SIX PARK GENES EXPLAINING FAmilial

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1 ORIGINAL CONTRIBUTION Clinical Features of Parkinson Disease Patients With Homozygous Leucine-Rich Repeat Kinase 2 G2019S Mutations Lianna Ishihara, MPhil; Liling Warren, PhD; Rachel Gibson, PhD; Rim Amouri, PhD; Suzanne Lesage, PhD; Alexandra Dürr, MD, PhD; Meriem Tazir, MD; Zbigniew K. Wszolek, MD; Ryan J. Uitti, MD; William C. Nichols, PhD; Alida Griffith, MD; Nobutaka Hattori, MD, PhD; David Leppert, MD; Ray Watts, MD; Cyrus P. Zabetian, MD, MS; Tatiana M. Foroud, PhD; Matthew J. Farrer, PhD; Alexis Brice, MD; Lefkos Middleton, MD; Faycal Hentati, MD Background: The G2019S mutation is the most common pathogenic substitution in the leucine-rich repeat kinase 2 (LRRK2) gene, which has recently been identified in familial and sporadic Parkinson disease (PD). Objectives: To report the clinical characteristics of PD patients with homozygous LRRK2 6055G A (G2019S) mutations and to compare them with previously published descriptions of heterozygous patients. Design: Descriptive clinical report from an international consortium of studies. Subjects: Patients with familial PD and homozygous LRRK2 mutations included 23 Tunisians, 2 Algerians, 2 US patients, 1 Canadian, and 1 Moroccan. Results: There were no observable differences between the homozygote and heterozygote phenotypes. Conclusions: Parkinson disease related to LRRK2 is characterized by typical clinical features, and the similarities between patients with homozygous and heterozygous mutations do not support a gene dosage effect. Arch Neurol. 2006;63: Author Affiliations are listed at the end of this article. SIX PARK GENES EXPLAINING FAmilial Parkinson disease (PD) have been identified, with much interest in the most recently identified leucine-rich repeat kinase 2 gene (LRRK2). Parkinson disease associated with LRRK2 has an autosomal dominant pattern of inheritance; however, many patients with LRRK2 G2019S substitutions do not have a family history of PD. The clinical and neuropathological features appear to be indistinguishable from those of sporadic PD. 1,2 Twenty pathogenic or putative pathogenic mutations have been identified in familial and sporadic parkinsonism, and 6055G A (G2019S) is the most common. 3-6 The G2019S mutation has been found in various populations across the world, but homozygous substitutions appear to be very rare. 4,5,7-16 This report presents the clinical features of homozygotes and compares them with the clinical phenotype of LRRK2 G2019S heterozygotes in published literature. 8 METHODS We recruited patients with PD (hereafter referred to as PD patients) from the following sites: the Institut National de Neurologie in Tunis, Tunisia; Groupe Hôpital de la Pitié-Salpêtrière in Paris, France; the Service de Neurologie at the Centre Hospitalier Universitaire Mustapha in Algiers; the Departments of Neurology and Neurosciences at the Mayo Clinic, Jacksonville, Fla; 59 Parkinson Study Group centers in the United States and Canada, including Indiana University, Indianapolis; and the Department of Neurology at University of Washington School of Medicine and collaborating medical centers in Kirkland and Seattle. Parkinson disease was diagnosed using United Kingdom PD Society Brain Bank criteria. 17 Family history and demographic information were collected and neurological examinations were completed for all family members. Results of the Mini-Mental State Examination and clinical examination were used to assess cognitive function. In Tunisia, owing to a high prevalence of illiteracy, the Mini- Mental State Examination may not be a valid measure; therefore, the presence of cognitive impairment was judged only by neurologist assessment. 18 The study sites obtained local ethics committee or investigational review board approval before beginning subject recruitment. Subjects were informed of all aspects pertaining to their participation in the study, and they gave written or proxy consent. After the first G2019S-homozygous patient was described, this international consortium was formed by one of us (Z.K.W.). Genotyping of all subjects for LRRK2 6055G A (G2019S) was performed by means 1250

2 Table 1. Individuals Who Underwent Screening for LRRK2 6055G A (G2019S) Mutation Group France* United States Tunisia Arab European Florida Washington Canada/USA No. of PD patients No. (%) male 110 (53) 54 (51) 98 (56) 1122 (59) 302 (81) 633 (59) Age, mean ± SD, y At onset of disease 51.9 ± ± ± 15.7 NA 58.2 ± ± 12.9 At examination 62.3 ± ± ± ± ± ± 11.7 No. of unaffected subjects Age at examination, mean ± SD, y 53.4 ± ± ± 9.5 NA 64.8 ± ± 10.4 No. of families Abbreviations: LRRK2, leucine-rich repeat kinase 2 gene; NA, not available; PD, Parkinson disease. *The French group had Arab and European study populations. The unaffected individuals in this study were unrelated healthy controls, not family members. Includes a total of 59 Parkinson Study Group centers in the United States and Canada, including Indiana University, Indianapolis. Table 2. Demographic Characteristics of Individuals With LRRK2 G2019S Homozygous Substitutions Patient No. Family No. Study Current Age, y Sex Ancestral Country Ethnicity 1 T1 Tunisia 47 F Tunisia AB 2 T2 Tunisia 66 M Tunisia AB 3 T3 Tunisia 63 F Tunisia AB 4 T3 Tunisia 67 F Tunisia AB 5 T4 Tunisia 72 M Tunisia AB 6 T5 Tunisia 75 F Tunisia AB 7 T5 Tunisia 76 M Tunisia AB 8 T6 Tunisia 45 F Tunisia AB 9 T7 Tunisia 73 M Tunisia AB 10 T8 Tunisia 68 F Tunisia AB 11 T9 Tunisia 42 M Tunisia AB 12 T10 Tunisia 69 M Tunisia AB 13 T11 Tunisia 72 M Tunisia AB 14 T12 Tunisia 58 F Tunisia AB 15 T12 Tunisia 58 F Tunisia AB 16 T13 Tunisia 75 F Tunisia AB 17 T14 Tunisia 47 M Tunisia AB 18 T14 Tunisia 44 M Tunisia AB 19 T15 Tunisia 73 F Tunisia AB 20 T15 Tunisia 87 F Tunisia AB 21 F1 France 72 F Algeria AB 22 F2 France 69 M Algeria AB 23 F3 France 68 F Morocco AB 24 US1 Mayo Clinic, Jacksonville, Fla 74 M Ukraine, Poland White 25 US2 Seattle, Wash 66 (D) M Russia Ashkenazi Jewish 26 Canada* Canada and Indiana 73 M NA White Abbreviations: AB, Arab Berber; D, dead; LRRK2, leucine-rich repeat kinase 2 gene; NA, not available. *Recruited through the Parkinson s Research: the Organized Genetics Initiative study. of direct sequencing of exon 41 of the LRRK2 gene (in France 16 and Washington 7 ) and a modification of the single base chain extension assay previously described. 19 Details of all subjects undergoing screening are presented in Table 1. RESULTS The homozygous LRRK2 6055G A mutation was identified in 26 PD patients from the following 5 studies: 20 Tunisians (11 women and 9 men in 15 families), 2 Algerians (1 man and 1 woman in 2 families), 16 2USmen (2 families), 1 Canadian man, and 1 Moroccan woman. Demographic and clinical characteristics are presented in Table 2 and Table 3, respectively. One of the US patients was of Ukrainian and Polish descent, and the other was of Ashkenazi Jewish descent. The ethnicity of all Tunisian, Algerian, and Moroccan patients was Arab Berber. Three Tunisian clinically unaffected individuals (1 man and 2 women) were homozygous for the mutation. Their 1251

3 Table 3. Clinical Characteristics of Individuals With LRRK2 G2019S Homozygous Substitutions Patient No. Initial Symptoms PD Type AAO, y Bradykinesia Rigidity Rest Tremor Postural Instability Response to Levodopa Predominant Side 1 NA NA 42 NA NA NA 2 Tremor MD 48 NA R 3 Loss of gait, balance MD 58 NA L 4 Tremor TD 60 NA L 5 Tremor MD 66 NA L 6 Loss of gait, balance AR 57 NA L 7 Tremor MD 72 NA R 8 Loss of gait, balance AR 40 NA NA R 9 Tremor MD 58 NA R 10 Tremor MD 53 NA R 11 Loss of dexterity AR 30 NA NA R 12 NA NA 70 NA NA NA NA 13 Loss of gait, balance MD 60 NA L 14 Tremor MD 60 NA R 15 Tremor MD 55 NA R 16 Tremor MD 60 NA R 17 Loss of gait, balance MD 40 NA R 18 Tremor MD 40 NA L 19 Tremor MD 60 NA L 20 Tremor MD 82 NA L 21 Rest tremor, rigidity NA 56 L 22 Akinesia, rest tremor NA 54 L 23 Rest tremor in left foot NA 62 L 24 Shuffle gait, slurred speech NA 55 L 25 Rest tremor, bradykinesia NA 62 R 26 Slow gait NA 58 L Abbreviations: AAO, age at onset; AR, kinetic-rigid; L, left; LRRK2, leucine-rich repeat kinase 2 gene; MD, mixed tremor/rigidity dominant; NA, not available; PD, Parkinson disease; R, right; TD, tremor dominant;, present;, absent. ages at examination were 42, 45, and 70 years, and their neurological findings were normal. Patient medical history was available for most cases. None had a history of encephalitis or meningitis. A head injury was reported only by the Canadian patient; however, this information was not specifically requested in the Tunisian questionnaire. Hypertension was reported by US patient 24 and Tunisian patients 3, 4, and 6. Diabetes was reported by French patient 23, US patient 25, and 16 patients from Tunisia. Patients were asked whether they had any additional neurological disorders, and only US patient 25 reported peripheral neuropathy. Family history of PD was reported by all patients except French patients 22 and 23, with missing information. Few patients reported other neurological diseases in their families. French patient 23 had a sister with multiple sclerosis. Both parents of US patient 25 had dementia. The US patient 24 had one son with epilepsy and another with schizophrenia and autism. Tunisian patients 15, 17, and 18 had relatives with essential tremor. The clinical characteristics of PD appeared to be similar among the cases from different study populations (Table 3). The mean age at onset was 56 years, ranging from 30 to 82 years, with both extreme values in Tunisian patients. All individuals reported the presence of bradykinesia and rigidity, and all except for 4 Tunisian patients, US patient 24, and Canadian patient 26 reported resting tremor. Of 24 patients reporting their initial PD symptoms, 16 reported tremor or tremor and another symptom. The second most common presenting symptom was a change in gait, reported by 7 patients. Tunisian patients 4, 16, and 18 and US patient 25 reported postural tremor. All patients showed asymmetry of symptoms, but the predominant side was divided almost equally among the 24 responses (11 right and 13 left). Of those patients for whom the information was available, all reported a positive response to levodopa therapy. Cognitive and psychiatric data were collected from clinical observations and by using the Mini-Mental State Examination. French patient 22 and Canadian patient 26 had Mini- Mental State Examination scores within the reference range. In general, there were no indications of cognitive impairment, depression, anxiety, or psychiatric abnormalities in any of the homozygous patients, with the exception of mild memory difficulty in US patient 24. Imaging data were available from 15 patients. French patient 21 and US patient 24 had normal findings on computed tomographic scans, and 13 Tunisian patients had normal magnetic resonance imaging results. As of the last follow-up, pathological evaluations were not available for any patients. COMMENT Herein we report the clinical characteristics for individuals with homozygous LRRK2 G2019S substitutions. The patients were identified from various international studies, but the characteristics appear to be relatively consistent across studies, despite ethnic differences. The large 1252

4 number of patients with the homozygous mutation in Tunisia is likely owing to the high proportion of consanguineous marriages. Eleven (T1-T4, T6-T10, T14, and T15) of 15 Tunisian families and French patients 22 and 23 had consanguinity. The US patient 25 was of Ashkenazi Jewish descent, which is believed to have a higher prevalence of this substitution. 20 The homozygous clinical phenotype is similar to that of sporadic PD and PD with heterozygous G2019S substitutions. Asymmetry is a key element in the diagnosis of PD. All patients had asymmetric onset of various presenting symptoms, but most often tremor. We found no obvious male or female preponderance. Of the main cardinal signs of PD, rigidity and bradykinesia were present in all patients, and rest tremor was present in most of the patients. These characteristics of homozygous patients were comparable with those of the heterozygous patients in various populations who presented most often with asymmetric tremor and also bradykinesia, gait disturbance, rigidity, or micrographia. 4,7,8,10-12,14,15,21-30 Patients with heterozygous substitutions reported the presence of bradykinesia, resting tremor, and rigidity in all or most cases. The age at onset in homozygous patients ranged from 30 to 82 years, with both extremes in the Tunisian population. The age at onset in heterozygous patients ranged from 28 to 86 years, and encompassed a similarly wide range of values. 8,10-12,14,15,21-31 With the exception of 1 patient for whom the information was not available, all of the homozygous patients reported positive responses to levodopa, and most of the heterozygous patients in the literature also reported positive or unknown responses, with the exception of 13 patients from 2 studies. 14,26 One difference that has been noted is the presence of dementia or cognitive decline in a number of the heterozygous patients, but not in the homozygous patients. 4,8,12,15,22,27 This difference may be owing to the small number of patients with homozygous mutations compared with heterozygous mutations. Overall, we did not find any major clinical differences between PD patients with homozygous and those with heterozygous LRRK2 G2019S substitutions. This finding does not support a gene dosage effect. Accepted for Publication: March 2, Author Affiliations: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England (Ms Ishihara); Research and Development, GlaxoSmithKline, Greenford, England (Drs Warren, Gibson, Leppert, and Middleton); Service de Neurologie, Institut National de Neurologie, Tunis, Tunisia (Drs Amouri and Hentati); Neurology and Experimental Therapeutics, Institut National de la Santé etdelarécherche Médicale U679 (Drs Lesage, Dürr, and Brice), Département de Neurologie (Drs Lesage, Dürr, and Brice) and Département de Génétique, Cytogénétique et Embryologie (Drs Dürr and Brice), Groupe Hôpital de la Pitié- Salpêtrière, Assitance Publique-Hôpitaux de Paris (AP- HP), Faculté de Médecine, Université Pierre et Marie Curie (Drs Lesage, Dürr, and Brice), and Fédération de Neurologie, Centre Hospitalier Universitaire (CHU) Pitié- Salpêtrière, AP-HP (Drs Dürr and Brice), Paris, France; Service de Neurologie, CHU Mustapha, Algiers, Algeria (Dr Tazir); Departments of Neurology (Drs Wszolek and Uitti) and Neuroscience (Dr Farrer), Mayo Clinic Jacksonville, Jacksonville, Fla; Division of Human Genetics, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio (Dr Nichols); Booth Gardner Parkinson s Care Center, Evergreen Hospital Medical Center, Kirkland, Wash (Dr Griffith); Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan (Dr Hattori); Department of Neurology, University of Alabama at Birmingham (Dr Watts); Department of Neurology, University of Washington School of Medicine (Dr Zabetian), and Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System (Dr Zabetian), Seattle; and Department of Medical and Molecular Genetics, Indiana University Medical Center, Indianapolis (Dr Foroud). Correspondence: Lianna Ishihara, MPhil, Department of Public Health and Primary Care, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2SR, England (L.Ishihara.01@cantab.net). Author Contributions: Study concept and design: Ishihara, Warren, Gibson, Amouri, Wszolek, Hattori, Watts, Farrer, Middleton, and Hentati. Acquisition of data: Gibson, Amouri, Lesage, Dürr, Tazir, Wszolek, Uitti, Nichols, Griffith, Watts, Zabetian, Foroud, Brice, and Hentati. Analysis and interpretation of data: Ishihara, Warren, Gibson, Lesage, Dürr, Wszolek, Uitti, Leppert, Watts, Zabetian, Farrer, and Brice. Drafting of the manuscript: Ishihara, Gibson, Hattori, Leppert, and Watts. Critical revision of the manuscript for important intellectual content: Ishihara, Warren, Gibson, Amouri, Lesage, Dürr, Tazir, Wszolek, Uitti, Nichols, Griffith, Watts, Zabetian, Foroud, Farrer, Brice, Middleton, and Hentati. Statistical analysis: Ishihara and Warren. Obtained funding: Gibson, Dürr, Watts, Zabetian, Brice, and Middleton. Administrative, technical, and material support: Ishihara, Warren, Gibson, Lesage, Tazir, Wszolek, Griffith, Hattori, Watts, Zabetian, Foroud, and Farrer. Study supervision: Gibson, Wszolek, Uitti, Nichols, Hattori, Leppert, Watts, Zabetian, and Brice. Financial Disclosure: Ms Ishihara has received a graduate stipend from GlaxoSmithKline. Drs Wszolek and Farrer have a patent pending for the discovery of the G2019S LRRK2 mutation. Funding/Support: The Tunisian PD study was supported by GlaxoSmithKline (Ms Ishihara and Drs Warren, Gibson, Amouri, Leppert, Watts, Middleton, and Hentati). The French Parkinson s Disease Genetics Study Group was supported by contract 4CH03G from Cohortes et Collections 2001 Institut National de la Santé et de la Récherche Médicale and the French Ministry of Research and Technology, European Union Contract LSHM-CT /APOPIS from the European commission; grant NS A1 from the Association France-Parkinson and the National Institutes of Health, and ANR-05-NEUR-019 from the Agence Nationale de la Recherche (Drs Lesage, Dürr, Tazir, and Brice). The Mayo Clinic Jacksonville study was also supported by the National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, and M. K. Udall Parkinson s Disease Center of Excellence grant P50NS (Drs Wszolek, Uitti, and Farrer); by grant 1253

5 R01 NS for the Parkinson s Research: the Organized Genetics Initiative study (Drs Foroud and Nichols); and by grant K08-NS from the National Institutes of Health, American Parkinson Disease Association, and a merit review award from the Department of Veterans Affairs (Dr Zabetian). Acknowledgment: We thank all of the patients and families and the supporting staff at each site. Additional Information: A summary table of studies used to characterize patients with PD and heterozygous G2019S substitutions is available at /~lsi20/hetero_table.doc or by contacting the corresponding author. REFERENCES 1. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomaldominant parkinsonism with pleomorphic pathology. Neuron. 2004;44: Ross OA, Toft M, Whittle AJ, et al. LRRK2 and Lewy body disease. Ann Neurol. 2006;59: Berg D, Schweitzer K, Leitner P, et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson s disease. 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