Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism

RESEARCH LETTERS

Tylenol use

Deaths*

Personyears

Age-adjusted RR (95% CI)

Multivariate adjusted† RR (95% CI)

Nonuser Current user

1337 236

5894 207 1320 235

1·00 (--------) 0·97 (0·84–1·11)

1·00 (--------) 0·98 (0·85–1·13)

Frequency Occasional 1–14 month 15–29 month 30+ month

127 87 14 8

683 869 502 729 59 951 63 686

0·98 (0·82–1·18) 0·99 (0·79–1·23) 1·24 (0·73–2·09) 0·53 (0·26–1·06)

0·99 (0·83–1·19) 1·00 (0·80–1·24) 1·27 (0·75–2·15) 0·55 (0·27–1·09)

Duration <10 years ⭓10 years

157 79

879 794 430 441

0·94 (0·80–1·11) 1·03 (0·82–1·29)

0·95 (0·81–1·12) 1·04 (0·83–1·31)

*Excludes women with prevalent cancer. †Adjusted for age, race, age at menarche, menopausal status/age at menopause, parity, tubal ligation, years of oral contraceptive use, years of ERT use, and family history of breast and/or ovarian cancer.

Risk of ovarian cancer mortality according to reported use of paracetamol. Cancer Prevention Study II, 1982–1994

listed was “Tylenol”. The other categories included aspirin, vitamins, tranquillisers, and medications for specific medical conditions. Mortality follow-up was completed through December 31, 1994.4 At the end of 12 years follow-up, 1573 ovarian cancer deaths were observed among 616 189 women who were cancer free at study entry. Cox proportional hazards modelling was used to compute rate ratios (RR) and to adjust for age, race, age at menarche, menopausal status, parity, history of tubal ligation, duration of oralcontraceptive use, duration of oestrogen replacement therapy, and family history of breast and/or ovarian cancer. Overall, 11 482 (35·5%) women reported using paracetamol in the month before enrolment; of those 5731 (5%) had used it daily. Ovarian cancer death rates were not significantly different between women reporting current paracetamol use and those reporting no use (RR=0·98, 95% CI=0·85–1·13) (table). Women who reported using paracetamol daily had a 45% lower death rate from ovarian cancer than women reporting no use (RR=0·55, 95% CI=0·27–1·09). No further trend of lower risk with increasing frequency of use was observed. The decreased risk of ovarian cancer mortality observed in this cohort among women taking paracetamol daily is not inconsistent with the protective effect observed by Cramer et al.1 However, chance, confounding, or bias cannot be ruled out as a possible explanaton for the finding. In our cohort the association was observed only among women taking the medication daily and was based on few cases (eight deaths among daily users). No dose-response trend was observed with increasing frequency of duration of use. One limitation of our study is that medication intake was established at enrolment and may not precisely reflect exposure at the time of the disease occurrence. However, the prospective design of our study and the exclusion of women with cancer at baseline minimised the potential that disease status might bias reported use of paracetamol. 1

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Cramer DW, Harlow BL, Titus-Ernstoff L, Bohlke K, Welch WR, Greenberg ER. Over-the-counter analgesics and risk of ovarian cancer. Lancet 1998; 351: 104–07. National Toxicology Program. Toxicology and carcinogenesis studies of acetaminophen (CAS No 103-9-2) in F344?N rates and B6C3F1 mice (feed studies). Technical report series no 394. NIH publication no 93-2849, Research Triangle Park, North Carolina, USA, 1993. Garfinkel L. Selection, follow-up and analysis in the American Cancer Society prospective studies. In: Selection, follow-up, and analysis in prospective studies: a workshop. National Cancer Institute monograph 67. Washington, DC: Government Printing Office, 1985: 49–52. (NIH publication no 85-2713). Calle EE, Terrell DD. Utility of the National Death Index for ascertainment of mortality among Cancer Prevention Study II participants. Am J Epidemiol 1993; 137: 235–41.

Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA 30329-4251, USA (C Rodriguez)

THE LANCET • Vol 352 • October 24, 1998

Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism C B Lücking, N Abbas, A Dürr, V Bonifati, A-M Bonnet, T de Broucker, G De Michele, N W Wood, Y Agid, A Brice, for The European Consortium on Genetic Susceptibility in Parkinson’s Disease and The French Parkinson’s Disease Genetics Study Group

Autosomal recessive juvenile parkinsonism (ARJP), a monogeneic form of parkinsonism, was first described in Japan.1 ARJP is characterised by the typical signs of parkinsonism (rigidity, tremor, akinesia), a striking response to levodopa, and onset before the age of 40 years. Dystonia, especially of the lower limbs, and early, severe levodopainduced dyskinesias are common. After genetic mapping of an ARJP gene locus (PARK2) to chromosome 6q25.2-q27,2 PARK2-linked families were found in America, Europe, the Middle East, and North Africa.3,4 Kitada and colleagues5 reported Japanese ARJP families with deletions of either exon 4 or exons 3–7 of a new gene of unknown function designated parkin. To determine the frequency of this type of mutation and the corresponding phenotype, we searched for homozygous deletions in the parkin gene in 12 PARK2-linked ARJP families with known or suspected consanguinity (total 32 patients). The families originated from Italy (n=5), France (n=4), the Netherlands (n=1), Portugal (n=1), and Algeria (n=1). Informed consent was received from all patients examined. Six of the families were previously described.4 The inclusion criteria were: clinical parkinsonism with a good response to levodopa (except in four untreated cases); onset of disease before the age of 45 in at least one family member; inheritance compatible with autosomal recessive transmission; cosegregation of the disease with four microsatellite markers closely linked to the PARK2 locus (D6S1579, D6S411, D6S1550, D6S305); and known consanguinity (n=6), or homozygosity for at least two adjacent markers, or both. We amplified the 12 coding exons by PCR with published primers.5 In some families, an additional pair of exon 3 primers was used that yielded a 243 bp product: Ex3innerFor (5'AATTGTGACCTGGATCAGC-3') and Ex3innerRev (5'-CTGGACTTCCAGCTGGTGGTGAG-3'). The annealing temperature was 55ºC for all primers, except for Ex 1 and Ex3outer (59ºC). We found two novel homozygous deletions in eight patients from three families (figure). The Algerian family (FR-001) carried a deletion of exons 8 and 9, which corresponds to the previously shown deletion of microsatellite markers D6S411, D6S1550, AFMA155TD9, AFMB281WF1, and of the STS WI4940 at the PARK2 locus.4 Deletions of exon 3 were found in one French BL (FR-024) and one Portuguese family (FR-711, figure). Deletions in the parkin gene therefore led to autosomal recessive parkinsonism in only a quarter of the PARK2linked families with known or suspected consanguinity, which suggests that point mutations may be more common. Mean age at onset was similar in the deleted and nondeleted families (29 [SD 16] vs 35 [9] years), as was clinical severity assessed by the Hoehn and Yahr score (table available from the authors and The Lancet). The overall clinical features were also similar in both groups, except that patients with exon 3 deletions had significantly lower frequencies of tremor than the non-deleted patients (one of five vs 19 of 23, p<0·005), a significantly later mean age at

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RESEARCH LETTERS

leading to a shorter truncated protein, since these patients are more severely affected. The exon 8–9 deletion is, however, associated with earlier age at onset, as if the less truncated protein results in an additional toxic effect. Further phenotype and genotype correlations in patients with different types of mutations will help to clarify this question. The phenotypes associated with ARJP varied according to the location of the two new deletions, but, in some families, could not be distinguished from that of other putative mutations of the parkin gene that might be more frequent. This study was supported by the AP-HP, the Association FranceParkinson, and the European Community Biomed 2 (BMH4CT960664). We would like to thank the other members of the European Consortium on Genetic Susceptibility in Parkinson’s Disease (J R Vaughan, UK; M Martinez, J Feingold, France; T Gasser, B Müller-Myhsok, Germany; M Breteler, S Harhangi, B Oostra, Netherlands; E Fabrizio, G Meco, G Volpe, A Filla, Italy) and of the French Parkinson’s Disease Genetics Study Group (M Vidailhet, S Medjbeur, J Tassin, C Penet, M Borg, E Broussolle, A Destée, F Durif, J Feingold, G Fénelon, J-R Fève, M Martinez, P Pollak, O Rascol, F Tison, C Tranchant, J-M Warter, M Vérin, F Viallet). 1

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Ishikawa A, Tsuji S. Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology 1996; 47: 160–66. Matsumine H, Saito M, Shimoda Matsubayashi S, et al. Localisation of a gene for an autosomal recessive form of juvenile parkinsonism to chromosome 6q25.2-27. Am J Hum Genet 1997; 60: 588–96. Jones AC, Yamamura Y, Almasy L, et al. Autosomal recessive juvenile parkinsonism maps to 6q25.2-q27 in four ethnic groups: detailed genetic mapping of the linked region. Am J Hum Genet 1998; 63: 80–87. Tassin J, Dürr A, de Broucker T, et al. Chromosome 6-linked autosomal recessive early-onset parkinsonism: linkage in european and algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family. Am J Hum Genet 1998; 63: 88–94. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392: 605–08.

INSERM U 289, Hôpital de la Salpêtrière, 75651 Paris, Cedex 13, France (A Brice; e-mail [email protected]); Dipartimento di Scienze Neurologiche, Università La Sapienza, Rome, Italy; Service de Neurologie, Hôpital Casanova, Saint Denis, France; Dipartimento di Scienze Neurologiche, Università Federico II, Naples, Italy; and Institute of Neurology, Queen Square, London, UK

Epidemic of malaria in north-eastern Kenya Vincent Brown, Mohamed Abdir Issak, Maria Rossi, Philipe Barboza, André Paugam

Homozygous exon deletions in three families with known or suspected consanguinity Bands (PCR products) correspond to the numbered individuals. Black squares (men) and circles (women) represent affected individuals. Age at onset (in years) is indicated above the patient’s symbol. Barred symbols indicate deceased individuals. The number of unaffected sibs not analysed is given in diamonds. Ex=exon, i=inner, o=outer.

onset than those with exon 8–9 deletions (39 [11] vs 13 [6] years, p<0·01), and a trend towards greater severity for similar disease durations (Hoehn and Yahr score: 3·6 [1·1] vs 2·6 [0·9]). Both deletions are expected to cause frameshifts introducing a premature stop codon and should result in truncated proteins with probable loss of function. The exon 3 deletion might have more harmful effects,

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From January to May, 1998, a major epidemic of Plasmodium falciparum malaria occurred in a non-immune population in north-eastern Kenya, an area of unstable malaria transmission. This epidemic happened after low transmission of P falciparum during 1996 and 1997 droughts, followed by major rainfall and floods in November to December, 1997, due to El Niño. Such an outbreak had not been reported since 1952 in this area. At the end of March, 1998, we investigated retrospectively the outbreak in Wajir, a town of 60 000 inhabitants. Surveillance data from Wajir Government Hospital and Ministry of Health and Médecins Sans Frontières mobile clinics were reviewed. We used a twostage cluster-sampling survey to assess mortality retrospectively during Jan 1 to March 8. To assess the clinical and parasitological status of suspected malaria cases, a cross-sectional survey was carried out at mobile clinics, with systematic sampling of a fifth of patients. A case was defined as any patient living in Wajir town with a recent history of fever, after exclusion of other causes. A

THE LANCET • Vol 352 • October 24, 1998