Movement Disorders Vol. 23, No. 9, 2008, pp. 1205–1210 Ó 2008 Movement Disorder Society
Review
Parkinson’s Disease in Arabs: A Systematic Review Hani T.S. Benamer, PhD, FRCP,1* Rajith de Silva, MD, FRCP,2 Khurram A. Siddiqui, MB, MRCP,3 and Donald G. Grosset, MD, FRCP 4 1
Department of Neurology, Queen Elizabeth Neuroscience Centre, Queen Elizabeth University Hospital, Birmingham, United Kingdom 2 Department of Neurology, Essex Centre for Neurological Sciences, Queen’s Hospital, Romford, Essex, United Kingdom 3 Section of Neurology, Neuroscience Center, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia 4 Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom
Abstract: Studies of specific populations have provided invaluable knowledge about Parkinson’s disease (PD), especially in the field of genetics. The present report systematically reviews the medical literature on PD in Arabs. Medline and Embase were searched, and 24 article were identified: genetic (n 5 17), epidemiological (n 5 3), and clinical series (n 5 5). Both autosomal dominant and recessive forms of inherited PD are described, associated with four genes (Parkin, PINK1, LRRK2, and PARK9). The G2019S LRRK2 mutation is more common in both familial (37–42%) and apparently sporadic PD (41%) in North African Arabs than in Europeans and North Americans (2–3%). The incidence of PD is reported at 4.5 per 100,000 person-
years and reported prevalence at 27 to 43 per 100,000 persons. Hospital-based clinical series suggest that parkinsonism is the commonest movement disorder. Clinical features of PD in Arabs are not significantly different from those reported elsewhere. PD was reported as the cause of dementia in around 7% of Arabs. The majority of studies relate to the role of genes in the etiology of PD in North African Arabs. Further genetic, epidemiological and clinical studies from the majority of Arabic countries may enhance our understanding of PD. Ó 2008 Movement Disorder Society Key words: Parkinson’s disease; parkinsonism; Arabs; genetics; epidemiology
Parkinson’s disease (PD) is a common neurodegenerative disorder, especially in the elderly.1 Environmental and genetic factors may cause the disease, possibly interacting with each other.2 A substantially increased understanding of genetic defects resulting in PD has come from the study of families and populations, largely in ‘‘westernized’’ societies.3 The Arabic countries cover a large geographical area stretching over two continents, Africa and Asia. The
Arab population is estimated at 315 million. Twelve million Arabs live in Europe and North America. Ethnic groups such as Berbers, Kurds, and black Africans form part of Arabic societies.4 Arabic populations are characterized demographically by large family units, high birth rates and high rates of consanguineous marriages, making genetic diseases a common health issue.4 Over the last two decades, living standards and health services have improved in the majority of Arab countries, especially those with oil-based economies. This is expected to increase survival, which might also increase the incidence of PD. In addition to potential research benefits, medical service planning for PD would be facilitated by increased knowledge of PD in these populations. To our knowledge, no previous systematic reviews of PD in Arab populations have been undertaken.
*Correspondence to: Hani TS Benamer, Department of Neurology, Queen Elizabeth Neuroscience Centre, Queen Elizabeth University Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail:
[email protected] Received 11 October 2007; Revised 21 February 2008; Accepted 23 February 2008 Published online 28 April 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22041
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Arabs were defined on a primarily geographic basis for the purpose of this study, as those who live in, or originate from, 23 countries which are members of the Arab league, as follows: Mauritania, Morocco, Algeria, Tunisia, Libya, Egypt, Sudan, Djibouti, Comoros, Somalia, Eritrea, Lebanon, The Palestine territory (Gaza strip and West Bank), Jordan, Syria, Iraq, Saudi Arabia, Qatar, Kuwait, United Arab Emirates, Oman, Bahrain, and Yemen. Publications on PD in Arabs were identified by keywords ‘‘Parkinson’s disease,’’ ‘‘Parkinsonism,’’ ‘‘Paralysis agitans,’’ ‘‘Movement disorders,’’ and ‘‘Tremor’’, combined with ‘‘Arabs,’’ ‘‘Arab countries,’’ ‘‘North Africa,’’ ‘‘Middle East,’’ ‘‘Gulf,’’ and ‘‘Specific Country Names’’ in Medline (1950–2007) and Embase (1974–2007) databases. References in all relevant papers were reviewed for additional publications. Papers published before July 31st, 2007, were included. Only papers written in English were considered, which included all Arabic medical journals (which are invariably published in English). RESULTS Twenty nine published reports (dated 1986–2007) relating to PD in Arabs were identified, of which four case reports were excluded. The 25 reports included5–29 were classified as follows: genetic (n 5 17), epidemiological (n 5 3), and clinical series (n 5 5). Genetic Studies Parkin (PARK2) is reported in two Algerian families,21,23 one Tunisian family,12 and one Saudi family.17 A microdeletion of the Parkin gene (PARK2, 6q25.2-27) was reported in the Tunisian family and pathological examination in one case showed the expected absence of Lewy bodies.12 A deletion of exons 8 and 9 in Parkin was found in one of the Algerian families.21 Leucine-rich repeat kinase 2 (LRRK2, dardarin, or PARK8) is reported in North African countries from Morocco, Algeria, and Tunisia.11,16,18,19,27,28 The frequency of G2019S LRRK2 was very high at 37–41% in North African families and apparently sporadic PD in an Arabic population, when compared with European and American studies (2–3%).16,19,27 The G2019S LRRK2 mutation is also described in patients with apparently sporadic PD in North Africans of Berberian origin.11 The clinical features of patients with PD associated with LRRK2 mutations (with both homozygous and heterozygous G2019S substitutions) were similar
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to those seen in apparently sporadic PD in North African patients.28 PTEN-induced putative kinase 1 (PINK1, Park 6) was reported in Saudi,10 Sudanese,20 and Algerian families.15 A novel mutation, p.A217D, was found as the cause of autosomal recessive early-onset parkinsonism in eight patients from two generations of a Sudanese family20 and a homozygous T313M PINK1 mutation in one Saudi family with four affected members.10 Kufor-Rakeb disease was first described in 1994 in five patients of a consanguineous marriage in a large Jordanian family. All patients had parkinsonian features associated with pyramidal signs, and up-gaze and convergence paralysis. Dementia was present in three subjects. All patients responded to levodopa. Onset was around 13 years of age and autosomal recessive inheritance was proposed.24 Clinical features in the surviving four patients were described in detail.26 Linkage studies identified a locus on 1p36 that was assigned as PARK9, and recently homozygous and compound heterozygous mutations of ATP13A2 at the same locus have been associated with this phenotype.25,30 A mix of autosomal dominant and recessive PD was described in 21 families with PD in Tunisia. No molecular genetic analysis was conducted and the mode of the inheritance was assumed from viewing the pedigrees.13 Genetic studies in Arabs are summarized in Table 1. Epidemiological Studies Three studies report the epidemiology of PD in Arabic countries.6,8,9 One Libyan study was dedicated to PD, while the other two included all neurological disorders. Within a population of 518,745 in Benghazi, Libya, the crude prevalence was 31.4 per 100,000 persons and incidence was 4.5 per 100,000 person-years.8 The prevalence was 285.1 per 100,000 for those more than 50 years of age. The diagnosis of PD was based on two or more cardinal signs from: resting tremor, rigidity, hypokinesia, changes in postural/righting reflexes. Exclusion criteria were not well-defined but ‘‘arteriosclerotic parkinsonism’’ was not considered as an etiological subgroup. In a two-phase door-to-door community study in Thugbah, Saudi Arabia, all Saudi nationals were screened for neurological disorders by trained interviewers using a pre-tested questionnaire in a face-to-face interview.6 A neurologist then evaluated individuals with abnormal responses, and their family members. The study population was 23, 227 of whom only 1.5% were aged over 60 years. The prevalence of PD, based on ‘‘the presence of at least two of the cardinal features of parkinsonism’’ was 27 per 100,000.
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TABLE 1. Genetic studies of familial parkinsonism in Arabs Inheritance
Gene
Population
Number of families
AD
LRRK2 (PARK 8)
North African Arabs (Moroccan, Algerian, Tunisian)18,19 Tunisian16 North African11
Ten (20 patients with ‘‘apparently sporadic’’ PD)
Classic PD
39 (One patient with ‘‘apparently sporadic’’ PD) 38a 18a
Classic PD Classic PD
AD AD
LRRK2 (PARK 8) LRRK2 (PARK 8)
AD AD
LRRK2 (PARK 8) LRRK2 (PARK 8)
AR
Parkin (PARK 2)
Tunisian27 North African (Moroccan, Algerian, Tunisian)28 Tunisian12
AR AR AR AR
Parkin (PARK 2) Parkin (PARK 2) Parkin (PARK 2) PINK1 (PARK 6)
Algerian23 Algerian21 Saudi17 Saudi10
1 1 1 1
AR
PINK1 (PARK6)
Sudanese20
1
AR AR
PINK1 (PARK 6) ATP13A2 (PARK9)
Algerian15 Jordanian24–26
1 1
1
Clinical phenotype
Not stated Classic PDb Juvenile (age of onset 21–34) parkinsonism, good response to levodopa. No Lewy body in postmortem of one patient Similar to early onset PD Similar to early onset PD Young onset PD with dystonia Young onset (28–34), bradykinesia, tremor, dystonia, good response to levodopa Young onset (9–17), bradykinesia, dystonia, good response to levodopa Age of onset of 40, classic PD Age of onset of 13, levodopa-responsive parkinsonism, pyramidal and cognitive dysfunction, supranuclear gaze palsy (5Kufor-Rakeb syndrome)
a
The families were reported in previous studies. This study was mainly reporting the clinical features of patients with PD related to G2019S LRRK2.
b
Drug-induced and postencephalitic parkinsonism were excluded as well as cases with supranuclear palsy. In Kelibia, Tunisia, the two-phased World Health Organization protocol for common neurological conditions was used.9 The first phase involved a questionnaire and screening. The instrument is not specific to PD, but includes one question on tremor and two relating to bradykinesia. A neurologist examined persons who screened positive but specific diagnostic criteria for PD were not defined. In a population of 34, 874, the prevalence of PD was 43 per 100,000, which increased to 68 per 100,000 when age-adjusted to the world population. Clinical Series There are five clinical series, two dedicated to PD,5,29 one for movement disorders7 and two others mainly for dementia.14,22 The clinical spectrum and electrophysiological responses in 54 patients with PD attending a university hospital in Saudi Arabia were described.5 PD was diagnosed from two or more cardinal signs. Supported by a detailed table of clinical symptoms and signs, the authors concluded that ‘‘the clinical characteristics of PD in Saudi patients are not significantly different from those reported for patients elsewhere.’’ Forty-three Egyptian patients with PD and
37 normal volunteers were subjected to detailed clinical, neuropsychological, neurophysiological, and radiological study.29 Patients with PD were assessed by the following: Hoehn & Yahr staging, Schwab & England scale, and the Unified PD Rating Scale. Both global and specific cognitive function tests were applied. Event-related evoked potentials/P300 component were measured. All study subjects had brain computed tomography. The study found that neither global nor specific cognitive functions were related to duration, severity of motor disability or depression. P300 latency was prolonged in patients with PD compared with controls. In a retrospective hospital, review of movement disorder cases referred to a Saudi university hospital, PD was the commonest movement disorder (90%), the others being progressive supranuclear palsy, Wilson’s disease, multiple system atrophy, and drug-induced/ vascular parkinsonism. In two hospital-based studies of cases of dementia, PD was the cause in 7.8% of patients in Saudi Arabia22 and 6% in Qatar.14
DISCUSSION Familial PD, both autosomal dominant and recessive, is described in Arabs.13 Mutations in four genes
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(Parkin, PINK1, LRRK2, and PARK9) have been associated with PD in Arabic families.10,12,15–21,23–26 Nearly all families are from North African Arabic countries (Morocco, Algeria, Tunisia)12,15,16,18,19,21,23 with only one family from Sudan,20 two from Saudi Arabia10,17 and one from Jordan.24–26 The G2019S mutation in the LRRK2 gene is consistently more frequent in North African Arabs than in Europeans and North Americans with PD, whether familial or apparently sporadic, suggesting a significant genetic contribution to the causation of PD in this population.16,18,19,27,31 The same mutation of LRRK2 is also present at a relatively high frequency in Ashkenazi Jews (30% in familial PD and 13% in apparently sporadic PD),32 implicating a common founder effect for the mutation, possibly dating back to the 13th century.33 Alternatively, two separate founding events (coinciding with the Jewish Diasporas some 2250 years ago (586 BC to 70 AD) have been suggested.34 A founding haplotype shared by Tunisian, North American, European, and Middle Eastern countries has been identified.27 The relatively high prevalence of LRRK2associated PD among North African Arabs may, however, be contributed by ascertainment bias, if family members manifesting parkinsonian features are more likely to seek medical attention when first degree relatives are affected, compared to patients with ‘‘apparently sporadic’’ PD in relatively deprived communities, who may never reach medical attention. The apparent high frequency of G2019S LRRK2 mutations in apparently sporadic cases in this population may also be artifactual, at least in part. No comment can be made about those subjects who are firstdegree relatives and are reported without clinical evaluation (which should preferably be undertaken by movement disorder specialists). Given the age-dependent penetrance of LRRK2-associated PD, death at a relatively young age could also underestimate the prevalence of PD in subjects’ parents. Consequently, further studies of G2019S LRRK2 in other Arabic populations (especially in Egypt and Saudi Arabia) are warranted. The large extended families and consanguineous marriages (up to 50% of marriages in Arabic families are between first cousins6) provide a unique opportunity for further genetic research, exemplified by the original description of Kufor-Rakeb disease in a consanguineous Arabic family.24,26 There is only one incidence study in Arab countries, which suggests that the incidence of PD is less than that found in many other populations. The incidence of 4.5 per 100,000 person-years in Benghazi, Libya, a
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south Mediterranean city,8 compares with 10 per 100,000 in Ferrara, North Italy,35 and elsewhere in Europe, United States, and Japan rates range from 10 to 19 per 100,000.36–41 However, study design and diagnostic criteria, as well as genetics, age distribution, and environment could all affect these figures. The prevalence of PD among Arabs (27–43 per 100,000 persons)6,8,9 is higher than in Black Africans (Nigeria 10 per 100,000, Ethiopia 7 per 100,000, Togo 20 per 100,000)42–44 and Chinese (18 per 100,000).45 It is lower than in developed countries (more than 100 per 100,000).1,38,46 However, adjustment of prevalence figures according to demographics of a comparator population increased the raw rate of 31.4 per 100,000 in Benghazi, Libya8 to 60.1 per 100,000, which is much closer to that of the Sardinian population at 65.5 per 100,000, and this might indicate common factors for populations in the Mediterranean area.47 Prevalence estimates are subject to many influences, but even studies with similar methodology have shown highly variable rates, e.g., twice as high in the Faroe Islands compared with the Island of Als, Denmark.48 Further studies in different areas of the Arab world, as well as studies on other ethnic groups living in Arab countries such as the Berbers and Kurds, could help to determine geographic and racial susceptibility to PD. Presenting features, disease stage, and follow-up were not described in detail except in the only clinical series from an Arab country, with 54 patients.5 The data on subtypes of parkinsonism are very limited and are exclusive to hospital cases.7 The proportions of PD cases in Arab patients with dementia have been described,14,22 but the prevalence of dementia in patients with PD in these populations is not known. Longer-term prospective studies are needed in Arab countries to determine whether the clinical presentation, progression and prognosis are similar to other parts of the world. In conclusion, there are significant opportunities for further epidemiological, genetic, and natural history studies in PD in Arab countries. Clinical presentation, drug responsiveness, nonmotor features, duration of illness, socioeconomic status, and quality of life studies are very limited. Studies in differing ethnic groups living in the Arab countries such as Berbers, Kurds, and Blacks are needed. No data are available on PD in Arab-Americans. Such studies are likely to enrich our knowledge about PD and parkinsonism, including the interplay between genetic and environmental factors. Acknowledgment: There are no conflicts of interest relating to this article.
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