- Email: [email protected]
Mutation in C9orf72 changes the boundaries of ALS and FTD
Comment
AS has received a research grant and advisory board or consultancy fees from Bayer; has been a consultant or advisory board member for CoAxia, Pfizer, Sanofi, AstraZeneca, Lundbeck, and d-Pharm; and has received honoraria for presentations from Bristol-Myers Squibb. MPK declares that he has no conflicts of interest. 1
2
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4
5
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Atrial Fibrillation Investigators. Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449–57. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M, CCS Atrial Fibrillation Guidelines Committee. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011; 27: 74–90. Hart RG, Pearce LA, Aguilare MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857–67. Connolly SJ, Ezekowitz MD, Yusuf S, et al, and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–51. Patel MR, Mahaffey KW, Garg J, et al, and the ROCKET AF Steering Committee for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–91. Granger CB, Alexander JH, McMurray JJ, et al, and ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981–92. Connolly SJ, Eikelboom J, Joyner C, et al, and AVERROES Steering Committees and Investigators Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806–17.
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Diener H-C, Eikelboom J, Connolly SJ, et al Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol 2012; 11: 225–31. ACTIVE Writing Group on behalf of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, et al . Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–12. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360: 2066–78. Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol 2010; 9: 1157–63. Eikelboom JW, O’Donnell M, Yusuf S, et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 2010; 159: 348–53. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey. Chest 2010; 138: 1093–100. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010; 137: 263–72.
Mutation in C9orf72 changes the boundaries of ALS and FTD In this issue of The Lancet Neurology, Susan Byrne and colleagues1 report clinical descriptions of patients with mutations in C9orf72, a gene recently identified as being associated with amyotrophic lateral sclerosis (ALS) and dementia.2–4 These findings suggest that mutations in C9orf72 could be the most commonly identified cause of familial ALS and frontotemporal dementia (FTD). Just a few years after J-M Charcot’s classic depiction of ALS as a pure motor neuron disease with a nongenetic sporadic aetiology,5 O Dornblüth in 18896 and J Hoffman in 18957 described a few families in which ALS occurred with concomitant cognitive and personality changes. 100 years later, Gunnarsson and colleagues8 described familial ALS and FTD in 13 members of a family and linkage analysis undertaken between 1999 and 2000 revealed a new locus for ALS at 9p21 in this family.9 Analysis of other familial ALS-FTD pedigrees and genome wide association studies in cohorts of sporadic ALS cases confirmed the presence of a major locus for ALS at 9p21. Recently, the genetic defect was shown to be a substantial increase in the number of GGGGCC hexanucleotide repeats in a non-coding region of C9orf72.2–4 Patients with ALS, ALS and FTD, or pure FTD have 700–1600 repeats, whereas people without these www.thelancet.com/neurology Vol 11 March 2012
diseases have fewer than 24 repeats.2 The GGGGCCrepeat expansions segregate as a dominant trait with ALS or FTD in these families. Byrne and colleagues now present the essential clinical aspects of ALS caused by mutant C9orf72 in a well characterised population of patients with ALS; such details were absent in previous reports. By use of the prospective patient data register in Ireland, the investigators studied a population-based incident cohort of 435 patients with ALS and reported that 20 (41%) of 49 cases of familial ALS and 19 (5%) of 386 cases of apparently sporadic ALS had more than 30 expansions in C9orf72 (no expansions were found in 188 controls). The mean age of onset was 5 years younger and the survival time significantly shorter in patients with the C9orf72 mutation. Cognitive and behavioural impairment on neuropsychological testing and a characteristic pattern of 3 T MRI lesions in non-motor cortex areas were significantly associated with carriers of the C9orf72 mutation. Patients with ALS and a C9orf72 mutation were more likely to have a relative with another neurodegenerative disorder, most commonly FTD. The C9orf72 expansion was not identified in patients with sporadic ALS who had a normal cognitive profile and a
Published Online February 3, 2012 DOI:10.1016/S14744422(12)70020-0 See Articles page 232
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Comment
negative family history for neurodegeneration. In six of 15 pedigrees with a pathological expansion in C9orf72, penetrance was incomplete in some elderly family members. Byrne and colleagues’ findings strengthen the notion that some subtypes of ALS are aetiologically associated with cognitive or behavioural impairment and sometimes FTD. This association has previously been reported in rare families with ALS and mutations in SOD1, TARDBP, OPTN, UBQLN2, or FUS, but seems to be more common in families with the C9orf72 mutation. In fact, most genes linked to an ALS motor phenotype might, in some carriers of the gene defect, also give rise to cognitive or behavioural impairment and sometimes fulminant FTD,10 suggesting that the frontal lobes including the motor cortex might be a primary target for the effects of mutations in these genes. An important question is whether the non-motor areas are affected before, in parallel with, or after the involvement of the motor system. A PET study in carriers of SOD1 suggests that non-motor areas might become involved very early in the disease course.11 Byrne and colleagues present an interesting algorithm in which a familial disposition for FTD, ALS, and to a lesser degree behavioural impairment have the highest predictive values for the presence of a pathological C9orf72 expansion. This type of algorithm has not previously been presented for any subtype of ALS and needs validation in other populations. Notably, a large subgroup of patients with ALS were characterised by the presence of three features: no cognitive or behavioural impairment even on longitudinal neuropsychological testing; no family history for ALS or FTD; and no imaging changes on 3 T MRI. None of these patients carried an expansion in C9orf72 (perhaps these patients were the type described by Charcot in 1869).5 Probably because of small numbers, patients with mutations in SOD1, FUS, TARDBP, and ANG were excluded from this study. Future studies will show if this algorithm fits with patients who have mutations in other ALScausing genes, and also whether the cognitive and behavioural impairment profile of the many carriers of the C9orf72 hexanucleotide expansion is unique to these individuals. Byrne and colleagues also report evidence for reduced disease penetrance. This important observation shows that predictive genetic testing in C9orf72-associated 206
ALS-FTD pedigrees should be undertaken with caution: we have no robust data on disease penetrance for either ALS or FTD in C9orf72-linked families, no data on possible anticipation of disease, and no knowledge about why the phenotype becomes ALS, ALS-FTD, or FTD in some carriers. The past decade of genetic research has firmly established incomplete disease penetrance to be present in many pedigrees associated with SOD1, FUS, TARDBP, and ANG mutations, and clinical guidelines for genetic testing have been published.12 Byrne and colleagues’ findings substantially increase our knowledge about families with the C9orf72 repeat expansion but I concur with the investigators that predictive testing in these families is premature. Unfortunately, the high prevalence of this repeat expansion might tempt DNA diagnostic laboratories to offer this test soon. Other consequences of the study might be that the Awaji-El Escorial diagnostic criteria for ALS13 need to be revised to incorporate tests for cognitive and behavioural impairment, and the definition of familial ALS should include the presence of a family history of other neurodegenerative diseases, especially FTD. Peter M Andersen Department of Clinical Neuroscience, Umeå University, Umeå, Sweden [email protected] I declare that I have no conflicts of interest. 1
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Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; published online Feb 3. DOI:10.1016/S1474-4422(12)70014-5. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72: 245–56. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72: 257–68. Gijselinck I, van Langenhove T, van der See J, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 2012; 11: 54–65. Charcot J-M. Lecons sur les maladies du système nerveux. 2nd series, collected by Bourneville 1873. Charcot J-M, Sigerson G (trans and ed). Lectures on the diseases of the nervous system, vol. 2, series 2. London: New Sydenham Society, 1881: 163–204. Dornblüth O. Anatomische Untersuchung eines Falles von amyotrophischer Lateralsklerose. Neurologisches Centralblatt 1889; 13: 24–33. Hoffmann J. Ueber einen eigenartigen Symptomencomplex, eine Combination von angeborenem Schwachsinn mit progressiver Muskelatrophie, als weiteren Beitrag zu den erblichen Nervenkrankheiten. Dtsch Z Nervenheilkd 1895; 6: 150–66. Gunnarsson LG, Dahlbom K, Strandman E. Motor neuron disease and dementia reported among 13 members of a single family. Acta Neurol Scand 1991: 84: 429–33.
www.thelancet.com/neurology Vol 11 March 2012
Comment
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Morita M, AL-Chalabi A, Andersen PM, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 2006; 66: 839–44. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 2011; 7: 603–15. Turner MR, Hammers A, Al-Chalabi A, et al. Distinct cerebral lesions in sporadic and ‘D90A’ SOD1 ALS: Studies with[11C]-flumazenil PET. Brain 2005; 128: 1323–29.
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Andersen PM, Abrahams S, Borasio GD, et al. EFNS Task Force on Management of Amyotrophic Lateral Sclerosis. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS)—revised report of an EFNS task force. Eur J Neurol 2011; published online Sept 14. DOI:10.1111/j.1468-1331.2011.03501.x. Carvalho M, Swash M. Awaji diagnostic algorithm increases sensitivity of El Escorial criteria for ALS diagnosis. Amyotroph Lateral Scler 2009; 10: 53–57.
ARIA from off-key operas? The most comprehensive and up to date review1 of drug therapy in patients with Alzheimer’s disease reports that one in five drugs currently in preclinical or phase 1–3 testing is some form of immunotherapy aimed at lowering amyloid β burden in the brain. Despite the occurrence of meningoencephalitis in 18 of 298 patients (6%) in the first immunotherapy trial2 (active immunisation with AN1792), immunotherapy is still thriving. Understanding of the biological mechanism underlying meningoencephalitis caused by AN1792—adjuvant activating cell-mediated autoimmunity—has enabled the development of safer strategies. Despite some scepticism about the role of amyloid β in the pathophysiology of Alzheimer’s disease, strategies directed at amyloid β (including those aimed at decreasing amyloid production or aggregation) account for three of every five drugs under investigation.1 In my country, Italy, the word “aria” evokes the operatic genius of Giuseppe Verdi. In the Article3 by Reisa Sperling and colleagues in this issue of The Lancet Neurology, ARIA (amyloid-related imaging abnormalities) represent an intriguing occurrence related to immunotherapy in patients with Alzheimer’s disease, with important theoretical and practical implications. Immunotherapy strategies developed since AN1792 have three basic mechanisms of action: solubilisation of brain amyloid β by direct antibody binding, phagocytosis of opsonised amyloid β by microglia, and solubilisation of brain amyloid β by binding to peripheral amyloid β (the sink effect). Bapineuzumab, the effects of which are described in Sperling and colleagues’ Article,3 is a humanised monoclonal antibody against amyloid β that, in a post-hoc analysis of a phase 2 randomised trial,4 has been shown not to be efficacious for cognitive endpoints in patients with Alzheimer’s disease who do not carry APOE ε4.1 Hopefully, ongoing www.thelancet.com/neurology Vol 11 March 2012
phase 3 trials, appropriately powered to detect diseasemodifying effects, will be able to show efficacy. Sperling and colleagues3 report risk factors associated with the development of ARIA-E (abnormalities suggestive of vasogenic oedema and sulcal effusions) and closely related parenchymal microhaemorrhages (ARIA-H) in patients infused with bapineuzumab in two phase 2 trials and an open-label extension study. Overt meningoencephalitis has not been reported with bapineuzumab infusion, which provides reassurance about its possible clinical use should the drug be proven effective. However, incident ARIA-E occurred in about a sixth of patients exposed to bapineuzumab. Most cases of ARIA-E (about 80%) were asymptomatic and detected only by the close monitoring of patients with repeated MRI scans. The few symptomatic patients reported mild to severe non-focal brain symptoms (headache, confusion, decreased vigilance, gait disturbance, and psychiatric symptoms) that resolved either spontaneously or after steroid treatment in 1–6 months. One patient had a stroke that led to death, but its relation to ARIA and treatment with bapineuzumab is unclear. Despite the relatively benign course of ARIA-associated symptoms in the 36 symptomatic patients, the scarcity of CSF data does not allow the exclusion of the possibility that some cases of ARIA might represent an attenuated form of meningoencephalitis. Although five patients had normal CSF, three had increased protein concentrations and red cell counts, two of whom also had increased white blood cell counts and were symptomatic. ARIA-H were clearly related to ARIA-E; they were more than 10 times more prevalent in patients with ARIA-E than in those without and most occurred in the same areas of the brain. ARIA were also related to APOE ε4 carrier status (hazard ratio [HR] 2·55 per allele, 95% CI 1·57–4·12;
See Articles page 241
207
AS has received a research grant and advisory board or consultancy fees from Bayer; has been a consultant or advisory board member for CoAxia, Pfizer, Sanofi, AstraZeneca, Lundbeck, and d-Pharm; and has received honoraria for presentations from Bristol-Myers Squibb. MPK declares that he has no conflicts of interest. 1
2
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Atrial Fibrillation Investigators. Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449–57. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M, CCS Atrial Fibrillation Guidelines Committee. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011; 27: 74–90. Hart RG, Pearce LA, Aguilare MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857–67. Connolly SJ, Ezekowitz MD, Yusuf S, et al, and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–51. Patel MR, Mahaffey KW, Garg J, et al, and the ROCKET AF Steering Committee for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–91. Granger CB, Alexander JH, McMurray JJ, et al, and ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981–92. Connolly SJ, Eikelboom J, Joyner C, et al, and AVERROES Steering Committees and Investigators Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806–17.
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Diener H-C, Eikelboom J, Connolly SJ, et al Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol 2012; 11: 225–31. ACTIVE Writing Group on behalf of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, et al . Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–12. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360: 2066–78. Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol 2010; 9: 1157–63. Eikelboom JW, O’Donnell M, Yusuf S, et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 2010; 159: 348–53. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey. Chest 2010; 138: 1093–100. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010; 137: 263–72.
Mutation in C9orf72 changes the boundaries of ALS and FTD In this issue of The Lancet Neurology, Susan Byrne and colleagues1 report clinical descriptions of patients with mutations in C9orf72, a gene recently identified as being associated with amyotrophic lateral sclerosis (ALS) and dementia.2–4 These findings suggest that mutations in C9orf72 could be the most commonly identified cause of familial ALS and frontotemporal dementia (FTD). Just a few years after J-M Charcot’s classic depiction of ALS as a pure motor neuron disease with a nongenetic sporadic aetiology,5 O Dornblüth in 18896 and J Hoffman in 18957 described a few families in which ALS occurred with concomitant cognitive and personality changes. 100 years later, Gunnarsson and colleagues8 described familial ALS and FTD in 13 members of a family and linkage analysis undertaken between 1999 and 2000 revealed a new locus for ALS at 9p21 in this family.9 Analysis of other familial ALS-FTD pedigrees and genome wide association studies in cohorts of sporadic ALS cases confirmed the presence of a major locus for ALS at 9p21. Recently, the genetic defect was shown to be a substantial increase in the number of GGGGCC hexanucleotide repeats in a non-coding region of C9orf72.2–4 Patients with ALS, ALS and FTD, or pure FTD have 700–1600 repeats, whereas people without these www.thelancet.com/neurology Vol 11 March 2012
diseases have fewer than 24 repeats.2 The GGGGCCrepeat expansions segregate as a dominant trait with ALS or FTD in these families. Byrne and colleagues now present the essential clinical aspects of ALS caused by mutant C9orf72 in a well characterised population of patients with ALS; such details were absent in previous reports. By use of the prospective patient data register in Ireland, the investigators studied a population-based incident cohort of 435 patients with ALS and reported that 20 (41%) of 49 cases of familial ALS and 19 (5%) of 386 cases of apparently sporadic ALS had more than 30 expansions in C9orf72 (no expansions were found in 188 controls). The mean age of onset was 5 years younger and the survival time significantly shorter in patients with the C9orf72 mutation. Cognitive and behavioural impairment on neuropsychological testing and a characteristic pattern of 3 T MRI lesions in non-motor cortex areas were significantly associated with carriers of the C9orf72 mutation. Patients with ALS and a C9orf72 mutation were more likely to have a relative with another neurodegenerative disorder, most commonly FTD. The C9orf72 expansion was not identified in patients with sporadic ALS who had a normal cognitive profile and a
Published Online February 3, 2012 DOI:10.1016/S14744422(12)70020-0 See Articles page 232
205
Comment
negative family history for neurodegeneration. In six of 15 pedigrees with a pathological expansion in C9orf72, penetrance was incomplete in some elderly family members. Byrne and colleagues’ findings strengthen the notion that some subtypes of ALS are aetiologically associated with cognitive or behavioural impairment and sometimes FTD. This association has previously been reported in rare families with ALS and mutations in SOD1, TARDBP, OPTN, UBQLN2, or FUS, but seems to be more common in families with the C9orf72 mutation. In fact, most genes linked to an ALS motor phenotype might, in some carriers of the gene defect, also give rise to cognitive or behavioural impairment and sometimes fulminant FTD,10 suggesting that the frontal lobes including the motor cortex might be a primary target for the effects of mutations in these genes. An important question is whether the non-motor areas are affected before, in parallel with, or after the involvement of the motor system. A PET study in carriers of SOD1 suggests that non-motor areas might become involved very early in the disease course.11 Byrne and colleagues present an interesting algorithm in which a familial disposition for FTD, ALS, and to a lesser degree behavioural impairment have the highest predictive values for the presence of a pathological C9orf72 expansion. This type of algorithm has not previously been presented for any subtype of ALS and needs validation in other populations. Notably, a large subgroup of patients with ALS were characterised by the presence of three features: no cognitive or behavioural impairment even on longitudinal neuropsychological testing; no family history for ALS or FTD; and no imaging changes on 3 T MRI. None of these patients carried an expansion in C9orf72 (perhaps these patients were the type described by Charcot in 1869).5 Probably because of small numbers, patients with mutations in SOD1, FUS, TARDBP, and ANG were excluded from this study. Future studies will show if this algorithm fits with patients who have mutations in other ALScausing genes, and also whether the cognitive and behavioural impairment profile of the many carriers of the C9orf72 hexanucleotide expansion is unique to these individuals. Byrne and colleagues also report evidence for reduced disease penetrance. This important observation shows that predictive genetic testing in C9orf72-associated 206
ALS-FTD pedigrees should be undertaken with caution: we have no robust data on disease penetrance for either ALS or FTD in C9orf72-linked families, no data on possible anticipation of disease, and no knowledge about why the phenotype becomes ALS, ALS-FTD, or FTD in some carriers. The past decade of genetic research has firmly established incomplete disease penetrance to be present in many pedigrees associated with SOD1, FUS, TARDBP, and ANG mutations, and clinical guidelines for genetic testing have been published.12 Byrne and colleagues’ findings substantially increase our knowledge about families with the C9orf72 repeat expansion but I concur with the investigators that predictive testing in these families is premature. Unfortunately, the high prevalence of this repeat expansion might tempt DNA diagnostic laboratories to offer this test soon. Other consequences of the study might be that the Awaji-El Escorial diagnostic criteria for ALS13 need to be revised to incorporate tests for cognitive and behavioural impairment, and the definition of familial ALS should include the presence of a family history of other neurodegenerative diseases, especially FTD. Peter M Andersen Department of Clinical Neuroscience, Umeå University, Umeå, Sweden [email protected] I declare that I have no conflicts of interest. 1
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Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; published online Feb 3. DOI:10.1016/S1474-4422(12)70014-5. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72: 245–56. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72: 257–68. Gijselinck I, van Langenhove T, van der See J, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 2012; 11: 54–65. Charcot J-M. Lecons sur les maladies du système nerveux. 2nd series, collected by Bourneville 1873. Charcot J-M, Sigerson G (trans and ed). Lectures on the diseases of the nervous system, vol. 2, series 2. London: New Sydenham Society, 1881: 163–204. Dornblüth O. Anatomische Untersuchung eines Falles von amyotrophischer Lateralsklerose. Neurologisches Centralblatt 1889; 13: 24–33. Hoffmann J. Ueber einen eigenartigen Symptomencomplex, eine Combination von angeborenem Schwachsinn mit progressiver Muskelatrophie, als weiteren Beitrag zu den erblichen Nervenkrankheiten. Dtsch Z Nervenheilkd 1895; 6: 150–66. Gunnarsson LG, Dahlbom K, Strandman E. Motor neuron disease and dementia reported among 13 members of a single family. Acta Neurol Scand 1991: 84: 429–33.
www.thelancet.com/neurology Vol 11 March 2012
Comment
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Morita M, AL-Chalabi A, Andersen PM, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 2006; 66: 839–44. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 2011; 7: 603–15. Turner MR, Hammers A, Al-Chalabi A, et al. Distinct cerebral lesions in sporadic and ‘D90A’ SOD1 ALS: Studies with[11C]-flumazenil PET. Brain 2005; 128: 1323–29.
12
13
Andersen PM, Abrahams S, Borasio GD, et al. EFNS Task Force on Management of Amyotrophic Lateral Sclerosis. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS)—revised report of an EFNS task force. Eur J Neurol 2011; published online Sept 14. DOI:10.1111/j.1468-1331.2011.03501.x. Carvalho M, Swash M. Awaji diagnostic algorithm increases sensitivity of El Escorial criteria for ALS diagnosis. Amyotroph Lateral Scler 2009; 10: 53–57.
ARIA from off-key operas? The most comprehensive and up to date review1 of drug therapy in patients with Alzheimer’s disease reports that one in five drugs currently in preclinical or phase 1–3 testing is some form of immunotherapy aimed at lowering amyloid β burden in the brain. Despite the occurrence of meningoencephalitis in 18 of 298 patients (6%) in the first immunotherapy trial2 (active immunisation with AN1792), immunotherapy is still thriving. Understanding of the biological mechanism underlying meningoencephalitis caused by AN1792—adjuvant activating cell-mediated autoimmunity—has enabled the development of safer strategies. Despite some scepticism about the role of amyloid β in the pathophysiology of Alzheimer’s disease, strategies directed at amyloid β (including those aimed at decreasing amyloid production or aggregation) account for three of every five drugs under investigation.1 In my country, Italy, the word “aria” evokes the operatic genius of Giuseppe Verdi. In the Article3 by Reisa Sperling and colleagues in this issue of The Lancet Neurology, ARIA (amyloid-related imaging abnormalities) represent an intriguing occurrence related to immunotherapy in patients with Alzheimer’s disease, with important theoretical and practical implications. Immunotherapy strategies developed since AN1792 have three basic mechanisms of action: solubilisation of brain amyloid β by direct antibody binding, phagocytosis of opsonised amyloid β by microglia, and solubilisation of brain amyloid β by binding to peripheral amyloid β (the sink effect). Bapineuzumab, the effects of which are described in Sperling and colleagues’ Article,3 is a humanised monoclonal antibody against amyloid β that, in a post-hoc analysis of a phase 2 randomised trial,4 has been shown not to be efficacious for cognitive endpoints in patients with Alzheimer’s disease who do not carry APOE ε4.1 Hopefully, ongoing www.thelancet.com/neurology Vol 11 March 2012
phase 3 trials, appropriately powered to detect diseasemodifying effects, will be able to show efficacy. Sperling and colleagues3 report risk factors associated with the development of ARIA-E (abnormalities suggestive of vasogenic oedema and sulcal effusions) and closely related parenchymal microhaemorrhages (ARIA-H) in patients infused with bapineuzumab in two phase 2 trials and an open-label extension study. Overt meningoencephalitis has not been reported with bapineuzumab infusion, which provides reassurance about its possible clinical use should the drug be proven effective. However, incident ARIA-E occurred in about a sixth of patients exposed to bapineuzumab. Most cases of ARIA-E (about 80%) were asymptomatic and detected only by the close monitoring of patients with repeated MRI scans. The few symptomatic patients reported mild to severe non-focal brain symptoms (headache, confusion, decreased vigilance, gait disturbance, and psychiatric symptoms) that resolved either spontaneously or after steroid treatment in 1–6 months. One patient had a stroke that led to death, but its relation to ARIA and treatment with bapineuzumab is unclear. Despite the relatively benign course of ARIA-associated symptoms in the 36 symptomatic patients, the scarcity of CSF data does not allow the exclusion of the possibility that some cases of ARIA might represent an attenuated form of meningoencephalitis. Although five patients had normal CSF, three had increased protein concentrations and red cell counts, two of whom also had increased white blood cell counts and were symptomatic. ARIA-H were clearly related to ARIA-E; they were more than 10 times more prevalent in patients with ARIA-E than in those without and most occurred in the same areas of the brain. ARIA were also related to APOE ε4 carrier status (hazard ratio [HR] 2·55 per allele, 95% CI 1·57–4·12;
See Articles page 241
207