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Neurogenetic Disorders in the Basque Population

2014; Wiley; Volume: 79; Issue: 1 Linguagem: Inglês

10.1111/ahg.12088

1469-1809

J.F. Martí-Massó, J.J. Zarranz, David Otaegui, Adolfo López de Munaín,

Parkinson's Disease Mechanisms and Treatments

Annals of Human GeneticsVolume 79, Issue 1 p. 57-75 ReviewFree Access Neurogenetic Disorders in the Basque Population José Félix Martí Massó, José Félix Martí Massó Department of Neurology at Hospital Universitario Donostia (San Sebastián, Guipúzcoa), Basque Health Service (Osakidetza), Basque Country, Spain Department of Neurosciences, University of Basque Country (UPV-EHU) Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED); Carlos III Health Institute, Ministry of Economy and Competitiveness, Spain BioDonostia Institute, San Sebastián, Guipúzcoa JAKIUNDE, Academia de las Ciencias, de las Artes y de las LetrasSearch for more papers by this authorJuan José Zarranz, Juan José Zarranz Department of Neurology at Hospital Universitario Cruces (Baracaldo, Vizcaya), Basque Health Service (Osakidetza), Basque Country, Spain Department of Neurosciences, University of Basque Country (UPV-EHU) BioCruces Institute, Baracaldo, Vizcaya JAKIUNDE, Academia de las Ciencias, de las Artes y de las LetrasSearch for more papers by this authorDavid Otaegui, David Otaegui BioDonostia Institute, San Sebastián, GuipúzcoaSearch for more papers by this authorAdolfo López de Munain, Corresponding Author Adolfo López de Munain Department of Neurology at Hospital Universitario Donostia (San Sebastián, Guipúzcoa), Basque Health Service (Osakidetza), Basque Country, Spain Department of Neurosciences, University of Basque Country (UPV-EHU) Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED); Carlos III Health Institute, Ministry of Economy and Competitiveness, Spain BioDonostia Institute, San Sebastián, GuipúzcoaCorresponding author: Adolfo López De Munain, Department of Neurology, Hospital Universitario Donostia, Paseo del Dr. Beguiristain s/n, San Sebastián 20014, Spain. Tel: +34 943 00 62 94; Fax: +34 943 00 62 50; E-mail: [email protected]Search for more papers by this author José Félix Martí Massó, José Félix Martí Massó Department of Neurology at Hospital Universitario Donostia (San Sebastián, Guipúzcoa), Basque Health Service (Osakidetza), Basque Country, Spain Department of Neurosciences, University of Basque Country (UPV-EHU) Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED); Carlos III Health Institute, Ministry of Economy and Competitiveness, Spain BioDonostia Institute, San Sebastián, Guipúzcoa JAKIUNDE, Academia de las Ciencias, de las Artes y de las LetrasSearch for more papers by this authorJuan José Zarranz, Juan José Zarranz Department of Neurology at Hospital Universitario Cruces (Baracaldo, Vizcaya), Basque Health Service (Osakidetza), Basque Country, Spain Department of Neurosciences, University of Basque Country (UPV-EHU) BioCruces Institute, Baracaldo, Vizcaya JAKIUNDE, Academia de las Ciencias, de las Artes y de las LetrasSearch for more papers by this authorDavid Otaegui, David Otaegui BioDonostia Institute, San Sebastián, GuipúzcoaSearch for more papers by this authorAdolfo López de Munain, Corresponding Author Adolfo López de Munain Department of Neurology at Hospital Universitario Donostia (San Sebastián, Guipúzcoa), Basque Health Service (Osakidetza), Basque Country, Spain Department of Neurosciences, University of Basque Country (UPV-EHU) Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED); Carlos III Health Institute, Ministry of Economy and Competitiveness, Spain BioDonostia Institute, San Sebastián, GuipúzcoaCorresponding author: Adolfo López De Munain, Department of Neurology, Hospital Universitario Donostia, Paseo del Dr. Beguiristain s/n, San Sebastián 20014, Spain. Tel: +34 943 00 62 94; Fax: +34 943 00 62 50; E-mail: [email protected]Search for more papers by this author First published: 01 December 2014 https://doi.org/10.1111/ahg.12088Citations: 5AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Summary In the molecular era, the study of neurogenetic disorders in relict populations provides an opportunity to discover new genes by linkage studies and to establish clearer genotype-phenotype correlations in large cohorts of individuals carrying the same mutation. The Basque people are one of the most ancient populations living in Europe and represent an excellent resource for this type of analysis in certain genetic conditions. Our objective was to describe neurogenetic disorders reported in the Basque population due to the presence of ancestral mutations or an accumulation of cases or both. We conducted a search in PubMed with the terms: Basque, neurogenetic disorders, genetic risk, and neurological disorders. We identified nine autosomal and two recessive disorders in the Basque population attributable to ancestral mutations (such as in PNRP, PARK8, FTDP-TDP43, LGMD2A, VCP, c9ORF72, and CMT4A), highly prevalent (DM1) or involving unique mutations (PARK1 or MAPT). Other genes were reported for their role as protective/risk factors in complex diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. At the present time, when powerful sequencing techniques are identifying large numbers of genetic variants associated with unique phenotypes, the scrutiny of these findings in genetically homogeneous populations can help analyze genotype-phenotype correlations. Introduction The Basque lands were described by classical authors, such as Estrabon and Plinius the Elder, in terms of the Ager Vasconum, well-Romanized plains in the central and southern part of Navarre, and the Saltus Vasconum, formed by less Romanized areas from Navarre to the Pyrenees to the eastern Cantabrian coast (Fig. 1). In the Dark Ages that followed the fall of the Roman Empire and the entry into the western Roman Empire of the Germanic tribes, the Basque region was a key place of passage of several different groups of invaders, at which point the original more Romanized Basque tribes (Vasconum) may have moved to the west at the expense of less Romanized populations of Celtic origin that had been incorporated into the Empire late on, at the beginning of the Christian era (Aguirre et al., 1991; several authors, The Cantabrian Wars, 1999). Figure 1Open in figure viewerPowerPoint Geographical distribution of the Basques in the Roman era. Around the year 800 AD, there was the creation of an eastern Pyrenean kingdom, the Kingdom of Pamplona, with familial links to the Muslim governors of the southern Navarre, and both gained their independence from the Carolingian Empire in France and from the Omeyan Caliphate in Cordoba, respectively. Within a century, this nascent kingdom had become the Kingdom of Navarre, which encompassed all Basque lands around the year 1000 AC (Fig. 2). At the western border of the Basque lands, very soon after the Muslim invasion, another nucleus of organized resistance to the invader emerged under the influence of the Kingdom of Asturias. From these lands, where Cantabria, Burgos, and Alava converge (Fig. 3), there emerged an independent county which was later to become the Kingdom of Castile. The Kingdom of Aragón (originally a county dependent on the Crown of Navarre in the central Pyrenees in lands formerly populated by Basque people) became independent after the death of the King of Navarre, Sancho the Great in 1035. In the 15th century, after the marriage of Isabella of Castile and Ferdinand of Aragon, and the occupation and subsequent conquest of the Kingdoms of Granada (1492) and Southern Navarre (1512), these regions came under the Spanish Crown, as in the present day. Figure 2Open in figure viewerPowerPoint Iberian kingdoms in the period of Sancho the Great, King of Navarre (1035). Figure 3Open in figure viewerPowerPoint Iberian kingdoms immediately before the unification under the Catholic Kings (1492–1512). Figure 4Open in figure viewerPowerPoint (a) The Basque Country or Euskal Herria divided into seven territories in France and Spain. (b) Euskal Herria and distribution of dialectal variants of the Basque language, Euskara. Throughout all these changes in rulers, the Basques have preserved their ancient language, Euskara, one of the oldest languages spoken in Europe. This may have contributed to maintaining a high degree of genetic isolation until recently (Collins, 1986; Cavalli-Sforza, 1988), and would explain some genetically based characteristics of the population. These include a high frequency of blood group O and nearly complete absence of group B (Boyd & Boyd, 1937; Vallois, 1944; Cavalli-Sforza et al., 1944; Calafell & Bertranpetit, 1994; Manzano et al., 2002; Bauduer et al., 2004), the frequency of the latter trait being the lowest reported in the world (2–3%; Mourant, 1947; Moulinier, 1949; Levine et al., 1977), as well as a high frequency of Rh-negative blood (35.6% of a sample of Argentineans of Basque origin was found to be Rh-negative; Etcheverry, 1945). In contrast, modern genetic studies using SNPs and microsatellites in the HLA system, Chromosome Y, and mitochondrial DNA, showed that the current Basque population is quite similar to the neighbouring populations and that it exists as a partial genetic continuity between modern Basques and Paleolithic/Mesolithic settlers of the Basque Country (Behar et al., 2012; Martínez-Cruz et al., 2012). Only when the Kingdom of Navarre was at the height of its power (under Sancho the Great in the 11th century) have all lands populated by the Basques been part of a single political entity, in this case, together with other lands that had been recaptured from the Muslim invaders. The slow decline of the Kingdom of Navarre over the following centuries, until its conquest by the Crown of Castile in the 16th century, led to the division of the Basque population between two different political entities, France and Spain, and within the latter, between two autonomous regions that are now called the Basque Country (Euskadi) and Navarre (Fig. 4). Native Basques continue to be identified by their surnames (with their specific linguistic roots in the Basque language and Basque place names) and originate from a numerically small population (Gorrochategui, 1995). Specifically, from a population of around 800,000 in the late 19th century, the population of Navarre and the Basque Country has stabilized at around 2,700,000 since the restoration of democracy in Spain in 1978. The growth was mainly due to immigration from other regions of Spain, in the second half of the century mostly to Biscay and throughout the 20th century (especially the second half) to Guipúzcoa, Alava, and Navarre. The immigration flow has progressively declined in the past 50 years and the more recent waves of immigration from outside the European Union, in the decade 1997–2007, have had relatively little impact in Euskadi. In 2013, only 8.4% of the population were classified as born outside Spain (43% from America, 25.7% from elsewhere in Europe, and 23.8% from Africa) and 20.3% as from other parts of Spain, mainly from Castilla-León, Extremadura, Andalusia, and Galicia (http://www.irekia.euskadi.net/assets/attachments/1728/LA_INMIGRACION_EN_EUSKADI.pdf?1323870011). On the other hand, between 2001 and 2011, the foreign population living in Navarre grew from 4.4% to 10.3% and 30% of the current population of Navarre were born elsewhere (17% in other parts of Spain and 13% outside Spain; http://www.ine.es/prensa/np775.pdf). Overall, we can estimate that more than half of the current population of the Basque Country and Navarre descend from the successive waves of immigration over the last 150 years, with the percentages being highest in Alava and Biscay, intermediate in Navarre and lowest in Guipúzcoa (Picabea, 1993). Another important demographic phenomenon is the falling birth rate over the last 50 years, resulting in one of the most aged populations in Europe. In 2014, over 20.7% of the population is over 65 years of age, and this percentage is predicted to rise to 22.4% by 2020 (with 7.2% being older than 80 years; source, EUSTAT, Basque Institute of Statistics, 2014; http://www.eustat.es/). In parallel, the Basque Country has been a source of emigration since the time of the war against the Muslims (10th–15th centuries) to the south of the Iberian Peninsula, and to America after the 16th century. After the Latin American Wars of Independence (1810–1826), there were successive waves of emigration (associated with changes in the traditional Pyrenean mode of transmission of the familial property toward a system based on Roman law after the French Revolution in 1789, defections from Napoleon´s wars and the successive Spanish Civil wars during the 19th and 20th Centuries). As a result, as many as 10% of people in some Latin American countries, including Argentina, Colombia, Chile, Cuba, Mexico, Uruguay, and Venezuela, have Basque ancestry (Thayer Ojeda, 1919; Hagen, 1963; Retamal et al., 1992; Azcona, 2004; Douglass & Bilbao, 2005; Azcona, 2012). From the economic point of view, the Spanish Basque Country was one of the first regions in Spain to be industrialized in the last third of the 19th century, with intense development of heavy industry (coal mining, steel production, and shipbuilding) and manufacturing industry especially in the second half of the 20th century. Even today, despite the severe economic crisis and the phenomena arising from globalization processes, the Basque region has a heavily industrial economy with a higher GDP per capita than Spain overall and income levels in the region are in line with those of the more industrialized countries of the European Union (http://www.datosmacro.com/pib/espana-comunidades-autonomas; http://www.datosmacro.com/pib/alemania). As a result of this economic development and the political autonomy that the Basque Country recovered with the Spanish Constitution of 1978, the region has developed its own Public Health System integrating local health organizations with the previous national health network that had developed in Spain from 1944 onwards. The Basque Health System (called Osakidetza) integrates tertiary and community hospitals, as well as district and health centres, providing universal health coverage to all the population since 1987. Health parameters of the Basque Country are considered good, coming third in 2005 in the world ranking of Human Development (based on the Human Development Index, a global measure introduced by the United Nations that includes life expectancy, indicators of educational attainment and GDP; http://www.regleg.eu), and are comparable to those of the most developed countries in Europe with good rates of overall health and the highest female life expectancy in Europe (http://en.eustat.es/ci_ci/elementos/ele0010800/not0010869_i.html#axzz2rATE20XY). Neurologists who settled in the Basque Country in the mid-1970s have had the opportunity to provide care for almost two full generations of Basques, which together with the relatively small amount of immigration in the period, and economic stability, has allowed several disorders to be clearly seen to be related to genetics where identification of genetic basis in other open populations would have been more difficult. The current population of the Basque Country has special demographic features, in particular, a low geographic mobility around the ancestral home and a certain cultural inbreeding based on the influence of the Basque language, which facilitates marriages between people from the same cultural and linguistic background, especially in Guipúzcoa. Together, these characteristics favour the persistence in the region of dominant disorders derived from ancestral dominant mutations and recurrent emergence of some recessive disorders. Neurogenetic Disorders in the Basque Country In the past 30 years, the discovery of powerful techniques for DNA analysis has dramatically boosted the understanding of the molecular basis of both clearly inherited disorders and others that were previously considered to be nongenetic (sporadic) disorders. These new technical possibilities and the aforementioned characteristics of the Spanish Basque population have enabled us to identify a number of neurological disorders associated with specific mutations. These disorders affect both the central and peripheral nervous and musculoskeletal systems and are transmitted both in a dominant and recessive manner (Table 1). Dominant Disorders Prionopathy due to the D178N mutation in the PRNP gene Genetic prion diseases are late-onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP (OMIM 600072, 176640). Worldwide, the most prevalent mutation is the substitution of glutamic acid for lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (CJD) with several known clusters, including Jews of Libyan origin, and certain Chilean and Slovakian families (Hsiao et al., 1991; Goldfarb et al., 1991; Mitrova & Belay, 2002). Neurologists working in the Basque Country, however, have only diagnosed three cases of this mutation, all of them among immigrants of non-Basque origin. In contrast, 26 patients harbouring the D178N mutation have been reported prospectively to the Registry of the Basque Health Department between January 1993 and December 2013. These 26 cases represent around 50% of all cases diagnosed in Spain and reported to the national registry of the Carlos III Health Institute. Moreover, as well as these 26 prospectively reported cases, a further 12 cases have been identified retrospectively, not having been reported to the registry because they were diagnosed before the registry was created in 1993 or because families declined to give consent. Two main possible explanations for this unusually high incidence of familial prion diseases are proposed. First, ascertainment of cases by the community neurologists is likely to be complete, thanks to the facilities created by the Basque Health authorities (after the bovine spongiform encephalopathy crisis) to improve the identification all human prion diseases, particularly variant CJD. Second, there is a cluster of cases with an ancestral D178N mutation within families of Basque origin sharing a common haplotype (Rodríguez-Martínez et al., 2005). A genealogic search through parochial registries up to the XVI century could not identify the probable common ancestor. Our findings suggest a limited number of mutational events in the PNRP gene, and that most Basque and Spanish cases, as well as some of the Italian ones (from the Tuscany region) are genetically related (Rodríguez-Martínez et al., 2008). On the other hand, one apparently sporadic case carrying the same mutation and with a different haplotype was also detected in a non-Basque patient living in the Basque Country (Alzualde et al., 2010). The observation of these clusters of patients allows us to confirm the great phenotypic variability among D178N mutation carriers even among homozygous 129MM patients (carriers of the homozygous allele encoding methionine/methionine at a polymorphic site at codon 129 of the PNRP gene; Zarranz et al., 2005a). Some of the previously accepted genotype-phenotype correlations are challenged by our findings (Zarranz et al., 2005b). For instance, the fatal familial insomnia phenotype is always related to 129MM or 129MV genotypes but the reverse is not true, and seven out of 17 patients with a 129MM genotype in this series presented with clinicopathological features of CJD. Myotonic dystrophy type 1 Myotonic dystrophy type 1 (Steinert's disease), the most common neuromuscular disorder in the adult population, is characterized by progressive skeletal muscle weakness and wasting accompanied by extramuscular features that vary with the age of onset (OMIM 160900). This dominant condition is due to an expansion of an unstable (CTG)n trinucleotide repeat in the 3' UTR of a gene encoding a putative serine/threonine protein kinase (DMPK) on human Chromosome 19q13.3, but the details of the underlying mechanisms remain unclear (Udd & Krahe, 2012). In 1993, we conducted an epidemiological survey of the disease in the province of Guipúzcoa, finding a prevalence rate of 26.5 cases/100,000 inhabitants (López de Munain et al., 1993a), the second highest identified in the world after that reported in the region of Saguenay-Lac-St-Jean in Québec (Canada; Mathieu et al., 1990; Laberge et al., 2005). In our study, conducted around the time of the discovery of the DM1 gene, we detected both typical adult-onset and neonatal cases and also nearly asymptomatic carriers among at-risk relatives, some of them with only a partial syndrome (only cataracts; López de Munain et al., 1993b). This prevalence rate cannot be explained by consanguinity in a dominant condition. Furthermore, as the DM mutation in Caucasians comes from an ancestral chromosome common to all patients around the world (Imbert et al., 1993; Goldman et al., 1995; Deka et al., 1996), the rate cannot be attributed to a founder effect alone, although such an effect could contribute to the high prevalence, as in Québec (Yotova et al., 2005). Other factors that may have contributed to the current prevalence rate being notably high are the thoroughness of the epidemiological investigation, better than previously performed in other countries, but also demographic factors, such as the rapid growth of the Guipúzcoa population where the premutation was present in the last century. During the last 20 years, despite extensive genetic counselling, the prevalence of DM1 has not decreased and in early 2014 we estimate a prevalence of 35 cases/million people (data not published). These data, with more than half of the new cases born before the period when the first epidemiological survey was conducted, indicates the limitations of this kind of epidemiological study in rare genetic conditions with variable phenotypes and could be due to a strong presence of pre-expanded alleles in the community, giving rise to the emerging cases with premutation. The mild symptomatology associated with the newly ascertained cases makes them almost undetectable to the genetic counselling services. Parkinson's disease (PD) and Lewy body dementia due to the E46K mutation in the α-synuclein gene Polymeropoulos et al. reported in 1996 and 1997 a type of familial PD (PARK1; OMIM 168601) due to a G-to-A transition in nucleotide 209 of the SNCA gene, which resulted in an ala53-to-thr substitution in α-synuclein. A highly conserved protein, α-synuclein is abundant in neurons, especially in presynaptic terminals although its functions are still not completely understood. Since then, another three point mutations and pathogenic duplication and triplication of α-synuclein have been described. We reported a Basque family with autosomal dominant Parkinsonism, dementia, and sleep disorganization (Zarranz et al., 2004) due to a novel E46K point mutation in α-synuclein. Nine patients were ascertained across the history among the relatives of the two first generations and another nine patients were diagnosed and examined in the three next generations. Three additional individuals are carriers of the mutations and remain asymptomatic or suffer from a mild pure autonomic failure. The postmortem examination of the propositus showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to α-synuclein and ubiquitin in cortical and subcortical areas, fulfilling the neuropathological criteria for Lewy body dementia. A second still unreported autopsy confirmed selective and widespread α-synuclein pathology. The E46K mutation, which substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a highly conserved area of the protein, is likely to produce severe disturbance of protein function as several in vitro studies have demonstrated. However, we have observed a wide and still unexplained phenotypic variability among the six carriers of the mutation subsequently identified within the same family. Three of them presented with aggressive early-onset PD and cognitive deterioration, while the three others presented with a symptomatic or asymptomatic pure dysautonomia. In these cases isotopic and laboratory tests confirmed that cardiac sympathetic denervation precedes the nigrostriatal involvement (Tijero et al., 2010). The sympathetic denervation appears to be organ-specific, with selective involvement of the heart given that plasma norepinephrine levels and blood pressure were normal. Comprehensive and serial neuropsychological assessments indicate that tests of frontal function showed the first alterations in all patients but these vary in severity. The first cognitive complaints coincide with the deterioration of skills to complete tasks with a posterior cortical basis (Somme et al., 2011). In the polysomnographic (PSG) studies performed in four of the seven patients and in two asymptomatic carriers of the mutation, we detected a severe loss of both rapid eye movement (REM) and non-REM sleep in two patients complaining of insomnia and in a third parkinsonian member of the family who did not complain of trouble with sleeping. Another parkinsonian family member had mildly disorganized sleep architecture whereas the two asymptomatic carriers had minor changes in the PSG findings. Although several episodes of bizarre behaviour at night were reported historically in the two symptomatic patients, we never observed abnormal behaviour during the PSG studies. No episodes of REM sleep behaviour disorder were recorded in any of these cases. Our findings expanded the spectrum of sleep disorders reported in synucleinopathies whether sporadic or familial (Zarranz et al., 2005c; Tijero et al., 2013). PD due to the R1441G mutation in the LRRK2 gene Wszolek et al. and Hasegawa & Kowa in 1995 and 1997 respectively, reported two large families from Nebraska and Japan with an autosomal dominant Parkinsonism characterized by a unilateral Parkinsonism at onset, a mean age of onset between 50 and 65 years old and a favourable response to dopaminergic medication. Postmortem examination of cases from both families showed neuronal and pigmentary loss, gliosis, and Lewy bodies in the substantia nigra (Wszolek et al., 1995; Hasegawa & Kowa, 1997). In 2004, we cloned a novel gene that contains missense mutations segregating with PARK8-linked PD (OMIM 607060, 609007) in one family from England and in four from the same small region of Guipúzcoa in the Spanish Basque Country (Paisán-Ruíz et al., 2004; Paisán-Ruíz et al., 2005). Given the tremor observed in PD and that a number of the families are of Basque descent, we have named the corresponding protein dardarin, derived from the Basque word dardara, meaning tremor. The gene that codes dardarin is LRRK2 (leucine-rich repeat kinase 2). So far, seven pathogenetic mutations are known and one of them (G2019S) is the most frequent single mutation inducing PD around the world (with several geographic origins). While G2019S and R1441C are geographically widespread, the former being found in the Basque Country, it is R1441G that is the most prevalent in our region and this mutation is rare outside northern Spain. Seeking to improve our understanding of the processes that have shaped the current distribution of R1441G, we conducted a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the LRRK2 region. Nine of the patients were of Basque origin and 20 were from elsewhere. We inferred the haplotypes using a Bayesian approach and used a maximum-likelihood method to estimate the age of the most recent common ancestor. We estimated that the most recent common ancestor lived 1350 years ago (95% CI, 1.020—1.740) in approximately the 7th century (Mata et al., 2009). We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in northern Spain (Simón-Sánchez et al., 2006). From a clinical perspective, the disease observed in R1441G carriers is indistinguishable from that observed in noncarriers. The R1441G mutation causes a form of PD that is equivalent to that observed in idiopathic PD. PD-LRRK2-R1441G carriers showed less olfactory dysfunction and cardiac involvement than individuals with idiopathic PD (Ruíz-Martínez et al., 2011), while the penetrance is higher than that detected in G2019S mutation carriers (Ruíz-Martínez et al., 2010). The prevalence of this mutation depends on ethnicity and the place of residence in the Basque country. It was studied in Guipúzcoa in 418 PD patients and 138 unrelated controls. They were screened for LRRK2 G2019S and R1441G mutations. Of the patients, 3.82% were heterozygous carriers of G2019S and 13.15% of R1441G. The frequency of G2019S was higher in the non-Basque population (6.0%), while that of R1441G was high in people of Basque origin (22.4%; Gorostidi et al., 2009). Most of the brains studied from individuals with the R1414G mutation had pure nigral degeneration without Lewy bodies (Martí-Massó et al., 2009). Interestingly, we have also detected G2019S carriers among Basque PD patients but the penetrance of this mutation is less complete than that of R1441G and the study of haplotypes is ongoing. Autosomal dominant latero-temporal epilepsy due to mutations in