EDITORIAL
The G2019S LRRK2 Mutation: Another Morbid Burden for Ashkenazi Jews May Provide New Insights on Sporadic Parkinson’s Disease Eldad Melamed, MD* Neurology, Tel Aviv University, Tel Aviv, Israel
As a distinct ethnic group, the roots of Ashkenazi Jews are clearly in eastern, western and Mediterranean Europe. However, its origin in the remote past remains obscure, mythical and controversial with theories ranging from emigration of ancient predecessors from Judea during the reign of the Roman Empire, to conversion to Judaism of a population in the medieval empire of Khazaria located near the Caspian Sea.1,2 Although it has been one of the most persecuted ethnic groups over many generations, this community disproportionately generated many landmark scientific and cultural achievements and constitutes one of the highest ethnic-specific percentage among Nobel Prize winners.3 For many years, this specific population, many of which perished during the holocaust, remained relatively homogenous mainly due to tight religious and intermarriage rules. This led to the accumulation over the years of several very serious hereditary diseases that became common in this particular ethnic group including Tay-Sachs disease, lipid transport/storage disorders such as Niemann-Pick disease and Gaucher’s disease, familial dysautonomia, torsion dystonia and also hereditary breast cancer, familial hypercholesterolemia, and cystic fibrosis.4,5 The homogeneity of this distinct population also facilitated gene mutation discovery in many of the Ashkenaziassociated hereditary disorders. It is even hypothesized that compensatorily, by selection, these multiple disease genes might have contributed to the above-thanaverage intelligence believed to be prevalent in this ethnic group.6 The etiology of Parkinson’s disease is still largely unknown and for many years it has been debated whether it is due mainly to genetic or environmental factors or to a combination of both. It is estimated that in most populations, the disease is mainly spo-
------------------------------------------------------------
*Correspondence to: Dr. Eldad Melamed, Neurology, Tel Aviv University, Sackler School of Medicine, Tel Aviv, 69978 Israel; [email protected] Relevant conflicts of interest=financial disclosures: The author is an Ashkenazi Jew. There are, otherwise, no other conflicts of interest to report. Received: 25 September 2013; Accepted: 7 October 2013 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25728
1912
Movement Disorders, Vol. 28, No. 14, 2013
radic (90%-95%) whereas it is familial only in the minority (5%-10%) In recent years, the pendulum tilted heavily toward the genetic hypothesis with the successive ground-breaking discoveries of several autosomal dominant and recessive monogenic mutations, in patients with familial as well as in those with seemingly sporadic Parkinson’s disease. This included rare or not so common mutations in genes for a-synuclein (missense, duplication, triplication), Parkin,DJ-1 and Pink-1. Another recent breakthrough in the field was the discovery of several mutations in the gene encoding for leucine-rich repeat kinease3 (LRRK2). These mutations can cause autosomal dominant Lewy body positive, levodopa responsive Parkinson’s disease.7 In most populations (European, Asian, North and South Americans), the prevalence of Parkinson’s disease due to these mutations is rather low, ranging between 1%2% of patients or even less. One of the several mutations in LRRK2 is the G2019S. A dramatic and surprising discovery was that this specific mutation and its associated Parkinson’s disease is extremely prevalent in certain ethnic populations,including the North African Berbers8 and, alas again, the Ashkenazi Jews.9 In the latter, the prevalence of the mutation can be as high as 10%-30%, higher in patients with a positive family history and lower in those with none, in both US-American and Israeli Jewish Ashkenazim, respectively, with an age-dependent high penetrance rate. The identification of the mutation founder and time of its emergence are controversial. Some, but not all, suggest that the mutation first originated in the Ashkenazi group, sometime, somewhere in the east of the Mediterranean, whereas others believe that the founder came from the Berbers.10 As if this is not enough, it was found that mutations in the glucocerebrosidase (GBA) gene that cause Gaucher’s disease in Ashkenazi Jews, also act as a susceptibility gene, increasing the risk of developing Parkinson’s disease manifold.11,12 After so many years of research, it is still unknown where in the nervous system, when, and why Parkinson’s disease begins. Even more importantly, it is still unsettled how the neurodegenerative process of the disease progresses within and among various neuronal populations in the central and peripheral (mainly autonomic) nervous systems. Also, what exactly is
L R R K 2
Parkinson’s disease, is a question that repeatedly comes up, with different answers and definitions. Although patients with Parkinson’s disease are not identical and each has his or her own distinctive illness signature, there is, after all, a common clinical pattern which makes it fairly easy to diagnose this disorder premortem with a great degree of accuracy.13 Patients are generally similar (with variations), with regard to presence of motor and nonmotor clinical features, rate of progression, existence of a long preclinical/premotor period occasionally manifested by certain nonmotor features, response to levodopa and pathological findings. It is becoming increasingly evident that Parkinson’s disease is a heterogeneous disorder that can be caused by multiple etiologies that eventually lead to similar clinical and pathological phenotypes. The fact that mutations in different genes can apparently cause a similar disease pattern, (although the mechanisms are not yet clear) may lend support to such a view. Nevertheless, this aspect should be much more vigorously investigated and disease patterns should be compared among various Parkinson’s disease-causing mutations and between those and the sporadic form of the disorder. In this issue of Movement Disorders, the paper by Alcalay et al.14 describes a study design to explore exactly these issues. The authors compared the clinical characteristics of Parkinson’s disease in Ashkenazi Jews from New York, US and Tel Aviv, Israel, who were carriers of the G2019S LRRK2 mutation (n 5 97) and in non-carriers (n 5 391). They rightly excluded (most likely just for the time being) patients with GBA mutations to preserve homogeneity of the studied groups. In general, most of the investigated clinical features in the mutation carriers were similar to those observed in the non-carrier Ashkenazi patients with the sporadic form of the disease. There were some differences, however. For instance, among the carriers, there were more women, more reported first appearance of motor symptoms in the lower limbs, and there was also an increased tendency towards developing the postural instability gait difficulty (PIGD) subtype of the disease. Although this is not the first study of its kind, its strength relates to the larger size and homogeneity of the investigated cohorts. Other studies, such as that of Healy et al.15 have also examined the intriguing potential similarities and differences between LRRK2 mutation carriers and non-carriers with Parkinson’s disease. They had somewhat different findings than the present study, but, in general, the clinical features did not differ much among the groups suggesting that LRRK2 mutations and the yet obscure other causes of Parkinson’s disease can ensue in similar clinical and possibly also pathological phenotypes. The importance of expanding the field and carrying out many more similar studies is quite obvious. Long-term follow-up should be continued in large cohorts of LRRK2 G2019S Ashkenazi car-
M U T A T I O N
riers already with the disease as well as in non-affected family members with and without the mutations. Such cohorts should be compared, if possible, with those of North African Berbers carrying the same mutation as well as with patients carrying other LRRK2 mutations. Cohorts should again be compared to groups of patients with the sporadic form of the disease matched for age of onset, duration, gender and ethnicity. Such observations can provide a host of valuable data, among others on the preclinical period of Parkinson’s disease, patterns and rates of progression, gender, age at onset, life habits, exposure to environmental factors and response patterns to therapeutic interventions. It would be interesting to re-examine in such cohorts whether the clinical phenotype is identical or diverse, even in families carrying identical mutations and begin probing the underlying mechanisms. Since both LRRK2 and GBA mutations are prevalent in Ashkenazim, it would be interesting to expand the cohort and compare diseased and non-diseased G2019S carriers and non-carriers to those with and without GBA mutations. It is tempting to hypothesize that the LRRK2 and other Parkinson-causing mutations, interfere in different checkpoints of linear or parallel cellular pathways that culminate in the accumulation of a-synuclein oligomers or its adducts or of other toxic misfolded proteins that eventually kill the neuron.7 To achieve this information, there should be pathological examinations of brains of patients from such cohorts. In addition, fibroblasts grown from skin biopsies could be converted to induced pluripotent stem cells (iPS) and then, or directly (iN) to neurons (dopaminergic, others?) to facilitate pre-mortem study of cellular disease mechanisms in vitro. Also, there is a recent rekindled interest and thrust in identifying biomarkers for both diagnosis and progression of Parkinson’s disease.16 Such large homogenous mutation-carrying cohorts could play an important role in discovery and/or confirmation of such diseaserelated biomarkers. Finally, there is an additional consideration of utmost importance. Many previous or more recent disease-modifying clinical studies examining the potential benefit of various therapeutic interventions have been unsuccessful or, at best, yielded weak or equivocal results. There could have been many reasons to explain these disappointing repeated failures. One of the major arguments is that patients included in these studies are not homogenous. Although they are all generally considered as having the sporadic form of the disease, there could have been diverse underlying etiologies, some of them even linked to a variety of genetic mutations. This might have resulted in patients having, a priori, different rates of disease progression. Also, the pathogenetic target of the investigated specific disease-modifying intervention could be mechanistically appropriate, if at all, for only a small subgroup of the studied
Movement Disorders, Vol. 28, No. 14, 2013
1913
M E L A M E D
patients leading to dissipation of some potential partial benefits and consequently to negative or equivocal results. Cohorts, as the one studied by Alcalay et al.,14 can provide a novel relevant opportunity since they can incorporate very distinct homogenous groups of patients with apparently a single specific disease etiology that could be ideal for disease-modifying clinical studies. At the present, it is not yet clear how LRRK2 mutations cause neuronal degeneration in Parkinson’s disease. It may eventually be found that it is therapeutically worthwhile to either silence or, by contrast, enhance LRRK2 gene activity. In either case, use of such well-defined cohorts to study novel etiologytargeted treatments may mark a new groundbreaking development in designing disease-modifying studies. Thus, the clinical misfortune of Ashkenazi Jews may lead to a better understanding of basic etiological mechanisms and to the development of new, and hopefully, much more successful, therapeutic strategies in Parkinson’s disease.
References 1.
van Struten J. The Origin of Ashkenazi Jewry: The controversy unraveled. DeGruyter (Publisher), 1st ed, 2011, pp.234.
2.
Behar DM, Thomas MG, Skorecki K, et al. Multiple origins of Ashkenazi Levites: Y chromosome evidence of both near eastern and European ancestries. Am J Hum Genet 2003;73: 768–779.
3.
Biro J. The Jewish bias of the Nobel Prize. www.jambiro.com. Accessed 23 September 2013.
1914
Movement Disorders, Vol. 28, No. 14, 2013
4.
Chavrow J. Ashkenazi Jewish genetic disorders. Fam Cancer 2004; 30:201–206.
5.
Weinstein LB. Selected genetic disorders affecting Ashkenazi Jewish families. Fam Community Health 2007;30:50–62.
6.
Cochran G., Hardy J, Harpending H. Natural history of Ashkenazi intelligence. J Biosoc Sci 2006;38:659–693.
7.
Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601–607.
8.
Lesage S, Durr A, Tazir M, et al. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Eng J Med 2006; 354:422–423.
9.
Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Eng J Med 2006;354:424–425.
10.
Slatkin M. A population-genetic test of founder effects and implications for Ashkenazi Jewish diseases. Am J. Hum Genet 2004;75: 282–293.
11.
Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Eng J Med 2004;351:1972–1977.
12.
Nichols WC, Pankratz N, Marek DK, et al. Mutations in GBA are associated with familial Parkinson’s disease susceptibility and age at onset. Neurology 2009;72:310–316.
13.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–184.
14.
Alcalay R, Mirelman H, Saunders-Pullman R, et al. Parkinson’s disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations. Mov Disord 2013:28:1966–1971.
15.
Healy DG, Falchi M, O’Sullivan SS, et al. Phenotype, genotype and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7:583–590.
16.
Kany JH, Irwin DJ, Chen-Plotkin AS, et al. Association of cerebrospinal fluid ß-amyloid 1–42, T-tau, P-Tau181, and a-synuclein levels with clinical features of drug-na€ıve patients with early Parkinson’s disease. JAMA Neurol 2013;70:1242–1248.
The G2019S LRRK2 Mutation: Another Morbid Burden for Ashkenazi Jews May Provide New Insights on Sporadic Parkinson’s Disease Eldad Melamed, MD* Neurology, Tel Aviv University, Tel Aviv, Israel
As a distinct ethnic group, the roots of Ashkenazi Jews are clearly in eastern, western and Mediterranean Europe. However, its origin in the remote past remains obscure, mythical and controversial with theories ranging from emigration of ancient predecessors from Judea during the reign of the Roman Empire, to conversion to Judaism of a population in the medieval empire of Khazaria located near the Caspian Sea.1,2 Although it has been one of the most persecuted ethnic groups over many generations, this community disproportionately generated many landmark scientific and cultural achievements and constitutes one of the highest ethnic-specific percentage among Nobel Prize winners.3 For many years, this specific population, many of which perished during the holocaust, remained relatively homogenous mainly due to tight religious and intermarriage rules. This led to the accumulation over the years of several very serious hereditary diseases that became common in this particular ethnic group including Tay-Sachs disease, lipid transport/storage disorders such as Niemann-Pick disease and Gaucher’s disease, familial dysautonomia, torsion dystonia and also hereditary breast cancer, familial hypercholesterolemia, and cystic fibrosis.4,5 The homogeneity of this distinct population also facilitated gene mutation discovery in many of the Ashkenaziassociated hereditary disorders. It is even hypothesized that compensatorily, by selection, these multiple disease genes might have contributed to the above-thanaverage intelligence believed to be prevalent in this ethnic group.6 The etiology of Parkinson’s disease is still largely unknown and for many years it has been debated whether it is due mainly to genetic or environmental factors or to a combination of both. It is estimated that in most populations, the disease is mainly spo-
------------------------------------------------------------
*Correspondence to: Dr. Eldad Melamed, Neurology, Tel Aviv University, Sackler School of Medicine, Tel Aviv, 69978 Israel; [email protected] Relevant conflicts of interest=financial disclosures: The author is an Ashkenazi Jew. There are, otherwise, no other conflicts of interest to report. Received: 25 September 2013; Accepted: 7 October 2013 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25728
1912
Movement Disorders, Vol. 28, No. 14, 2013
radic (90%-95%) whereas it is familial only in the minority (5%-10%) In recent years, the pendulum tilted heavily toward the genetic hypothesis with the successive ground-breaking discoveries of several autosomal dominant and recessive monogenic mutations, in patients with familial as well as in those with seemingly sporadic Parkinson’s disease. This included rare or not so common mutations in genes for a-synuclein (missense, duplication, triplication), Parkin,DJ-1 and Pink-1. Another recent breakthrough in the field was the discovery of several mutations in the gene encoding for leucine-rich repeat kinease3 (LRRK2). These mutations can cause autosomal dominant Lewy body positive, levodopa responsive Parkinson’s disease.7 In most populations (European, Asian, North and South Americans), the prevalence of Parkinson’s disease due to these mutations is rather low, ranging between 1%2% of patients or even less. One of the several mutations in LRRK2 is the G2019S. A dramatic and surprising discovery was that this specific mutation and its associated Parkinson’s disease is extremely prevalent in certain ethnic populations,including the North African Berbers8 and, alas again, the Ashkenazi Jews.9 In the latter, the prevalence of the mutation can be as high as 10%-30%, higher in patients with a positive family history and lower in those with none, in both US-American and Israeli Jewish Ashkenazim, respectively, with an age-dependent high penetrance rate. The identification of the mutation founder and time of its emergence are controversial. Some, but not all, suggest that the mutation first originated in the Ashkenazi group, sometime, somewhere in the east of the Mediterranean, whereas others believe that the founder came from the Berbers.10 As if this is not enough, it was found that mutations in the glucocerebrosidase (GBA) gene that cause Gaucher’s disease in Ashkenazi Jews, also act as a susceptibility gene, increasing the risk of developing Parkinson’s disease manifold.11,12 After so many years of research, it is still unknown where in the nervous system, when, and why Parkinson’s disease begins. Even more importantly, it is still unsettled how the neurodegenerative process of the disease progresses within and among various neuronal populations in the central and peripheral (mainly autonomic) nervous systems. Also, what exactly is
L R R K 2
Parkinson’s disease, is a question that repeatedly comes up, with different answers and definitions. Although patients with Parkinson’s disease are not identical and each has his or her own distinctive illness signature, there is, after all, a common clinical pattern which makes it fairly easy to diagnose this disorder premortem with a great degree of accuracy.13 Patients are generally similar (with variations), with regard to presence of motor and nonmotor clinical features, rate of progression, existence of a long preclinical/premotor period occasionally manifested by certain nonmotor features, response to levodopa and pathological findings. It is becoming increasingly evident that Parkinson’s disease is a heterogeneous disorder that can be caused by multiple etiologies that eventually lead to similar clinical and pathological phenotypes. The fact that mutations in different genes can apparently cause a similar disease pattern, (although the mechanisms are not yet clear) may lend support to such a view. Nevertheless, this aspect should be much more vigorously investigated and disease patterns should be compared among various Parkinson’s disease-causing mutations and between those and the sporadic form of the disorder. In this issue of Movement Disorders, the paper by Alcalay et al.14 describes a study design to explore exactly these issues. The authors compared the clinical characteristics of Parkinson’s disease in Ashkenazi Jews from New York, US and Tel Aviv, Israel, who were carriers of the G2019S LRRK2 mutation (n 5 97) and in non-carriers (n 5 391). They rightly excluded (most likely just for the time being) patients with GBA mutations to preserve homogeneity of the studied groups. In general, most of the investigated clinical features in the mutation carriers were similar to those observed in the non-carrier Ashkenazi patients with the sporadic form of the disease. There were some differences, however. For instance, among the carriers, there were more women, more reported first appearance of motor symptoms in the lower limbs, and there was also an increased tendency towards developing the postural instability gait difficulty (PIGD) subtype of the disease. Although this is not the first study of its kind, its strength relates to the larger size and homogeneity of the investigated cohorts. Other studies, such as that of Healy et al.15 have also examined the intriguing potential similarities and differences between LRRK2 mutation carriers and non-carriers with Parkinson’s disease. They had somewhat different findings than the present study, but, in general, the clinical features did not differ much among the groups suggesting that LRRK2 mutations and the yet obscure other causes of Parkinson’s disease can ensue in similar clinical and possibly also pathological phenotypes. The importance of expanding the field and carrying out many more similar studies is quite obvious. Long-term follow-up should be continued in large cohorts of LRRK2 G2019S Ashkenazi car-
M U T A T I O N
riers already with the disease as well as in non-affected family members with and without the mutations. Such cohorts should be compared, if possible, with those of North African Berbers carrying the same mutation as well as with patients carrying other LRRK2 mutations. Cohorts should again be compared to groups of patients with the sporadic form of the disease matched for age of onset, duration, gender and ethnicity. Such observations can provide a host of valuable data, among others on the preclinical period of Parkinson’s disease, patterns and rates of progression, gender, age at onset, life habits, exposure to environmental factors and response patterns to therapeutic interventions. It would be interesting to re-examine in such cohorts whether the clinical phenotype is identical or diverse, even in families carrying identical mutations and begin probing the underlying mechanisms. Since both LRRK2 and GBA mutations are prevalent in Ashkenazim, it would be interesting to expand the cohort and compare diseased and non-diseased G2019S carriers and non-carriers to those with and without GBA mutations. It is tempting to hypothesize that the LRRK2 and other Parkinson-causing mutations, interfere in different checkpoints of linear or parallel cellular pathways that culminate in the accumulation of a-synuclein oligomers or its adducts or of other toxic misfolded proteins that eventually kill the neuron.7 To achieve this information, there should be pathological examinations of brains of patients from such cohorts. In addition, fibroblasts grown from skin biopsies could be converted to induced pluripotent stem cells (iPS) and then, or directly (iN) to neurons (dopaminergic, others?) to facilitate pre-mortem study of cellular disease mechanisms in vitro. Also, there is a recent rekindled interest and thrust in identifying biomarkers for both diagnosis and progression of Parkinson’s disease.16 Such large homogenous mutation-carrying cohorts could play an important role in discovery and/or confirmation of such diseaserelated biomarkers. Finally, there is an additional consideration of utmost importance. Many previous or more recent disease-modifying clinical studies examining the potential benefit of various therapeutic interventions have been unsuccessful or, at best, yielded weak or equivocal results. There could have been many reasons to explain these disappointing repeated failures. One of the major arguments is that patients included in these studies are not homogenous. Although they are all generally considered as having the sporadic form of the disease, there could have been diverse underlying etiologies, some of them even linked to a variety of genetic mutations. This might have resulted in patients having, a priori, different rates of disease progression. Also, the pathogenetic target of the investigated specific disease-modifying intervention could be mechanistically appropriate, if at all, for only a small subgroup of the studied
Movement Disorders, Vol. 28, No. 14, 2013
1913
M E L A M E D
patients leading to dissipation of some potential partial benefits and consequently to negative or equivocal results. Cohorts, as the one studied by Alcalay et al.,14 can provide a novel relevant opportunity since they can incorporate very distinct homogenous groups of patients with apparently a single specific disease etiology that could be ideal for disease-modifying clinical studies. At the present, it is not yet clear how LRRK2 mutations cause neuronal degeneration in Parkinson’s disease. It may eventually be found that it is therapeutically worthwhile to either silence or, by contrast, enhance LRRK2 gene activity. In either case, use of such well-defined cohorts to study novel etiologytargeted treatments may mark a new groundbreaking development in designing disease-modifying studies. Thus, the clinical misfortune of Ashkenazi Jews may lead to a better understanding of basic etiological mechanisms and to the development of new, and hopefully, much more successful, therapeutic strategies in Parkinson’s disease.
References 1.
van Struten J. The Origin of Ashkenazi Jewry: The controversy unraveled. DeGruyter (Publisher), 1st ed, 2011, pp.234.
2.
Behar DM, Thomas MG, Skorecki K, et al. Multiple origins of Ashkenazi Levites: Y chromosome evidence of both near eastern and European ancestries. Am J Hum Genet 2003;73: 768–779.
3.
Biro J. The Jewish bias of the Nobel Prize. www.jambiro.com. Accessed 23 September 2013.
1914
Movement Disorders, Vol. 28, No. 14, 2013
4.
Chavrow J. Ashkenazi Jewish genetic disorders. Fam Cancer 2004; 30:201–206.
5.
Weinstein LB. Selected genetic disorders affecting Ashkenazi Jewish families. Fam Community Health 2007;30:50–62.
6.
Cochran G., Hardy J, Harpending H. Natural history of Ashkenazi intelligence. J Biosoc Sci 2006;38:659–693.
7.
Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601–607.
8.
Lesage S, Durr A, Tazir M, et al. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Eng J Med 2006; 354:422–423.
9.
Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Eng J Med 2006;354:424–425.
10.
Slatkin M. A population-genetic test of founder effects and implications for Ashkenazi Jewish diseases. Am J. Hum Genet 2004;75: 282–293.
11.
Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Eng J Med 2004;351:1972–1977.
12.
Nichols WC, Pankratz N, Marek DK, et al. Mutations in GBA are associated with familial Parkinson’s disease susceptibility and age at onset. Neurology 2009;72:310–316.
13.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–184.
14.
Alcalay R, Mirelman H, Saunders-Pullman R, et al. Parkinson’s disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations. Mov Disord 2013:28:1966–1971.
15.
Healy DG, Falchi M, O’Sullivan SS, et al. Phenotype, genotype and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7:583–590.
16.
Kany JH, Irwin DJ, Chen-Plotkin AS, et al. Association of cerebrospinal fluid ß-amyloid 1–42, T-tau, P-Tau181, and a-synuclein levels with clinical features of drug-na€ıve patients with early Parkinson’s disease. JAMA Neurol 2013;70:1242–1248.
