- Email: [email protected]
Presymptomatic features of spinocerebellar ataxias
Comment
neurodegenerative diseases. Virtual roadmaps of disease in the minds of practitioners6 are good for care in the framework of the traditional patient encounter, but it takes substantial effort, teamwork, and genius to turn them into rigorous, quantifiable timelines that can be used to test efficacy in future therapeutic trials.
1
Francis O Walker
4
Department of Neurology, Wake Forest Medical School, Winston-Salem, NC 27157-1078, USA [email protected] I receive contract research support from CHDI, a non-profit organisation that also funds the TRACK-HD study.
2
3
5
6
Tabrizi SJ, Scahill RI, Owen G, et al, and the TRACK-HD Investigators. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 2013; published online May 9. http://dx.doi.org/10.1016/S1474-4422(13)70088-7. Tabrizi SJ, Langbehn DR, Leavitt FR, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009; 8: 791–801. Tabrizi SJ, Reilmann R, Roos RA, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol 2012; 11: 42–53. Kieburtz K, Venuto C. TRACK-HD: both promise and disappointment. Lancet Neurol 2012; 11: 24–25. Biglan KM, Eberly S, Oakes D, et al. Evaluating methods to enrich clinical trial populations in individuals at risk for Huntington’s disease: the prospective Huntington at-risk observational study (PHAROS). Mov Dis 2010; 25: S269–270. Walker FO. Huntington’s disease. Lancet 2007; 369: 218–28.
Presymptomatic features of spinocerebellar ataxias Although more than 30 genetically distinct forms of dominant progressive spinocerebellar ataxia (SCA) are now recognised,1 more than half of all families affected by SCAs have SCA1, SCA2, SCA3, or SCA6.2 All these forms are characterised by expanded polyglutamine repeats and have an inverse correlation between CAG repeat size and age at onset.3 In this issue of The Lancet Neurology, Heike Jacobi and colleagues report the biological and clinical characteristics of 123 presymptomatic carriers of such mutations, and compare them with 141 individuals from families affected by these SCAs but who do not carry the mutations.4 It is hardly surprising that their careful, standardised physical examination and MRI voxel-based morphometry (in a subset of 83 participants) identified neurological signs and differences between carriers and noncarriers on MRI.4 The mutations are obviously present throughout an individual’s life, but usually only become symptomatic in adulthood, implying the existence of a presymptomatic stage in which compensation for accumulating neurodegeneration is still possible. Similar findings have been well documented in the archetypal expanded polyglutamine tract disorder Huntington’s disease: affected individuals can have psychiatric and psychomotor changes,5,6 with accompanying morphological changes in the striatum that are identified by MRI,7 preceding development of onset-defining motor changes by several years. What, then, is the usefulness of Jacobi and colleagues’ study4 in the SCAs? Their analysis4 has several useful outcomes and conclusions. First, they reported that median scores www.thelancet.com/neurology Vol 12 July 2013
on the scale for the assessment and rating of ataxia (SARA) increased as estimated time from ataxia onset decreased in SCA1 (r=0·36, p=0·0112) and SCA2 (r=0·50, p=0·0038) mutation carriers, although a SARA score of less than three was an inclusion criterion, meaning that all were within the range of healthy individuals.8 Predicted time from onset was calculated from CAG repeat number and age, on the basis of the reported age at onset of gait ataxia (typically the first symptom) in the EUROSCA database.9 Such predictions are imperfect; repeat size accounts for only 41–67% of variability in age at onset.10 No doubt some of the remaining variation is a result of imperfect recollection of the timing of gradual symptom onset, which is evident in many clinical encounters. The correlations between SARA scores and predicted years from onset provide a degree of concurrent validity for these estimates. Because Jacobi and colleagues report baseline data4 from an intended prospective study, predictive validity will ultimately be assessed. Second, the data give a guide to the distribution of neurodegeneration in the earliest stages of each SCA type (eg, grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and decreased brainstem volume in SCA2 mutation carriers). The fact that regional susceptibility differs in a group of diseases in which expanded proteins are ubiquitously expressed in neurons presumably holds clues for disease pathogenesis and evolution, as has been exemplified in Alzheimer’s disease by the identification of transsynaptic spread of tau pathology.11 Identification of
Published Online May 22, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70116-9 See Articles page 650
625
Comment
which areas are affected earliest in each disorder is a necessary start to understand the disease process. Last and most importantly, Jacobi and colleagues’ study4 provides an estimate of when neurodegeneration will become detectable with the assessment methods presently available, at least for SCA1 and SCA2. This estimate will be important in study design for trials of any potentially disease-modifying treatments that might emerge. As with most clinical studies, there are caveats. No association was recorded between predicted time from onset and SARA score for SCA3 and SCA6.4 These results might be negative because few SCA3 (n=26) and SCA6 (n=16) carriers were included in the study, and because predicted time from onset of SCA6 was high (median –18 years, IQR –22 to –16). Poor sensitivity at the lower end of the SARA scale could also have affected the results, although the investigators also reported no correlation between time from onset and composite cerebellar functional severity score or SCA functional index, which were the other two measures of ataxia. 61 participants (22%) in Jacobi and colleagues’ study4 were aware of their carrier status. Although no significant differences were reported between carriers who were and were not aware (apart from a lower depression [patient’s health questionnaire] score in aware SCA2 carriers [median 0, IQR 0–2·0] than in non-aware carriers [3·0, 1·0–5·0; p=0·0379]), awareness is still a potential source of bias. Numbers in some MRI subgroups were small—only four SCA2 mutation carriers underwent MRI—although they were still sufficient to show significant brainstem atrophy. Cognitive function, measurably impaired in each
of these SCAs,12 was not assessed. Nevertheless, Jacobi and colleagues’ is the largest such series to be reported, and individuals who work with families affected by SCAs will find much of interest in their analysis. Elsdon Storey Monash University, Melbourne, VIC 3004, Australia [email protected] I declare that I have no conflicts of interest. 1 2
3
4
5
6
7
8
9
10 11 12
Matilla-Duenas A. The ever expanding spinocerebellar ataxias. Cerebellum 2012; 11: 821–27. Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics , and pathogenesis. Lancet Neurol 2004; 3: 291–304. Stevanin G, Durr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet 2000; 8: 4–18. Jacobi H, Reetz K, Tezenas du Montcel S, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013; published online May 22. http://dx.doi.org/10.1016/ S1474-4422(13)70104-2. Snowden JS, Craufurd D, Thompson J, Neary D. Psychomotor, executive, and memory function in preclinical Huntington’s disease. J Clin Exp Neuropsychol 2002; 24: 133–45. Nehl C, Ready RE, Hamilton J, Paulsen JS. Effects of depression on working memory in presymptomatic Huntington’s disease. J Neuropsychiatry Clin Neurosci 2001; 13: 342–46. Kipps CM, Duggins AJ, Mahant N, Gomes L, Ashburner J, McCusker EA. Progression of structural neuropathology in preclinical Huntington’s disease: a tensor-based morphometry study. J Neurol Neurosurg Psychiatry 2005; 76: 650–55. Schmitz-Hubsch T, Tezenas du Montcel S, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006; 66: 1717–20. Jacobi H, Hauser TK, Giunti P, et al. Spinocerebellar ataxia types 1, 2, 3 and 6: the clinical spectrum of ataxia and morphometric brainstem and cerebellar findings. Cerebellum 2012; 11: 155–66. Globas C, Tezenas du Montcel S, Baliko L, et al. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6. Mov Disord 2008; 23: 2232–38. Liu L, Drouet V, Wu JW, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One 2012; 7: e31302. Kawai Y, Suenaga M, Watanabe H, Sobue G. Cognitive impairment in spinocerebellar degeneration. Eur Neurol 2009; 61: 257–68.
From mice to man: chloride transport in leukoencephalopathy Published Online May 22, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70068-1 See Articles page 659
626
In The Lancet Neurology, Christel Depienne and colleagues1 show that mutations in CLCN2—the gene encoding the chloride channel ClC-2—underlie a specific form of human leukoencephalopathy. This important work confirms in human beings what was previously shown in ClC-2 knock-out (Clcn2–/–) mice whose leukodystrophy2 was suggested to result from impaired glial ion homoeostasis. It also raises the question as to whether the pathogenesis of human leukoencephalopathies caused by mutations in the cell adhesion molecule GlialCAM3 or the membrane protein MLC14 involve changes in ClC-2.
ClC-2 is expressed almost ubiquitously,5 including in neurons and glia. Clcn2-/- mice have retinal and testicular degeneration,6 which were thought to result from impaired ion homoeostasis in the extracellular clefts between supporting epithelia and photoreceptors and germ cells, respectively. Because these mice did not have relevant neurological phenotypes, the leukodystrophy was discovered only later.2 Clcn2-/- mice developed white matter vacuolation in several brain regions with vacuoles forming within myelin sheaths of axons.2 Knock-out-controlled immunohistochemistry detected www.thelancet.com/neurology Vol 12 July 2013
neurodegenerative diseases. Virtual roadmaps of disease in the minds of practitioners6 are good for care in the framework of the traditional patient encounter, but it takes substantial effort, teamwork, and genius to turn them into rigorous, quantifiable timelines that can be used to test efficacy in future therapeutic trials.
1
Francis O Walker
4
Department of Neurology, Wake Forest Medical School, Winston-Salem, NC 27157-1078, USA [email protected] I receive contract research support from CHDI, a non-profit organisation that also funds the TRACK-HD study.
2
3
5
6
Tabrizi SJ, Scahill RI, Owen G, et al, and the TRACK-HD Investigators. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 2013; published online May 9. http://dx.doi.org/10.1016/S1474-4422(13)70088-7. Tabrizi SJ, Langbehn DR, Leavitt FR, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009; 8: 791–801. Tabrizi SJ, Reilmann R, Roos RA, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol 2012; 11: 42–53. Kieburtz K, Venuto C. TRACK-HD: both promise and disappointment. Lancet Neurol 2012; 11: 24–25. Biglan KM, Eberly S, Oakes D, et al. Evaluating methods to enrich clinical trial populations in individuals at risk for Huntington’s disease: the prospective Huntington at-risk observational study (PHAROS). Mov Dis 2010; 25: S269–270. Walker FO. Huntington’s disease. Lancet 2007; 369: 218–28.
Presymptomatic features of spinocerebellar ataxias Although more than 30 genetically distinct forms of dominant progressive spinocerebellar ataxia (SCA) are now recognised,1 more than half of all families affected by SCAs have SCA1, SCA2, SCA3, or SCA6.2 All these forms are characterised by expanded polyglutamine repeats and have an inverse correlation between CAG repeat size and age at onset.3 In this issue of The Lancet Neurology, Heike Jacobi and colleagues report the biological and clinical characteristics of 123 presymptomatic carriers of such mutations, and compare them with 141 individuals from families affected by these SCAs but who do not carry the mutations.4 It is hardly surprising that their careful, standardised physical examination and MRI voxel-based morphometry (in a subset of 83 participants) identified neurological signs and differences between carriers and noncarriers on MRI.4 The mutations are obviously present throughout an individual’s life, but usually only become symptomatic in adulthood, implying the existence of a presymptomatic stage in which compensation for accumulating neurodegeneration is still possible. Similar findings have been well documented in the archetypal expanded polyglutamine tract disorder Huntington’s disease: affected individuals can have psychiatric and psychomotor changes,5,6 with accompanying morphological changes in the striatum that are identified by MRI,7 preceding development of onset-defining motor changes by several years. What, then, is the usefulness of Jacobi and colleagues’ study4 in the SCAs? Their analysis4 has several useful outcomes and conclusions. First, they reported that median scores www.thelancet.com/neurology Vol 12 July 2013
on the scale for the assessment and rating of ataxia (SARA) increased as estimated time from ataxia onset decreased in SCA1 (r=0·36, p=0·0112) and SCA2 (r=0·50, p=0·0038) mutation carriers, although a SARA score of less than three was an inclusion criterion, meaning that all were within the range of healthy individuals.8 Predicted time from onset was calculated from CAG repeat number and age, on the basis of the reported age at onset of gait ataxia (typically the first symptom) in the EUROSCA database.9 Such predictions are imperfect; repeat size accounts for only 41–67% of variability in age at onset.10 No doubt some of the remaining variation is a result of imperfect recollection of the timing of gradual symptom onset, which is evident in many clinical encounters. The correlations between SARA scores and predicted years from onset provide a degree of concurrent validity for these estimates. Because Jacobi and colleagues report baseline data4 from an intended prospective study, predictive validity will ultimately be assessed. Second, the data give a guide to the distribution of neurodegeneration in the earliest stages of each SCA type (eg, grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and decreased brainstem volume in SCA2 mutation carriers). The fact that regional susceptibility differs in a group of diseases in which expanded proteins are ubiquitously expressed in neurons presumably holds clues for disease pathogenesis and evolution, as has been exemplified in Alzheimer’s disease by the identification of transsynaptic spread of tau pathology.11 Identification of
Published Online May 22, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70116-9 See Articles page 650
625
Comment
which areas are affected earliest in each disorder is a necessary start to understand the disease process. Last and most importantly, Jacobi and colleagues’ study4 provides an estimate of when neurodegeneration will become detectable with the assessment methods presently available, at least for SCA1 and SCA2. This estimate will be important in study design for trials of any potentially disease-modifying treatments that might emerge. As with most clinical studies, there are caveats. No association was recorded between predicted time from onset and SARA score for SCA3 and SCA6.4 These results might be negative because few SCA3 (n=26) and SCA6 (n=16) carriers were included in the study, and because predicted time from onset of SCA6 was high (median –18 years, IQR –22 to –16). Poor sensitivity at the lower end of the SARA scale could also have affected the results, although the investigators also reported no correlation between time from onset and composite cerebellar functional severity score or SCA functional index, which were the other two measures of ataxia. 61 participants (22%) in Jacobi and colleagues’ study4 were aware of their carrier status. Although no significant differences were reported between carriers who were and were not aware (apart from a lower depression [patient’s health questionnaire] score in aware SCA2 carriers [median 0, IQR 0–2·0] than in non-aware carriers [3·0, 1·0–5·0; p=0·0379]), awareness is still a potential source of bias. Numbers in some MRI subgroups were small—only four SCA2 mutation carriers underwent MRI—although they were still sufficient to show significant brainstem atrophy. Cognitive function, measurably impaired in each
of these SCAs,12 was not assessed. Nevertheless, Jacobi and colleagues’ is the largest such series to be reported, and individuals who work with families affected by SCAs will find much of interest in their analysis. Elsdon Storey Monash University, Melbourne, VIC 3004, Australia [email protected] I declare that I have no conflicts of interest. 1 2
3
4
5
6
7
8
9
10 11 12
Matilla-Duenas A. The ever expanding spinocerebellar ataxias. Cerebellum 2012; 11: 821–27. Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics , and pathogenesis. Lancet Neurol 2004; 3: 291–304. Stevanin G, Durr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet 2000; 8: 4–18. Jacobi H, Reetz K, Tezenas du Montcel S, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013; published online May 22. http://dx.doi.org/10.1016/ S1474-4422(13)70104-2. Snowden JS, Craufurd D, Thompson J, Neary D. Psychomotor, executive, and memory function in preclinical Huntington’s disease. J Clin Exp Neuropsychol 2002; 24: 133–45. Nehl C, Ready RE, Hamilton J, Paulsen JS. Effects of depression on working memory in presymptomatic Huntington’s disease. J Neuropsychiatry Clin Neurosci 2001; 13: 342–46. Kipps CM, Duggins AJ, Mahant N, Gomes L, Ashburner J, McCusker EA. Progression of structural neuropathology in preclinical Huntington’s disease: a tensor-based morphometry study. J Neurol Neurosurg Psychiatry 2005; 76: 650–55. Schmitz-Hubsch T, Tezenas du Montcel S, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006; 66: 1717–20. Jacobi H, Hauser TK, Giunti P, et al. Spinocerebellar ataxia types 1, 2, 3 and 6: the clinical spectrum of ataxia and morphometric brainstem and cerebellar findings. Cerebellum 2012; 11: 155–66. Globas C, Tezenas du Montcel S, Baliko L, et al. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6. Mov Disord 2008; 23: 2232–38. Liu L, Drouet V, Wu JW, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One 2012; 7: e31302. Kawai Y, Suenaga M, Watanabe H, Sobue G. Cognitive impairment in spinocerebellar degeneration. Eur Neurol 2009; 61: 257–68.
From mice to man: chloride transport in leukoencephalopathy Published Online May 22, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70068-1 See Articles page 659
626
In The Lancet Neurology, Christel Depienne and colleagues1 show that mutations in CLCN2—the gene encoding the chloride channel ClC-2—underlie a specific form of human leukoencephalopathy. This important work confirms in human beings what was previously shown in ClC-2 knock-out (Clcn2–/–) mice whose leukodystrophy2 was suggested to result from impaired glial ion homoeostasis. It also raises the question as to whether the pathogenesis of human leukoencephalopathies caused by mutations in the cell adhesion molecule GlialCAM3 or the membrane protein MLC14 involve changes in ClC-2.
ClC-2 is expressed almost ubiquitously,5 including in neurons and glia. Clcn2-/- mice have retinal and testicular degeneration,6 which were thought to result from impaired ion homoeostasis in the extracellular clefts between supporting epithelia and photoreceptors and germ cells, respectively. Because these mice did not have relevant neurological phenotypes, the leukodystrophy was discovered only later.2 Clcn2-/- mice developed white matter vacuolation in several brain regions with vacuoles forming within myelin sheaths of axons.2 Knock-out-controlled immunohistochemistry detected www.thelancet.com/neurology Vol 12 July 2013