- Email: [email protected]
Disease onset in familial and sporadic multiple sclerosis in Argentina
Multiple Sclerosis and Related Disorders 6 (2016) 54–56
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Disease onset in familial and sporadic multiple sclerosis in Argentina J.I. Rojas a,n, L. Patrucco a, J. MIguez a, V. Sinay b, F. Pagani Cassara b, F. Cáceres c, N. Fernandez Liguori c,d, M.L. Saladino c,d, N. Deri k, G. Jaacks k, M. Parada Marcilla e, M.I. Arrigoni j, J. Correale f, M. Fiol f, M.C. Ysrraelit f, A. Carrá g, M.C. Curbelo g, A. Martinez g, J. Steinberg g, S. Bestoso m, J.P. Hryb h, J.L. Di Pace h, M.B. Perassolo h, E. Carnero Contentti i, A. Caride i, P.A. Lopez i, C. Martinez e, E. Reich l, E. Cristiano a a
Centro de Esclerosis Múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Argentina Instituto de Neurociencias, Fundación Favaloro, Argentina Neurosciences Institute of Buenos Aires (INEBA), Buenos Aires, Argentina d Multiple Sclerosis Section Hospital E.Tornú, Buenos Aires, Argentina e Private Office, Private Office, Argentina f Department of Neurology, Institute for Neurological Research Dr. Raúl Carrea, FLENI, Argentina g Hospital Británico Buenos Aires, Argentina h Hospital General de Agudos Carlos G Durand, Buenos Aires, Argentina i Hospital Alemán, Buenos Aires, Argentina j Hospital Italiano de Córdoba, Argentina k Centro de Investigación DIABAID, Argentina l Hospital Julio Mendez, Buenos Aires, Argentina m Hospital Escuela “José F. De San Martín”, Corrientes, Argentina b c
art ic l e i nf o
a b s t r a c t
Article history: Received 31 July 2015 Received in revised form 28 December 2015 Accepted 19 January 2016
The present study was carried out to assess if there is an anticipation of age at onset in younger generations of familial multiple sclerosis (FMS) vs. sporadic MS (SMS) in Argentina. Methods: multicenter study that included patients from 14 MS Centers of Argentina. Patients were considered as FMS if they had in their family at least one relative of first or second degree diagnosed with MS; otherwise, patients were considered to have SMS. We compared the age at onset between familial and sporadic cases as well as the age at onset between relatives from different generations in FMS vs. SMS. Results: 1333 patients were included, 97 of them were FMS (7.3%). A lower age at onset in the younger generations of FMS cases was found compared with older generations of FMS as well as. SMS cases (24.17 3.7 years vs. 30.3 75.7 years, and 32.4 79.4 respectively; p o0.001). No differences were observed between older generations of FMS vs. SMS cases (p ¼0.12). Conclusion: we observed an anticipation of age at onset of MS in younger generations of patients with FMS vs. older generations of FMS and SMS. & 2016 Elsevier B.V. All rights reserved.
Keywords: Argentina Multiple sclerosis Familial MS South America
1. Introduction Multiple sclerosis (MS) is a complex demyelinating disease of the CNS in which several environmental factors act together in a genetically susceptible individual to cause the disease (Marrie, 2004). Over the past years, some epidemiological studies on MS described an anticipation of age at onset in the younger generations as previously shown in other neurological diseases with genetic inheritance (Cocco et al., 2004; Koch et al., 2010; Lin et al., 2008; Romero-Pinel et al., 2010). The study of families with multiple n Correspondence to: MS Section, Italian Hospital of Buenos Aires Gascón 450 C1181ACH, Buenos Aires, Argentina. E-mail address: [email protected] (J.I. Rojas).
http://dx.doi.org/10.1016/j.msard.2016.01.004 2211-0348/& 2016 Elsevier B.V. All rights reserved.
sclerosis would allow the identification of genetic markers as well as other characteristics that would help to elucidate the cause and how these markers could interact with the environment to influence the disease (Koch et al., 2010). The studies that previously evaluated the anticipation process came principally from Europe and North America, but there is no data concerning the anticipation of age at onset in regions from South America, where several differences exist regarding the frequency and the severity of MS compared with European and North American populations (Cristiano et al., 2013). This study was performed to assess if there was an anticipation of age at onset in younger generations of familial multiple sclerosis (FMS) vs. sporadic MS (SMS) in Argentina.
J.I. Rojas et al. / Multiple Sclerosis and Related Disorders 6 (2016) 54–56
2. Methods This is a retrospective multicenter study that included patients from 14 MS Centers in Argentina that was approved by the ethics committee of each participating center. For the study, each principal investigator (PI) included all patients with MS diagnosis (McDonald et al., 2001; Polman et al., 2011, 2005; Poser et al., 1983) followed at their practice and whose information was made available for the study. A minimum of 20 patients per center was mandatory to participate. Patients were categorized as either familial (FMS) if the patient had at least one additional biological family member with MS, or sporadic (SMS) if the patient was the only biological family member with MS (Koch et al., 2010). Within the familial MS group, we selected pairs of patients from different generations belonging to the same family and were stratified according to whether they came from the same generation (siblings) or two generations (parentoffspring and uncle- nephew/niece) (Romero-Pinel et al., 2010). The age at onset was defined as the age at which patients presented the first neurological symptom attributable to MS. In the case of patients who were or had been treated at other centers, PI consulted the patient's neurologist for diagnosis certification and overlap exclusion. Documentation was obtained with the consent of the member being studied, or, in case of death, of the closest direct relative. The clinical course was relapsing remitting (RR) and primary progressive (PP), according to Lublin and Reingold (1996). For the analysis we compared the age at onset between members of each pair to establish if there was anticipation. We also compared the median age at onset of patients with FMS and SMS and the age at onset between relatives from different generations in FMS vs. SMS. Finally, we assessed the delay from symptom onset to confirmed diagnosis of MS in the younger generation of FMS and compared it to SMS patients matched by year of symptom onset, age and sex in order to analyse the possibility of reporting bias. For each FMS patients we identified three SMS patients. SMS were selected using a statistical program.
55
Table 1 Demographic characteristics of patients. SMS (n¼ 1236) FMS (n¼ 97) p Female sex, n (%) Age at disease onset (mean 7 SD) RRMS, n (%) PPMS, n (%) Families with 2 relatives affected, N (%) Families with4 2 relatives affected, n (%) Families with first degree affected, n (%) Families with second degree affected, n (%) Duration of follow-up in years (median7 SD)
827 (66) 32.4 7 9.4 1176 (95.1) 5 (4.9) – –
59 (60.8) 29.4 7 5.1 92 (94.8) 5 (5.2) 44 (95) 2 (5)
0.22 0.18 0.88 0.44 – –
–
30 (65)
–
–
16 (35)
–
7.5 7 3.1
9.17 4.1
0.10
SMS: sporadic multiple sclerosis; FMS: familial multiple sclerosis; SD: standard deviation; RRMS: relapsing remitting multiples sclerosis; PPMS: primary progressive multiple sclerosis.
Table 2 Age at onset comparisons.
N of patients N of families Age at onset (years 7SD)
p
FMS younger generation
FMS older generation
SMS
52 25 24.1 73.7
45 21 30.3 7 5.7
1236 – – 32.4 7 9.4 o 0.001
SMS: sporadic multiple sclerosis; FMS: familial multiple sclerosis; SD: standard deviation.
2.1. Statistics We used Pearson's chi-squared test and the Mann–Whitney Utest for comparisons between two groups. For comparisons between more than two groups we used Pearson's chi-squared test and the Kruskal–Wallis test where appropriate. Stata 10.1 was used to resume and analyse the data.
3. Results A total of 1333 patients were included, 97 were FMS (7.3%) and 1236 SMS. These 97 patients belong to 44 families with two relatives diagnosed with MS and two families had more than two affected relatives. Thirty families had relatives of first degree affected; in 25 of them we found the parent–child relation and in 5 they were siblings. In sixteen families we found relatives of second degree affected. No differences in gender and MS subtype were found between SMS and FMS. Demographic characteristics of included patients are displayed in Table 1. Comparing the age at onset within the members of 25 pairs composed of two relatives from different generations (parent–child and uncle/aunt–nephew/ niece), we found a lower age at onset in the younger generation vs. the older generation of FMS (mean 24.1 7 3.7 years vs. 30.3 75.7 years, p o0.001 respectively) and in the younger generation of FMS vs. SMS (mean 24.17 3.7 years vs. 32.4 79.4, p o0.001 respectively) (Table 2 and Fig. 1). When we compared age at onset of the entire group of FMS vs. SMS group we did not find differences (29.4 75.1 vs. 32.4 79.4 p¼ 0.18). The delay from symptom onset and diagnosis in the younger generation of FMS was 1.67 0.8 years while in SMS control matched by symptom onset the delay was
Fig. 1. Comparisons among age at disease onset between groups.
1.8 71 years (p¼ 0.14).
4. Discussion In our study performed in 14 MS centers of Argentina, where nearly 5000–7000 MS patients are estimated (Cristiano et al., 2009), we observed an anticipation of the age at onset of MS in the younger generations of patients with FMS vs. older generations of FMS and SMS, while no differences were observed between older generations of FMS vs. SMS. Our study is in line with previous studies performed in Europe and North America (Cocco et al., 2004; Koch et al., 2010, RomeroPinel et al., 2010), where anticipation of age at onset was also found in younger generations of patients with FMS. This is also probably related with previous genetic findings in our region where we found that HLADRB1* 15 allele was strongly associated
56
J.I. Rojas et al. / Multiple Sclerosis and Related Disorders 6 (2016) 54–56
with MS disease as it also was in Europe (Patrucco et al., 2009). It is worth to mention that we did not find differences at the age of onset when all FMS patients where compared with SMS. Considering our observation, we agree that a greater genetic load would shorten the preclinical phase of the disease and predispose to a lower age at onset, as has been shown in previous studies (Romero-Pinel et al., 2010). Anticipation is a characteristic on diseases where expanded triplets are present like Huntington's disease. It is currently accepted that MS is caused by the interaction of environment and genetic factors (Romero-Pinel et al., 2010), however, no triplets have yet been described for MS (Ebers, 2008) nor it is believed that familial MS is a monogenic disease. It is important to note that our study included patients of different ethnic origins and from a variety of regions around the country, probably limiting any selection bias. Another point to consider is the possibility that in our results a follow-up time bias can be present. In the younger generation group, there may be some people who still have not had time to develop symptoms of the disease at the time of this study, however, no differences in follow up time was observed in the sample evaluated. Finally, it is important to mention that the fact of having relatives with MS can increase the awareness of symptoms and lead into a prompt investigation of first events. However, we found no differences in the delay between first symptoms and diagnosis among the younger generation of FMS and SMS matched by the date of disease onset. This might reduce the possibility of reporting bias in the sample analyzed. In conclusion, our findings suggest a hereditary component in the disease process that anticipates the age at onset in affected patients in Argentina, as has been previously shown in other countries. Future studies will help to elucidate these initial findings as well as to better understand the genetic and environmental interaction in our region, where significant differences regarding frequency, evolution and prognosis stand in contrast to North American and European regions.
Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Author declaration We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further
confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
References Cocco, E., Sardu, C., Lai, M., Spinicci, G., Contu, P., Marrosu, M.G., 2004. Anticipation of age at onset in multiple sclerosis: a Sardinian cohort study. Neurology 62, 1794–1798. Cristiano, E., Patrucco, L., Rojas, J.I., Caceres, F., Carra, A., Correale, J., et al., 2009. Prevalence of multiple sclerosis in Buenos Aires, Argentina using the capturerecapture method. Eur. J. Neurol. 16, 183–187. Cristiano, E., Rojas, J., Romano, M., Frider, N., Machnicki, G., Giunta, D., et al., 2013. The epidemiology of multiple sclerosis in Latin America and the Caribbean: a systematic review. Mult. Scler. 19, 844–854. Ebers, G.C., 2008. Environmental factors and multiple sclerosis. Lancet Neurol. 7, 268–277. Koch, M., Zhao, Y., Yee, I., Guimond, C., Kingwell, E., Rieckmann, P., et al., 2010. Disease onset in familial and sporadic primary progressive multiple sclerosis. Mult. Scler. 16, 694–700. Lin, Y., Zheng, J.Y., Jin, Y.H., Xie, Y.C., Jin, Z.B., 2008. Trinucleotide expansions in the SCA7 gene in a large family with spinocerebellar ataxia and craniocervical dystonia. Neurosci. Lett. 434, 230–233. Lublin, F.D., Reingold, S.C., 1996. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46, 907–911. Marrie, R.A., 2004. Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol. 3, 709–718. McDonald, W.I., Compston, A., Edan, G., Goodkin, D., Hartung, H.P., Lublin, F.D., et al., 2001. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann. Neurol. 50, 121–127. Patrucco, L., Larriba, J., Redal, M.A., Rojas, J.I., Argibay, P.F., Cristiano, E., 2009. HLADRB1 and multiple sclerosis in Argentina. Eur. J. Neurol. 16, 427–429. Polman, C.H., Reingold, S.C., Banwell, B., Clanet, M., Cohen, J.A., Filippi, M., et al., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69, 292–302. Polman, C.H., Reingold, S.C., Edan, G., Filippi, M., Hartung, H.P., Kappos, L., et al., 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol. 58, 840–846. Poser, C.M., Paty, D.W., Scheinberg, L., McDonald, W.I., Davis, F.A., Ebers, G.C., et al., 1983. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13, 227–231. Romero-Pinel, L., Martinez-Yelamos, S., Gubieras, L., Matas, E., Bau, L., Kremenchutzky, M., et al., 2010. Anticipation of age at onset in familial multiple sclerosis. Eur. J. Neurol. 17, 572–575.
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Disease onset in familial and sporadic multiple sclerosis in Argentina J.I. Rojas a,n, L. Patrucco a, J. MIguez a, V. Sinay b, F. Pagani Cassara b, F. Cáceres c, N. Fernandez Liguori c,d, M.L. Saladino c,d, N. Deri k, G. Jaacks k, M. Parada Marcilla e, M.I. Arrigoni j, J. Correale f, M. Fiol f, M.C. Ysrraelit f, A. Carrá g, M.C. Curbelo g, A. Martinez g, J. Steinberg g, S. Bestoso m, J.P. Hryb h, J.L. Di Pace h, M.B. Perassolo h, E. Carnero Contentti i, A. Caride i, P.A. Lopez i, C. Martinez e, E. Reich l, E. Cristiano a a
Centro de Esclerosis Múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Argentina Instituto de Neurociencias, Fundación Favaloro, Argentina Neurosciences Institute of Buenos Aires (INEBA), Buenos Aires, Argentina d Multiple Sclerosis Section Hospital E.Tornú, Buenos Aires, Argentina e Private Office, Private Office, Argentina f Department of Neurology, Institute for Neurological Research Dr. Raúl Carrea, FLENI, Argentina g Hospital Británico Buenos Aires, Argentina h Hospital General de Agudos Carlos G Durand, Buenos Aires, Argentina i Hospital Alemán, Buenos Aires, Argentina j Hospital Italiano de Córdoba, Argentina k Centro de Investigación DIABAID, Argentina l Hospital Julio Mendez, Buenos Aires, Argentina m Hospital Escuela “José F. De San Martín”, Corrientes, Argentina b c
art ic l e i nf o
a b s t r a c t
Article history: Received 31 July 2015 Received in revised form 28 December 2015 Accepted 19 January 2016
The present study was carried out to assess if there is an anticipation of age at onset in younger generations of familial multiple sclerosis (FMS) vs. sporadic MS (SMS) in Argentina. Methods: multicenter study that included patients from 14 MS Centers of Argentina. Patients were considered as FMS if they had in their family at least one relative of first or second degree diagnosed with MS; otherwise, patients were considered to have SMS. We compared the age at onset between familial and sporadic cases as well as the age at onset between relatives from different generations in FMS vs. SMS. Results: 1333 patients were included, 97 of them were FMS (7.3%). A lower age at onset in the younger generations of FMS cases was found compared with older generations of FMS as well as. SMS cases (24.17 3.7 years vs. 30.3 75.7 years, and 32.4 79.4 respectively; p o0.001). No differences were observed between older generations of FMS vs. SMS cases (p ¼0.12). Conclusion: we observed an anticipation of age at onset of MS in younger generations of patients with FMS vs. older generations of FMS and SMS. & 2016 Elsevier B.V. All rights reserved.
Keywords: Argentina Multiple sclerosis Familial MS South America
1. Introduction Multiple sclerosis (MS) is a complex demyelinating disease of the CNS in which several environmental factors act together in a genetically susceptible individual to cause the disease (Marrie, 2004). Over the past years, some epidemiological studies on MS described an anticipation of age at onset in the younger generations as previously shown in other neurological diseases with genetic inheritance (Cocco et al., 2004; Koch et al., 2010; Lin et al., 2008; Romero-Pinel et al., 2010). The study of families with multiple n Correspondence to: MS Section, Italian Hospital of Buenos Aires Gascón 450 C1181ACH, Buenos Aires, Argentina. E-mail address: [email protected] (J.I. Rojas).
http://dx.doi.org/10.1016/j.msard.2016.01.004 2211-0348/& 2016 Elsevier B.V. All rights reserved.
sclerosis would allow the identification of genetic markers as well as other characteristics that would help to elucidate the cause and how these markers could interact with the environment to influence the disease (Koch et al., 2010). The studies that previously evaluated the anticipation process came principally from Europe and North America, but there is no data concerning the anticipation of age at onset in regions from South America, where several differences exist regarding the frequency and the severity of MS compared with European and North American populations (Cristiano et al., 2013). This study was performed to assess if there was an anticipation of age at onset in younger generations of familial multiple sclerosis (FMS) vs. sporadic MS (SMS) in Argentina.
J.I. Rojas et al. / Multiple Sclerosis and Related Disorders 6 (2016) 54–56
2. Methods This is a retrospective multicenter study that included patients from 14 MS Centers in Argentina that was approved by the ethics committee of each participating center. For the study, each principal investigator (PI) included all patients with MS diagnosis (McDonald et al., 2001; Polman et al., 2011, 2005; Poser et al., 1983) followed at their practice and whose information was made available for the study. A minimum of 20 patients per center was mandatory to participate. Patients were categorized as either familial (FMS) if the patient had at least one additional biological family member with MS, or sporadic (SMS) if the patient was the only biological family member with MS (Koch et al., 2010). Within the familial MS group, we selected pairs of patients from different generations belonging to the same family and were stratified according to whether they came from the same generation (siblings) or two generations (parentoffspring and uncle- nephew/niece) (Romero-Pinel et al., 2010). The age at onset was defined as the age at which patients presented the first neurological symptom attributable to MS. In the case of patients who were or had been treated at other centers, PI consulted the patient's neurologist for diagnosis certification and overlap exclusion. Documentation was obtained with the consent of the member being studied, or, in case of death, of the closest direct relative. The clinical course was relapsing remitting (RR) and primary progressive (PP), according to Lublin and Reingold (1996). For the analysis we compared the age at onset between members of each pair to establish if there was anticipation. We also compared the median age at onset of patients with FMS and SMS and the age at onset between relatives from different generations in FMS vs. SMS. Finally, we assessed the delay from symptom onset to confirmed diagnosis of MS in the younger generation of FMS and compared it to SMS patients matched by year of symptom onset, age and sex in order to analyse the possibility of reporting bias. For each FMS patients we identified three SMS patients. SMS were selected using a statistical program.
55
Table 1 Demographic characteristics of patients. SMS (n¼ 1236) FMS (n¼ 97) p Female sex, n (%) Age at disease onset (mean 7 SD) RRMS, n (%) PPMS, n (%) Families with 2 relatives affected, N (%) Families with4 2 relatives affected, n (%) Families with first degree affected, n (%) Families with second degree affected, n (%) Duration of follow-up in years (median7 SD)
827 (66) 32.4 7 9.4 1176 (95.1) 5 (4.9) – –
59 (60.8) 29.4 7 5.1 92 (94.8) 5 (5.2) 44 (95) 2 (5)
0.22 0.18 0.88 0.44 – –
–
30 (65)
–
–
16 (35)
–
7.5 7 3.1
9.17 4.1
0.10
SMS: sporadic multiple sclerosis; FMS: familial multiple sclerosis; SD: standard deviation; RRMS: relapsing remitting multiples sclerosis; PPMS: primary progressive multiple sclerosis.
Table 2 Age at onset comparisons.
N of patients N of families Age at onset (years 7SD)
p
FMS younger generation
FMS older generation
SMS
52 25 24.1 73.7
45 21 30.3 7 5.7
1236 – – 32.4 7 9.4 o 0.001
SMS: sporadic multiple sclerosis; FMS: familial multiple sclerosis; SD: standard deviation.
2.1. Statistics We used Pearson's chi-squared test and the Mann–Whitney Utest for comparisons between two groups. For comparisons between more than two groups we used Pearson's chi-squared test and the Kruskal–Wallis test where appropriate. Stata 10.1 was used to resume and analyse the data.
3. Results A total of 1333 patients were included, 97 were FMS (7.3%) and 1236 SMS. These 97 patients belong to 44 families with two relatives diagnosed with MS and two families had more than two affected relatives. Thirty families had relatives of first degree affected; in 25 of them we found the parent–child relation and in 5 they were siblings. In sixteen families we found relatives of second degree affected. No differences in gender and MS subtype were found between SMS and FMS. Demographic characteristics of included patients are displayed in Table 1. Comparing the age at onset within the members of 25 pairs composed of two relatives from different generations (parent–child and uncle/aunt–nephew/ niece), we found a lower age at onset in the younger generation vs. the older generation of FMS (mean 24.1 7 3.7 years vs. 30.3 75.7 years, p o0.001 respectively) and in the younger generation of FMS vs. SMS (mean 24.17 3.7 years vs. 32.4 79.4, p o0.001 respectively) (Table 2 and Fig. 1). When we compared age at onset of the entire group of FMS vs. SMS group we did not find differences (29.4 75.1 vs. 32.4 79.4 p¼ 0.18). The delay from symptom onset and diagnosis in the younger generation of FMS was 1.67 0.8 years while in SMS control matched by symptom onset the delay was
Fig. 1. Comparisons among age at disease onset between groups.
1.8 71 years (p¼ 0.14).
4. Discussion In our study performed in 14 MS centers of Argentina, where nearly 5000–7000 MS patients are estimated (Cristiano et al., 2009), we observed an anticipation of the age at onset of MS in the younger generations of patients with FMS vs. older generations of FMS and SMS, while no differences were observed between older generations of FMS vs. SMS. Our study is in line with previous studies performed in Europe and North America (Cocco et al., 2004; Koch et al., 2010, RomeroPinel et al., 2010), where anticipation of age at onset was also found in younger generations of patients with FMS. This is also probably related with previous genetic findings in our region where we found that HLADRB1* 15 allele was strongly associated
56
J.I. Rojas et al. / Multiple Sclerosis and Related Disorders 6 (2016) 54–56
with MS disease as it also was in Europe (Patrucco et al., 2009). It is worth to mention that we did not find differences at the age of onset when all FMS patients where compared with SMS. Considering our observation, we agree that a greater genetic load would shorten the preclinical phase of the disease and predispose to a lower age at onset, as has been shown in previous studies (Romero-Pinel et al., 2010). Anticipation is a characteristic on diseases where expanded triplets are present like Huntington's disease. It is currently accepted that MS is caused by the interaction of environment and genetic factors (Romero-Pinel et al., 2010), however, no triplets have yet been described for MS (Ebers, 2008) nor it is believed that familial MS is a monogenic disease. It is important to note that our study included patients of different ethnic origins and from a variety of regions around the country, probably limiting any selection bias. Another point to consider is the possibility that in our results a follow-up time bias can be present. In the younger generation group, there may be some people who still have not had time to develop symptoms of the disease at the time of this study, however, no differences in follow up time was observed in the sample evaluated. Finally, it is important to mention that the fact of having relatives with MS can increase the awareness of symptoms and lead into a prompt investigation of first events. However, we found no differences in the delay between first symptoms and diagnosis among the younger generation of FMS and SMS matched by the date of disease onset. This might reduce the possibility of reporting bias in the sample analyzed. In conclusion, our findings suggest a hereditary component in the disease process that anticipates the age at onset in affected patients in Argentina, as has been previously shown in other countries. Future studies will help to elucidate these initial findings as well as to better understand the genetic and environmental interaction in our region, where significant differences regarding frequency, evolution and prognosis stand in contrast to North American and European regions.
Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Author declaration We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further
confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
References Cocco, E., Sardu, C., Lai, M., Spinicci, G., Contu, P., Marrosu, M.G., 2004. Anticipation of age at onset in multiple sclerosis: a Sardinian cohort study. Neurology 62, 1794–1798. Cristiano, E., Patrucco, L., Rojas, J.I., Caceres, F., Carra, A., Correale, J., et al., 2009. Prevalence of multiple sclerosis in Buenos Aires, Argentina using the capturerecapture method. Eur. J. Neurol. 16, 183–187. Cristiano, E., Rojas, J., Romano, M., Frider, N., Machnicki, G., Giunta, D., et al., 2013. The epidemiology of multiple sclerosis in Latin America and the Caribbean: a systematic review. Mult. Scler. 19, 844–854. Ebers, G.C., 2008. Environmental factors and multiple sclerosis. Lancet Neurol. 7, 268–277. Koch, M., Zhao, Y., Yee, I., Guimond, C., Kingwell, E., Rieckmann, P., et al., 2010. Disease onset in familial and sporadic primary progressive multiple sclerosis. Mult. Scler. 16, 694–700. Lin, Y., Zheng, J.Y., Jin, Y.H., Xie, Y.C., Jin, Z.B., 2008. Trinucleotide expansions in the SCA7 gene in a large family with spinocerebellar ataxia and craniocervical dystonia. Neurosci. Lett. 434, 230–233. Lublin, F.D., Reingold, S.C., 1996. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46, 907–911. Marrie, R.A., 2004. Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol. 3, 709–718. McDonald, W.I., Compston, A., Edan, G., Goodkin, D., Hartung, H.P., Lublin, F.D., et al., 2001. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann. Neurol. 50, 121–127. Patrucco, L., Larriba, J., Redal, M.A., Rojas, J.I., Argibay, P.F., Cristiano, E., 2009. HLADRB1 and multiple sclerosis in Argentina. Eur. J. Neurol. 16, 427–429. Polman, C.H., Reingold, S.C., Banwell, B., Clanet, M., Cohen, J.A., Filippi, M., et al., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69, 292–302. Polman, C.H., Reingold, S.C., Edan, G., Filippi, M., Hartung, H.P., Kappos, L., et al., 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol. 58, 840–846. Poser, C.M., Paty, D.W., Scheinberg, L., McDonald, W.I., Davis, F.A., Ebers, G.C., et al., 1983. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13, 227–231. Romero-Pinel, L., Martinez-Yelamos, S., Gubieras, L., Matas, E., Bau, L., Kremenchutzky, M., et al., 2010. Anticipation of age at onset in familial multiple sclerosis. Eur. J. Neurol. 17, 572–575.