Comment
For more on EUROMOTOR see http://www.euromotorproject. eu
stages in Alzheimer’s disease and Parkinson’s disease has provided new insights into the natural history of these diseases. Although the aggressive nature of amyotrophic lateral sclerosis suggests parallels with cancer, no mechanistic similarities have been found with regard to pathogenesis. Perhaps the new epidemiological data will allow new mechanistic hypotheses to refine ideas about the pathogenesis of amyotrophic lateral sclerosis. Like the clinical approach in cancer, the focus should be on preclinical stages of the disease (ie, the first steps of the causal process) with the use of potential biomarkers such as serum microRNA.9 This approach might show the differences between the model proposed by Al-Chalabi and colleagues6 and the conventional liability model of other chronic diseases in which many genes and environmental risk factors add their effects and, if the adddition is beyond a certain threshold, the individual is affected. In future studies, the proposed model should be tested in familial and apparently sporadic cases and in individuals of different ethnic origins, and eventually be used with new epidemiological methods (eg, the inverse probability marginal structural model) to test causality in observational longitudinal studies.10 The findings of this study suggest that genetics might be insufficient to clarify all the steps needed to explain the pathogenesis of amyotrophic lateral sclerosis. The challenge for future studies of amyotrophic lateral sclerosis and neurodegeneration will be the exploration of causal heterogeneity, including exposomes (ie, the identification of nongenetic exposure), over a long time. Consequently,
large collaborations such as EURALS and EUROMOTOR, which are based on a prospective collection of data at the population level, are needed to advance understanding of amyotrophic lateral sclerosis. Giancarlo Logroscino, Albert Ludolph Neurodegenerative Diseases Unit, Department of Basic Medicine, Neuroscience and Sense Organs, Department of Clinical Research in Neurology of the University of Bari at Pia Fondazione Card G Panico, Hospital Tricase, University Aldo Moro, Bari 73 039, Italy (GL); and Department of Neurology, University of Ulm, Ulm, Germany (AL) [email protected] We declare no competing interests. 1 2
3
4
5 6
7 8
9
10
Logroscino G, Traynor BJ, Hardiman O, et al. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 2010; 81: 385–90. Phukan J, Elamin M, Bede P, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 2012; 83: 102–08. Uenal H, Rosenbohm A, Kufeldt J, et al. Incidence and geographical variation of amyotrophic lateral sclerosis (ALS) in Southern Germany-completeness of the ALS registry Swabia. PLoS One 2014; 9: e93932. Logroscino G, Traynor BJ, Hardiman O, et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry 2008; 79: 6–11. Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 2013; 9: 617–28. Al-Chalabi A, Calvo A, Chio A, et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol 2014; published online Oct 7. http://dx.doi.org/10.1016/S14744422(14)70219-4. Brettschneider J, Del Tredici K, Toledo JB, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 2013; 74: 20–38. Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. Amyotrophic lateral sclerosis: a model of corticofugal axonal spread. Nat Rev Neurol 2013; 9: 708–14. Freischmidt A, Müller K, Zondler L, et al. Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers. Brain 2014; published online Sept 5. DOI:10.1093/brain/awu249. Robins JM, Hernán MA. Estimation of the causal effects of time-varying exposures. In: Fitzmaurice G, Davidian M, Verbeke G, Molenberghs G, eds. Advances in longitudinal data analysis. New York: Chapman and Hall/CRC Press, 2009.
Lessons learned from genetic testing for channelopathies See Personal View page 1152
1068
Genetic testing has become routine for many inherited disorders and is rapidly emerging as the standard of care in some circumstances, including rare disorders affecting the nervous system. Nextgeneration sequencing methods (eg, exome and genome sequencing) are being adopted for clinical use to expand the speed and breadth of genetic testing.1,2 However, along with these extraordinary advances have emerged new challenges to clinicians regarding interpretation of test results.
Genetic testing is most often done for diagnostic purposes, when the primary genetic cause of a presumed inherited disorder is sought. In the clinical setting, this involves referring samples to a specialised diagnostic laboratory, which in the USA has to meet stringent criteria for quality assurance that conform to a federal law known as the Clinical Laboratory Improvement Amendments (CLIA).3 Similar accreditation standards apply to testing laboratories in Europe. By contrast, research laboratories usually do not have such certification, and data generated www.thelancet.com/neurology Vol 13 November 2014
Comment
by such labs are not appropriate for inclusion in patient medical records unless confirmed by a certified genetics laboratory. For reporting purposes, genetic variants identified by genetic testing laboratories are classified on the basis of the likelihood of pathogenicity. The American College of Medical Genetic (ACMG) Laboratory Quality Assurance Committee has defined categories of sequence variants to enable standardisation of the language used in genetic test reports.4 Two of the recommended categories are for variants with the strongest supporting evidence for either pathogenicity (eg, disease causing) or the absence of pathogenicity (eg, not disease causing). Unfortunately, genetic test results can be ambiguous and not diagnostically informative. The interpretation of a genetic test result might be confounded by the discovery of variants of unknown significance, for which there are insufficient data to establish the likelihood of pathogenicity. The ability to understand and manage these types of genetic data has become a crucial skill for physicians caring for patients with rare inherited disorders. In this issue of the Lancet Neurology, Waxman and colleagues express their personal view on interpreting the clinical significance of genetic findings in a subset of neuronal channelopathies.5 Specifically, they address the nuances and pitfalls of relating phenotype with genotype in familial pain syndromes caused by mutations in voltage-gated sodium channel genes SCN9A, SCN10A, and SCN11A, encoding NaV1.7, NaV1.8, and NaV1.9, respectively. They emphasise the importance of documenting the segregation of newly discovered variants (genotype) with disease traits (phenotype) in multigenerational families, as the best supporting evidence for pathogenicity. However, they include caveats that penetrance and phenotype expression might not be uniform within or among families who have the same mutation. They caution against assuming that all rare variants (eg, minor allele frequency
For more on EUROMOTOR see http://www.euromotorproject. eu
stages in Alzheimer’s disease and Parkinson’s disease has provided new insights into the natural history of these diseases. Although the aggressive nature of amyotrophic lateral sclerosis suggests parallels with cancer, no mechanistic similarities have been found with regard to pathogenesis. Perhaps the new epidemiological data will allow new mechanistic hypotheses to refine ideas about the pathogenesis of amyotrophic lateral sclerosis. Like the clinical approach in cancer, the focus should be on preclinical stages of the disease (ie, the first steps of the causal process) with the use of potential biomarkers such as serum microRNA.9 This approach might show the differences between the model proposed by Al-Chalabi and colleagues6 and the conventional liability model of other chronic diseases in which many genes and environmental risk factors add their effects and, if the adddition is beyond a certain threshold, the individual is affected. In future studies, the proposed model should be tested in familial and apparently sporadic cases and in individuals of different ethnic origins, and eventually be used with new epidemiological methods (eg, the inverse probability marginal structural model) to test causality in observational longitudinal studies.10 The findings of this study suggest that genetics might be insufficient to clarify all the steps needed to explain the pathogenesis of amyotrophic lateral sclerosis. The challenge for future studies of amyotrophic lateral sclerosis and neurodegeneration will be the exploration of causal heterogeneity, including exposomes (ie, the identification of nongenetic exposure), over a long time. Consequently,
large collaborations such as EURALS and EUROMOTOR, which are based on a prospective collection of data at the population level, are needed to advance understanding of amyotrophic lateral sclerosis. Giancarlo Logroscino, Albert Ludolph Neurodegenerative Diseases Unit, Department of Basic Medicine, Neuroscience and Sense Organs, Department of Clinical Research in Neurology of the University of Bari at Pia Fondazione Card G Panico, Hospital Tricase, University Aldo Moro, Bari 73 039, Italy (GL); and Department of Neurology, University of Ulm, Ulm, Germany (AL) [email protected] We declare no competing interests. 1 2
3
4
5 6
7 8
9
10
Logroscino G, Traynor BJ, Hardiman O, et al. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 2010; 81: 385–90. Phukan J, Elamin M, Bede P, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 2012; 83: 102–08. Uenal H, Rosenbohm A, Kufeldt J, et al. Incidence and geographical variation of amyotrophic lateral sclerosis (ALS) in Southern Germany-completeness of the ALS registry Swabia. PLoS One 2014; 9: e93932. Logroscino G, Traynor BJ, Hardiman O, et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry 2008; 79: 6–11. Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 2013; 9: 617–28. Al-Chalabi A, Calvo A, Chio A, et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol 2014; published online Oct 7. http://dx.doi.org/10.1016/S14744422(14)70219-4. Brettschneider J, Del Tredici K, Toledo JB, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 2013; 74: 20–38. Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. Amyotrophic lateral sclerosis: a model of corticofugal axonal spread. Nat Rev Neurol 2013; 9: 708–14. Freischmidt A, Müller K, Zondler L, et al. Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers. Brain 2014; published online Sept 5. DOI:10.1093/brain/awu249. Robins JM, Hernán MA. Estimation of the causal effects of time-varying exposures. In: Fitzmaurice G, Davidian M, Verbeke G, Molenberghs G, eds. Advances in longitudinal data analysis. New York: Chapman and Hall/CRC Press, 2009.
Lessons learned from genetic testing for channelopathies See Personal View page 1152
1068
Genetic testing has become routine for many inherited disorders and is rapidly emerging as the standard of care in some circumstances, including rare disorders affecting the nervous system. Nextgeneration sequencing methods (eg, exome and genome sequencing) are being adopted for clinical use to expand the speed and breadth of genetic testing.1,2 However, along with these extraordinary advances have emerged new challenges to clinicians regarding interpretation of test results.
Genetic testing is most often done for diagnostic purposes, when the primary genetic cause of a presumed inherited disorder is sought. In the clinical setting, this involves referring samples to a specialised diagnostic laboratory, which in the USA has to meet stringent criteria for quality assurance that conform to a federal law known as the Clinical Laboratory Improvement Amendments (CLIA).3 Similar accreditation standards apply to testing laboratories in Europe. By contrast, research laboratories usually do not have such certification, and data generated www.thelancet.com/neurology Vol 13 November 2014
Comment
by such labs are not appropriate for inclusion in patient medical records unless confirmed by a certified genetics laboratory. For reporting purposes, genetic variants identified by genetic testing laboratories are classified on the basis of the likelihood of pathogenicity. The American College of Medical Genetic (ACMG) Laboratory Quality Assurance Committee has defined categories of sequence variants to enable standardisation of the language used in genetic test reports.4 Two of the recommended categories are for variants with the strongest supporting evidence for either pathogenicity (eg, disease causing) or the absence of pathogenicity (eg, not disease causing). Unfortunately, genetic test results can be ambiguous and not diagnostically informative. The interpretation of a genetic test result might be confounded by the discovery of variants of unknown significance, for which there are insufficient data to establish the likelihood of pathogenicity. The ability to understand and manage these types of genetic data has become a crucial skill for physicians caring for patients with rare inherited disorders. In this issue of the Lancet Neurology, Waxman and colleagues express their personal view on interpreting the clinical significance of genetic findings in a subset of neuronal channelopathies.5 Specifically, they address the nuances and pitfalls of relating phenotype with genotype in familial pain syndromes caused by mutations in voltage-gated sodium channel genes SCN9A, SCN10A, and SCN11A, encoding NaV1.7, NaV1.8, and NaV1.9, respectively. They emphasise the importance of documenting the segregation of newly discovered variants (genotype) with disease traits (phenotype) in multigenerational families, as the best supporting evidence for pathogenicity. However, they include caveats that penetrance and phenotype expression might not be uniform within or among families who have the same mutation. They caution against assuming that all rare variants (eg, minor allele frequency
