families and professionals have pioneered the fusion of genetics and health care. Genetic testing for HD began with the localization of the gene by linkage analysis 30 years ago (Gusella et al., 1983) and became a standard of care with the discovery of the HD gene 20 years ago (MacDonald et al., 1993). Collaborative worldwide guidelines for predictive and diagnostic testing in HD
Alzheimer's disease
Heritability estimates for AD suggest genetic variations may account for 58%–80% of AD risk. Predicting the development and prognosis of AD is difficult, however, because only a small percentage of cases present with an autosomal dominant transmission pattern and an early disease onset that make genetic testing practical. To date, three causal genes have been identified which together account for less than 2% of AD: amyloid-beta protein precursor (APP) gene on chromosome 21 (Goate et al., 1991
Parkinson's disease
PD is the second most common neurodegenerative disorder, and as for AD and HD, intensive efforts are currently underway to identify early markers of the disease that precede the overt presence of diagnosable disease, and corresponding efforts to identify individuals with a high risk of developing disease due to genetic or environmental factors, or both. Earlier identification of Parkinsonism and its related dementias may be critical to the design of experimental therapeutics to forestall
Dementia with Lewy bodies
DLB has been considered a member of a disease continuum including AD and PD. Clinically, patients experience memory impairment similar to AD, motor symptoms as seen in PD, and also have prominent visual misperception and hallucinations. The neuropathological hallmark is widespread presence of alpha-synuclein-positive neuronal inclusions, called Lewy bodies. Only one large genome-wide linkage study for DLB has been reported to date, and although a locus was determined on chromosome 2, no simple
Frontotemporal dementia
FTD is the third most common cause of dementia beginning before age 65. FTD is a heterogeneous degenerative disorder encompassing a number of different clinical syndromes though the most common type presents with personality and behavioral changes and less common subtypes are described with primary language impairment (Cairns et al., 2007, Gorno-Tempini et al., 2004, Rohrer et al., 2009). There is an overlap of FTD with motor disorders such as the parkinsonian disorders, corticobasal syndromes,
Amyotrophic lateral sclerosis
Over 90% of adult-onset cases of ALS have no family history and are sporadic. Currently, there are five known genes found in Familial ALS (FALS). Approximately 30% are caused by mutations in the newly identified C9orf72 gene, 15–20% are caused by mutations in the SOD1 (superoxide dismutase) gene, and 7–8% of cases are caused by pathogenic variants in the TDP-43TAR DNA binding protein 43, FUS/TLS gene or the valosin-containing protein (VCP) gene (Gitcho et al., 2008, Kwiatkowski et al., 2009,
Prion diseases
Prion diseases are fatal neurodegenerative diseases in humans and animals caused by the misfolding and aggregation of prion protein (PrP). Although it is well established that prion diseases are under strong genetic control, few risk factors are known, aside from the PrP gene locus (PRNP) (Mead et al., 2012). About 85% of prion disease is sporadic and 15% is familial. Familial prion diseases include Creutzfeldt-Jakob disease (CJD), Gertmann–Straussler disease (GSS) and fatal familial insomnia
Hereditary ataxias
The first ataxia gene (spinocerebellar ataxia type 1 (SCA1)) was identified by a research team led by Drs. Orr and Zoghbi in 1993 and, as of today, over 36 autosomal dominant cerebellar ataxias, 20 autosomal recessive, two X-linked and several forms of mitochondrial defects are known (Orr et al., 1993). Even now, in 40% of familial ataxia cases, no responsible gene abnormality is identified (Matilla-Dueñas et al., 2012, Sailer and Houlden, 2012). With the rapid advances in genetic sequencing (
Dentatorubral-pallidoluysian atrophy (DRPLA)
DRPLA is a progressive disorder leading to ataxia, choreoathetosis, and dementia in adults, and ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children. Age of onset ranges from 1 to 62 years, with a mean age of onset of 30 years. Diagnosis is based on family history, clinical findings, and detection of an expansion in the length of CAG repeats in the ATN1 gene. Treatment is symptomatic, with appropriate environmental adaptations for dementia in adults and adapted
Wilson's disease
WD is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging from age three years to over 50 years. The disease gene responsible for WD, known as the ATP7B gene, is located on the long arm (q) of chromosome 13 (13q14.3) and inherited as an autosomal recessive trait. The protein regulated by this gene plays a role in the transport of copper (copper-transporting ATPase). ATP7B is the only gene known
Direct-to-consumer (DTC) testing
A number of companies offer online DTC genetic tests, where consumers order test kits over the Internet and send a DNA sample (usually saliva or a cheek swab) to a laboratory for analysis. The results are available to the individual over the Internet after several weeks. These tests are currently poorly regulated and, thus, the quality and reliability of the results vary. Counseling may be available but is not required. The Genetics and Public Policy Center at Johns Hopkins University prepared
Summary of safety/benefit of predictive testing in neurodegenerative diseases
The current review revealed about 41 studies examining health-related outcomes following predictive genetic testing for neurodegenerative disease. The majority of this research was for HD (28 studies or 71%) with the other studies focusing on AD, FTD, and the ataxias. In general, data suggest that predictive testing is feasible and safe for dominantly inherited disorders. Collectively, these studies have shown that (a) extreme or catastrophic outcomes are rare; (b) consequences commonly include
Novel protocols
With 20 years of experience showing that predictive genetic testing is safe under current protocols, it is time to consider updating and fine-tuning testing protocols. For example, flexible genetic counseling protocols are needed to address under-represented geographic regions, where there is limited in-person access to genetic counselors. Novel systems could be developed to ensure that laboratories and counselors have up-to-date information about the relationship between the presence of the
Decision-making for predictive genetic testing
Feasibility of predictive genetic testing in neurodegenerative diseases for which no Mendelian genes are identified requires further consideration. It is well understood by health care professionals that the complexity of the genetic test can meaningfully alter the utility of predictive tests. Research findings to date show that decisions to test and outcomes of testing vary depending on the perceived value in the information (see Neumann et al., 2012 for an example of experimental methodology
Incorporation of genetics into the early detection of HD
Currently in its twelfth year of funding by the NIH and CHDI Foundation, the PREDICT-HD research study has enrolled more than 1200 gene-expanded but not clinically diagnosed participants, as well as a smaller sample of demographically matched, non-gene-expanded participants (n = 350) that serve as a comparison group. To date, 206 participants from the PREDICT-HD study have been prospectively clinically diagnosed. In addition, a proxy measure of “estimated years to HD clinical diagnosis” (AKA
Integration of genetic information for the diagnosis of HD
Diagnostic criteria for neurodegenerative diseases must be re-conceptualized in light of genetic findings. Validity and reliability of diagnosis will remain a top priority although a gene's presence, penetrance, and heritability can significantly impact the identification and assessment of progressive decline. Efforts have been ongoing to reconsider the diagnostic criteria for MCI, AD, PD, HIV, LBD, and Vascular dementia over the past few years, incorporating evidence from imaging and biomarker
Implications for other diseases
Recent experience in the Dominantly Inherited Alzheimer Network (DIAN), investigating patients with presenilin and amyloid precursor protein gene mutations, found that concentrations of Aβ in the CSF probably decreased 25 years before predicted onset of symptoms and Aβ deposition, as measured by positron-emission tomography using Pittsburgh compound B, was found 15 years before; increased concentrations of tau in the CSF and increase in brain atrophy were also discovered 15 years before symptom
Conclusion
The past decade has witnessed an explosion of evidence suggesting that many neurodegenerative diseases can be detected years, if not decades, earlier than previously thought. Unfortunately, these scientific advances have not yet provoked any parallel translational or clinical improvements. There is an urgency to capitalize on this momentum so that earlier detection of disease can be more readily translated into improved QOL for families at risk for, or suffering with, neurodegenerative
Acknowledgments
We thank the PREDICT-HD sites, the study participants, the National Research Roster for Huntington Disease Patients and Families, the Huntington's Disease Society of America and the Huntington Study Group. This publication was supported by the NIH, NS040068, 5R01HG003330, NS077946, NS054893, NGHG003330, National Center for Advancing Translational Sciences, and the NIH, UL1 TR000442-06. The content is solely the responsibility of the authors and does not necessarily represent the official views
References (283)
Apolipoprotein E genotyping in Alzheimer's disease
Lancet
(1996)- et al.
A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease
Am. J. Human Genet.
(1999) - et al.
Perceptions of genetic discrimination among at-risk relatives of colorectal cancer patients
Genet. Med.
(2004) - et al.
Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington's disease
Parkinsonism Related Dis.
(2010) - et al.
Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer's disease
Alzheimer's Dementia: J. Alzheimer's Assoc.
(2008) - et al.
Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer's disease
Alzheimer's Dementia: J. Alzheimer's Assoc.
(2008) - et al.
The neurology quality-of-life measurement initiative
Arch. Phys. Med. Rehab.
(2011) - et al.
a The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008
J. Clin. Epidemiol.
(2010) - et al.
The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008
J. Clin. Epidemiol.
(2010) - et al.
Pathological correlates of gastrointestinal dysfunction in Parkinson's disease
Neurobiol. Dis.
(2012)
Postgenomics, uncertain futures, and the familiarization of susceptibility genes
Social Sci. Med.
A de novo missense mutation of the FUS gene in a “true” sporadic ALS case
Neurobiol. Aging
Uptake of presymptomatic predictive testing for Huntington's disease
Lancet
Interest in predictive testing for Parkinson's disease: impact of neuroprotective therapy
Parkinsonism Related Dis.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
Experience over fifteen years with a protocol for predictive testing for Huntington disease
Mol. Genet. Metab.
An international survey of predictive genetic testing in children for adult onset conditions
Genet. Med.
Legal update: living with the Genetic Information Nondiscrimination Act
Genet. Med.
The psychological complexity of predictive testing for late onset neurogenetic diseases and hereditary cancers: implications for multidisciplinary counselling and for genetic education
Soc. Sci. Med.
Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors
Neuroscience
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing
Genet. Med.
Ethical issues policy statement, on Huntington's disease molecular genetics predictive test
J. Neurol. Sci.
DRPLA
Genetic testing in adoption
Am. J. Human Genet.
Guidance for Industry: Questions and Answers Regarding Food Allergens, including the Food Allergen Labeling and Consumer Protection Act of 2004 (Edition 4); Final Guidance
Genetic Information Nondiscrimination Act of 2008
Psychological consequences and predictors of adverse events in the first 5 years after predictive testing for Huntington's disease
Clin. Genet.
The ethics of disclosing genetic diagnosis for Alzheimer's disease: do we need a new paradigm?
Brit. Med. Bull.
Guidelines for the molecular genetics predictive test in Huntington's disease
J. Med. Genet.
The clinical utility of gene testing for Alzheimer's disease
Neurol. Intern.
Longitudinal change in regional brain volumes in prodromal Huntington disease
J. Neurol. Neurosurg. Psychiat.
Attitudes toward direct predictive testing for the Huntington disease gene. Relevance for other adult-onset disorders. The Canadian Collaborative Group on Predictive Testing for Huntington Disease
JAMA
Clinical and biomarker changes in dominantly inherited Alzheimer's disease
New England J. Med.
Principles of Biomedical Ethics
United Kingdom experience with presymptomatic testing of individuals at 25% risk for Huntington's disease
Clin. Genet.
Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease
J. Neuropathol. Exp. Neurol.
The sickness impact profile: development and final revision of a health status measure
Med. Care
The genetic epidemiology of neurodegenerative disease
J. Clin. Invest.
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses
Nat. Rev. Neurosci.
Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study
Mov. Disord.
Refining the diagnosis of Huntington disease: the PREDICT-HD study
Front. Aging Neurosci.
Predictive testing for Huntington disease in Canada: the experience of those receiving an increased risk
Am. J. Med. Genet.
A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder
Brain: J. Neurol.
Engagement with genetic discrimination: concerns and experiences in the context of Huntington disease
Eur. J. Hum. Genet.
Perceptions of genetic discrimination among people at risk for Huntington's disease: A cross sectional survey
Br. Med. J.
Carrier testing in minors: a systematic review of guidelines and position papers
Eur. J. Hum. Genet.
Cited by (108)
Phosphatidylserine: An overview on functionality, processing techniques, patents, and prospects
2023, Grain and Oil Science and TechnologyStem cell therapies for neurodegenerative disorders: An ethical analysis
2023, Clinical Ethics at the Crossroads of Genetic and Reproductive Technologies, Second EditionRisk disclosure in prodromal Parkinson's disease – A survey of neurologists
2023, Parkinsonism and Related DisordersCitation Excerpt :Moreover, studies on Alzheimer and Huntington diseases showed that such informing could generate psychological distress, including suicidal behavior, even if individuals deliberately request to be informed about their risk [22–25]. Considering the long latency period before clinical symptoms allow the diagnosis of PD (median: 11 years, range: 2–24 years [19]), and the fact that future PD is not a certainty but a (high) probability, risk disclosure for a potential disease that may never develop may impose psychological harm [21,25,26]. Prognostic uncertainty was also reported as a concern among sleep specialists [18].
Genetic counseling for prion disease: Updates and best practices
2022, Genetics in MedicineCitation Excerpt :Although some studies report after-test divergence in distress levels between those who test positive and negative, these gaps typically close within weeks to months.42,46,55,56 Many people report important benefits from receiving their genetic information, regardless of outcome.47,57 Relief from uncertainty can be a significant psychological factor, capable of more than compensating for an unwanted result42,57,58 and the act of gathering information through testing can itself be an effective coping mechanism.59
- 1
Tel.: +952 993 5000.
- 2
Tel.: +319 335 8765; fax: +319 353 4438.
- 3
Tel.: +734 763 8917; fax: +734 763 7186.
- 4
Tel.: +618 6380 2255; fax: +618 6380 2055.
- 5
Tel.: +713 500 5963.
- 6
Tel.: +9816 0513.
- 7
Tel.: +61 2 9845 6793; fax: +61 2 9635 6684.
- 8
Tel.: +319 335 7046.