Letters COMMENT & RESPONSE
Multiple Sclerosis and Alcohol Misuse To the Editor I read with interest the article by Pakpoor and colleagues1 investigating the risk for hospital admission for multiple sclerosis (MS) after admission for alcohol misuse. While interesting, the study is far from proving a causal relationship of alcohol misuse on MS risk. As likely seen in another study by the same team,2 there is an issue of reverse causality that is not remedied by excluding admissions in the same year because MS risk factors likely act many years before the clinical onset of the disease.3 Furthermore, because MS has significant psychological impact, it is likely that alcohol misuse is a result of the impact of having MS.4 Therefore, the authors should test whether there is a risk for alcohol misuse admission in patients with MS. Furthermore, it is notable that the association is seen primarily in men, suggesting that the association is a result of having MS (as documented in the literature5) rather than reflecting confounding. Claudio Voci, BA Author Affiliation: University of Bologna, Bologna, Italy. Corresponding Author: Claudio Voci, BA, University of Bologna, Via Zamboni 33, 40126 Bologna, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Pakpoor J, Goldacre R, Disanto G, Giovannoni G, Goldacre MJ. Alcohol misuse disorders and multiple sclerosis risk. JAMA Neurol. 2014;71(9):1188-1189. 2. Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ. Testicular hypofunction and multiple sclerosis risk: a record-linkage study. Ann Neurol. 2014;76(4):625-628. 3. Ascherio A. Environmental factors in multiple sclerosis. Expert Rev Neurother. 2013;13(12)(suppl):3-9. 4. Stenager EN, Jensen B, Stenager M, Stenager K, Stenager E. Suicide attempts in multiple sclerosis. Mult Scler. 2011;17(10):1265-1268. 5. Beier M, D’Orio V, Spat J, Shuman M, Foley FW. Alcohol and substance use in multiple sclerosis. J Neurol Sci. 2014;338(1-2):122-127.
rate ratios were 0.84 (95% CI, 0.42-1.50; P = .65), 0.98 (95% CI, 0.86-1.11; P = .82), and 0.88 (95% CI, 0.77-1.00; P = .06) for alcohol use, abuse, and dependence, respectively. Although not significant, low rates of alcohol misuse disorders in the later years after first MS diagnosis lead us to speculate that perhaps, after a diagnosis of MS, people with it become more health conscious. These findings—combined with our previous results that there was a significantly elevated risk for MS within 1 year of first admission for alcohol abuse only and a significantly elevated risk for MS following all alcohol misuse disorders with an interval of more than 1 year between first recorded admission with the alcohol misuse disorder and firstrecorded admission with MS—make us consider reverse causality to be unlikely to explain our findings. Of note, Dr Voci’s comment that reverse causality is likely seen in another study reported from this data set is not supported by the results of that study where, as we have previously reported, the positive association was similarly only significant in 1 direction.2 We hope our study of a positive association between alcohol misuse disorders and subsequent MS, in combination with the findings reported by Hedström et al,3 stimulates further work to confirm or refute our findings in striving to establish the currently largely uncharacterized role of alcohol in MS pathophysiology. Julia Pakpoor, BA Raph Goldacre, BA Michael J. Goldacre, FFPH, FRCP Author Affiliations: Oxford University Medical School, John Radcliffe Hospital, Oxford, England (Pakpoor); Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, England (R. Goldacre, M. J. Goldacre). Corresponding Author: Michael J. Goldacre, FFPH, FRCP, Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, Oxfordshire OX3 7LF, England (michael.goldacre @dph.ox.ac.uk). Conflict of Interest Disclosures: None reported.
In Reply We thank Dr Voci for his comments on our article1 reporting a positive association between alcohol misuse disorders and subsequent multiple sclerosis (MS), particularly in men. The possibility of reverse causality whereby alcohol misuse may be a consequence of as yet undiagnosed MS is a necessary consideration. Using the same method and reference cohort as in our original study, we analyzed the data set for the risk for alcohol misuse disorders following an admission for MS. Comparing the MS cohort with the control cohort, the rate ratios were 1.04 (95% CI, 0.59-1.69; P = .98), 1.13 (95% CI, 1.021.25; P = .02), and 1.01 (95% CI, 0.91-1.13; P = .82) for alcohol use, alcohol abuse, and alcohol dependence, respectively. In reducing the possibility of surveillance bias and reverse causality, including only cases of alcohol misuse disorders observed at least 1 year following the first admission for MS, the 238
1. Pakpoor J, Goldacre R, Disanto G, Giovannoni G, Goldacre MJ. Alcohol misuse disorders and multiple sclerosis risk. JAMA Neurol. 2014;71(9):1188-1189. 2. Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ. Reply. Ann Neurol. 2014;76(5):765-766. 3. Hedström AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol. 2014;71(3): 300-305.
Autosomal Recessive Cerebellar Ataxia 3 Due to Homozygote c.132dupA Mutation Within the ANO10 Gene To the Editor With great interest we read the article by Renaud et al1 reporting a case series of 9 patients with autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations. The authors discussed the previously reported c.132dupA mutation with a heterozygote carrier frequency of 1/184 and pos-
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tulated that the homozygote state of this mutation would either have a more severe phenotype or not be viable at all. We diagnosed a German patient as having autosomal recessive cerebellar ataxia type 3 with a homozygous c.132dupA mutation in ANO10 (consanguine family) from the University Hospital Bonn using next-generation sequencing. The mutation was validated by Sanger sequencing in the index and both parents were shown to be heterozygous carriers. The female patient experienced tension headache for several months starting at age 20 years and magnetic resonance imaging brain scan revealed prominent cerebellar atrophy. Slight symptoms of ataxia were only noticed afterwards by the patient. With hindsight, the patient mentioned previous clumsiness requiring the use of stair railing but motor milestones were normal. The patient had gait ataxia and rotational vertigo during fast head movements. The tension headache had improved after medication with amitriptyline. Neurological examination revealed cerebellar oculomotor signs, slight dysmetria, bradykinesia, and intention tremor of upper limbs. There was mild ataxia in tandem gait and stance (5 of 40 points in the Scale for the Assessment and Rating of Ataxia2). Tendon reflexes and plantar responses were normal. She presented slight distal atrophy of lower limbs but no fasciculation or paresis. No sensory disturbance was noted and the results of nerve conduction studies and somatosensory evoked potentials were normal. Follow-up at the age of 24 years revealed moderate disease progress with appearance of discrete cerebellar dysarthria (Scale for the Assessment and Rating of Ataxia score 8 of 40 points). The patient’s sister, aged 26 years, also sought medical advice because of occasional vertigo and tension headache but had no further symptoms. Magnetic resonance imaging brain scan revealed cerebellar atrophy but detailed further neurological examination was not requested. Thus, our patient (and most likely also the sister) demonstrates that homozygote c.132dupA mutations exist in patients with autosomal recessive cerebellar ataxia type 3 and do not necessarily lead to a particular severe clinical phenotype. Martina Minnerop, MD Peter Bauer, MD Author Affiliations: Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich GmbH, Jülich, Germany (Minnerop); Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany (Bauer). Corresponding Author: Martina Minnerop, MD, Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich GmbH, D-52425 Jülich, Germany ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Bauer received funding from the Integrated European Project on Omics Research of Rare Neuromuscular and Neurodegenerative Diseases funded by the European Union (grant 2012-305121) and the ANR/Erare JTC 2011 Euro-SCAR (2011-RARE-004-01); part of the genetic data analysis (assay validation) was performed within these projects. No other disclosures were reported. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication Additional Information: The patient gave a signed statement of informed consent to publish (in print and online) the patient description. jamaneurology.com
1. Renaud M, Anheim M, Kamsteeg EJ, et al. Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol. 2014;71(10):1305-1310. 2. Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the Assessment and Rating of Ataxia: development of a new clinical scale [published correction appears in Neurology. 2006;67(2):299]. Neurology. 2006;66(11):1717-1720.
In Reply We identified the c.132dupA mutation of anoctamin 10 (ANO10), coding for an 8 transmembrane putative chloride channel, as being the most frequent mutation causing autosomal recessive cerebellar ataxia type 3 (ARCA3).1 In an attempt to explain why all of our 4 c.132dupA independent cases were compound heterozygous with another ANO10 mutation, rather than being homozygous (which is commonplace for rare recessive disorders), we speculated that c.132dupA homozygote carriers might present with a significantly more severe phenotype (which did not enter our screening criteria) or might not be viable at all. Our identification of a fifth family (M. Koenig and Erik-Jan Kamsteeg; unpublished observation; October 2014) and the publication of 2 additional families with a compound heterozygous c.132dupA mutation2 was consistent with this prediction. However, the discovery of a c.132dupA homozygous family with typical ARCA3 presentation by Minnerop and Bauer, together with the report of another c.132dupA homozygous family identified in an exome cohort of ataxic patients,3 demonstrate that this is not the case but confirm that c.132dupA (also variably named c.123_124insA,3 c.132_133insA, and c.132_133insT2) is definitively the most common ARCA3 mutation. What remains correct is the significantly different age at onset between patients homozygous for the truncating mutation c.1150_1151delTT (onset ranging from 6 to 15 years) and all the other patients, whether they have early truncating mutations (such as c.132dupA), in-frame deletions or splice site mutations, or missense mutations (onset ranging from 17 to 43 years, P < .01). The c.1150_1151delTT mutation may cause the expression of a truncated protein that functionally interferes with other anoctamin family members4 or may be associated with a second mutation in cis, possibly explaining the more severe phenotype of the patients harboring this homozygous mutation. Because c.132dupA heterozygote carriers have a predicted frequency of 1 in 184 among control individuals (Exome Variant Server; http://evs.gs.washington.edu /EVS), the fact that c.132dupA homozygous patients have typical ARCA3 presentation suggests that ARCA3 frequency might be higher than 1 in 135 (1/184 × 184 × 4), which would be at least as common as ataxia telangiectasia.5 However, the 1 in 184 frequency of c.132dupA heterozygote carriers might be overestimated because this is based on next-generation sequencing data that are prone to some artifacts, particularly when dealing with sequence of mononucleotide repeat tracts, which is the case of the c.132dupA mutation (the adenylate duplication occurs after a stretch of 9 adenylates). Further screening for patients with ARCA3 is warranted before a conclusion on ARCA3 frequency can be drawn. Michel Koenig, MD, PhD Christine Tranchant, MD Mathieu Anheim, MD, PhD (Reprinted) JAMA Neurology February 2015 Volume 72, Number 2
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Multiple Sclerosis and Alcohol Misuse To the Editor I read with interest the article by Pakpoor and colleagues1 investigating the risk for hospital admission for multiple sclerosis (MS) after admission for alcohol misuse. While interesting, the study is far from proving a causal relationship of alcohol misuse on MS risk. As likely seen in another study by the same team,2 there is an issue of reverse causality that is not remedied by excluding admissions in the same year because MS risk factors likely act many years before the clinical onset of the disease.3 Furthermore, because MS has significant psychological impact, it is likely that alcohol misuse is a result of the impact of having MS.4 Therefore, the authors should test whether there is a risk for alcohol misuse admission in patients with MS. Furthermore, it is notable that the association is seen primarily in men, suggesting that the association is a result of having MS (as documented in the literature5) rather than reflecting confounding. Claudio Voci, BA Author Affiliation: University of Bologna, Bologna, Italy. Corresponding Author: Claudio Voci, BA, University of Bologna, Via Zamboni 33, 40126 Bologna, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Pakpoor J, Goldacre R, Disanto G, Giovannoni G, Goldacre MJ. Alcohol misuse disorders and multiple sclerosis risk. JAMA Neurol. 2014;71(9):1188-1189. 2. Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ. Testicular hypofunction and multiple sclerosis risk: a record-linkage study. Ann Neurol. 2014;76(4):625-628. 3. Ascherio A. Environmental factors in multiple sclerosis. Expert Rev Neurother. 2013;13(12)(suppl):3-9. 4. Stenager EN, Jensen B, Stenager M, Stenager K, Stenager E. Suicide attempts in multiple sclerosis. Mult Scler. 2011;17(10):1265-1268. 5. Beier M, D’Orio V, Spat J, Shuman M, Foley FW. Alcohol and substance use in multiple sclerosis. J Neurol Sci. 2014;338(1-2):122-127.
rate ratios were 0.84 (95% CI, 0.42-1.50; P = .65), 0.98 (95% CI, 0.86-1.11; P = .82), and 0.88 (95% CI, 0.77-1.00; P = .06) for alcohol use, abuse, and dependence, respectively. Although not significant, low rates of alcohol misuse disorders in the later years after first MS diagnosis lead us to speculate that perhaps, after a diagnosis of MS, people with it become more health conscious. These findings—combined with our previous results that there was a significantly elevated risk for MS within 1 year of first admission for alcohol abuse only and a significantly elevated risk for MS following all alcohol misuse disorders with an interval of more than 1 year between first recorded admission with the alcohol misuse disorder and firstrecorded admission with MS—make us consider reverse causality to be unlikely to explain our findings. Of note, Dr Voci’s comment that reverse causality is likely seen in another study reported from this data set is not supported by the results of that study where, as we have previously reported, the positive association was similarly only significant in 1 direction.2 We hope our study of a positive association between alcohol misuse disorders and subsequent MS, in combination with the findings reported by Hedström et al,3 stimulates further work to confirm or refute our findings in striving to establish the currently largely uncharacterized role of alcohol in MS pathophysiology. Julia Pakpoor, BA Raph Goldacre, BA Michael J. Goldacre, FFPH, FRCP Author Affiliations: Oxford University Medical School, John Radcliffe Hospital, Oxford, England (Pakpoor); Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, England (R. Goldacre, M. J. Goldacre). Corresponding Author: Michael J. Goldacre, FFPH, FRCP, Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, Oxfordshire OX3 7LF, England (michael.goldacre @dph.ox.ac.uk). Conflict of Interest Disclosures: None reported.
In Reply We thank Dr Voci for his comments on our article1 reporting a positive association between alcohol misuse disorders and subsequent multiple sclerosis (MS), particularly in men. The possibility of reverse causality whereby alcohol misuse may be a consequence of as yet undiagnosed MS is a necessary consideration. Using the same method and reference cohort as in our original study, we analyzed the data set for the risk for alcohol misuse disorders following an admission for MS. Comparing the MS cohort with the control cohort, the rate ratios were 1.04 (95% CI, 0.59-1.69; P = .98), 1.13 (95% CI, 1.021.25; P = .02), and 1.01 (95% CI, 0.91-1.13; P = .82) for alcohol use, alcohol abuse, and alcohol dependence, respectively. In reducing the possibility of surveillance bias and reverse causality, including only cases of alcohol misuse disorders observed at least 1 year following the first admission for MS, the 238
1. Pakpoor J, Goldacre R, Disanto G, Giovannoni G, Goldacre MJ. Alcohol misuse disorders and multiple sclerosis risk. JAMA Neurol. 2014;71(9):1188-1189. 2. Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ. Reply. Ann Neurol. 2014;76(5):765-766. 3. Hedström AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol. 2014;71(3): 300-305.
Autosomal Recessive Cerebellar Ataxia 3 Due to Homozygote c.132dupA Mutation Within the ANO10 Gene To the Editor With great interest we read the article by Renaud et al1 reporting a case series of 9 patients with autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations. The authors discussed the previously reported c.132dupA mutation with a heterozygote carrier frequency of 1/184 and pos-
JAMA Neurology February 2015 Volume 72, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/23/2015
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Letters
tulated that the homozygote state of this mutation would either have a more severe phenotype or not be viable at all. We diagnosed a German patient as having autosomal recessive cerebellar ataxia type 3 with a homozygous c.132dupA mutation in ANO10 (consanguine family) from the University Hospital Bonn using next-generation sequencing. The mutation was validated by Sanger sequencing in the index and both parents were shown to be heterozygous carriers. The female patient experienced tension headache for several months starting at age 20 years and magnetic resonance imaging brain scan revealed prominent cerebellar atrophy. Slight symptoms of ataxia were only noticed afterwards by the patient. With hindsight, the patient mentioned previous clumsiness requiring the use of stair railing but motor milestones were normal. The patient had gait ataxia and rotational vertigo during fast head movements. The tension headache had improved after medication with amitriptyline. Neurological examination revealed cerebellar oculomotor signs, slight dysmetria, bradykinesia, and intention tremor of upper limbs. There was mild ataxia in tandem gait and stance (5 of 40 points in the Scale for the Assessment and Rating of Ataxia2). Tendon reflexes and plantar responses were normal. She presented slight distal atrophy of lower limbs but no fasciculation or paresis. No sensory disturbance was noted and the results of nerve conduction studies and somatosensory evoked potentials were normal. Follow-up at the age of 24 years revealed moderate disease progress with appearance of discrete cerebellar dysarthria (Scale for the Assessment and Rating of Ataxia score 8 of 40 points). The patient’s sister, aged 26 years, also sought medical advice because of occasional vertigo and tension headache but had no further symptoms. Magnetic resonance imaging brain scan revealed cerebellar atrophy but detailed further neurological examination was not requested. Thus, our patient (and most likely also the sister) demonstrates that homozygote c.132dupA mutations exist in patients with autosomal recessive cerebellar ataxia type 3 and do not necessarily lead to a particular severe clinical phenotype. Martina Minnerop, MD Peter Bauer, MD Author Affiliations: Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich GmbH, Jülich, Germany (Minnerop); Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany (Bauer). Corresponding Author: Martina Minnerop, MD, Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich GmbH, D-52425 Jülich, Germany ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Bauer received funding from the Integrated European Project on Omics Research of Rare Neuromuscular and Neurodegenerative Diseases funded by the European Union (grant 2012-305121) and the ANR/Erare JTC 2011 Euro-SCAR (2011-RARE-004-01); part of the genetic data analysis (assay validation) was performed within these projects. No other disclosures were reported. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication Additional Information: The patient gave a signed statement of informed consent to publish (in print and online) the patient description. jamaneurology.com
1. Renaud M, Anheim M, Kamsteeg EJ, et al. Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol. 2014;71(10):1305-1310. 2. Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the Assessment and Rating of Ataxia: development of a new clinical scale [published correction appears in Neurology. 2006;67(2):299]. Neurology. 2006;66(11):1717-1720.
In Reply We identified the c.132dupA mutation of anoctamin 10 (ANO10), coding for an 8 transmembrane putative chloride channel, as being the most frequent mutation causing autosomal recessive cerebellar ataxia type 3 (ARCA3).1 In an attempt to explain why all of our 4 c.132dupA independent cases were compound heterozygous with another ANO10 mutation, rather than being homozygous (which is commonplace for rare recessive disorders), we speculated that c.132dupA homozygote carriers might present with a significantly more severe phenotype (which did not enter our screening criteria) or might not be viable at all. Our identification of a fifth family (M. Koenig and Erik-Jan Kamsteeg; unpublished observation; October 2014) and the publication of 2 additional families with a compound heterozygous c.132dupA mutation2 was consistent with this prediction. However, the discovery of a c.132dupA homozygous family with typical ARCA3 presentation by Minnerop and Bauer, together with the report of another c.132dupA homozygous family identified in an exome cohort of ataxic patients,3 demonstrate that this is not the case but confirm that c.132dupA (also variably named c.123_124insA,3 c.132_133insA, and c.132_133insT2) is definitively the most common ARCA3 mutation. What remains correct is the significantly different age at onset between patients homozygous for the truncating mutation c.1150_1151delTT (onset ranging from 6 to 15 years) and all the other patients, whether they have early truncating mutations (such as c.132dupA), in-frame deletions or splice site mutations, or missense mutations (onset ranging from 17 to 43 years, P < .01). The c.1150_1151delTT mutation may cause the expression of a truncated protein that functionally interferes with other anoctamin family members4 or may be associated with a second mutation in cis, possibly explaining the more severe phenotype of the patients harboring this homozygous mutation. Because c.132dupA heterozygote carriers have a predicted frequency of 1 in 184 among control individuals (Exome Variant Server; http://evs.gs.washington.edu /EVS), the fact that c.132dupA homozygous patients have typical ARCA3 presentation suggests that ARCA3 frequency might be higher than 1 in 135 (1/184 × 184 × 4), which would be at least as common as ataxia telangiectasia.5 However, the 1 in 184 frequency of c.132dupA heterozygote carriers might be overestimated because this is based on next-generation sequencing data that are prone to some artifacts, particularly when dealing with sequence of mononucleotide repeat tracts, which is the case of the c.132dupA mutation (the adenylate duplication occurs after a stretch of 9 adenylates). Further screening for patients with ARCA3 is warranted before a conclusion on ARCA3 frequency can be drawn. Michel Koenig, MD, PhD Christine Tranchant, MD Mathieu Anheim, MD, PhD (Reprinted) JAMA Neurology February 2015 Volume 72, Number 2
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