We analyzed the PINK1 gene in 58 patients with early-onset Parkinsonism and detected the homozygous mutation W437X in 1 patient. The clinical phenotype was characterized by early onset (22 years of age), good re- sponse to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinson’s disease and 3 further relatives were reported affected, according to an autosomal dominant transmission

CRISCUOLO C

DALLAPICCOLA B

DE MICHELE, GIUSEPPE

DE ROSA, ANNA

FILLA, ALESSANDRO

MANCINI P

MARONGIU R

SALVATORE, ELENA

VALENTE EM

VARRONE A

VOLPE G

English

Archivio della ricerca - Università degli studi di Napoli Federico II

PINK1 Homozygous W437XMutation in a Patient withApparent Dominant Transmissionof ParkinsonismChiara Criscuolo, MD,1* Giampiero Volpe, MD,1Anna De Rosa, MD,1 Andrea Varrone, MD,2Roberta Marongiu, BSc,3,4 Pietro Mancini, BSc, PhD,1Elena Salvatore, MD,1 Bruno Dallapiccola, MD,3,4Alessandro Filla, MD,1Enza Maria Valente, MD, PhD,3and Giuseppe De Michele, MD11Department of Neurological Sciences, Federico IIUniversity, Naples, Italy; 2 Department of Biomorphologicaland Functional Sciences, IBB, CNR, Federico II University,Naples, Italy; 3CSS IRCCS, Mendel Institute, Rome, Italy;4Department of Experimental Medicine and Pathology,“La Sapienza” University, Rome, ItalyAbstract: We analyzed the PINK1 gene in 58 patients withearly-onset Parkinsonism and detected the homozygousmutation W437X in 1 patient. The clinical phenotype wascharacterized by early onset (22 years of age), good re-sponse to levodopa, early fluctuations and dyskinesias, andpsychiatric symptoms. The mother, heterozygote forW437X mutation, was affected by Parkinson’s disease and3 further relatives were reported affected, according to anautosomal dominant transmission. © 2006 Movement Dis-order SocietyKey words: PINK1; familial Parkinsonism; PARK6; earlyonsetThree autosomal recessive genes have been identifiedto date as causative of early-onset Parkinsonism (EOP).According to a referral based study, the Parkin generepresents the most frequent cause of EOP, being respon-sible for up to 50% of familial cases and 15% of sporadiccases with onset younger than 45 years of age.1 Muta-tions in the DJ-1 gene have a much lower prevalence, notexceeding 1%.2 A third gene, PINK1, was found mutatedin several EOP families and further reports suggest a1.5% to 2% prevalence in sporadic patients.3–9In addition to the typical parkinsonian signs, EOPpatients present slow progression of the disease, excel-lent response to levodopa, and early L-dopa–inducedfluctuations and dyskinesias. Dementia and dysautono-mia are rarely observed, whereas other atypical featuresoccasionally can be present. The range of Parkin pheno-types is well known, because a large number of familialand sporadic cases have been described to date.10–12Conversely, only a limited number of patients with DJ-1or PINK1 mutations have been reported, and the associ-ated phenotypic spectrum still needs further definition.We evaluated the presence of PINK1 mutations in acohort of 58 EOP cases from Southern Italy and describethe phenotype of 2 patients from a family with appar-ently dominant inheritance.PATIENTS AND METHODSPatientsAfter obtaining informed consent, 58 consecutive un-related Italian patients (40 men, 18 women) with EOP(onset  50 years of age) were recruited as inpatients oroutpatients at the Movement Disorder Clinic of the De-partment of Neurology, Federico II University of Naples,since June 2001. All patients originated from SouthernItaly, mostly from Campania. Diagnosis was made ac-cording to the UK Brain Bank criteria for Parkinson’sdisease (PD), except the criterion that excludes familialcases. Patients underwent a detailed neurological exam-ination, including the Unified Parkinson’s Disease Rat-ing Scale (UPDRS) and Hoehn & Yahr scale.Mean age at onset  SD was 41.3  7.8 years (range,20–49 years). A total of 34 patients were sporadic,whereas 24 had at least 1 affected relative. An affectedfirst-degree relative was reported in 15 cases (a parent in9 and a sibling in 6). Parental consanguinity was reportedfor 7 cases.Molecular AnalysisGenomic DNA was isolated from peripheral bloodusing standard techniques. PINK1 coding sequence wasamplified by polymerase chain reaction (PCR) and di-rectly sequenced.4 When a homozygous mutation ofPINK1 was found in 1 patient, her parents were analyzedby direct sequencing and by a quantitative PCR-basedexon dosage assay, to rule out heterozygous exon rear-rangements.4 The presence of the mutation was excludedin 50 healthy individuals from Campania.RESULTSOf 58 probands, 1 (1.7%) carried a homozygous1311GA change in exon 7, resulting in the W437Xnonsense mutation. The patient’s mother and 3 otherrelatives in the maternal line were reported to be affected*Correspondence to: Dr. Chiara Criscuolo, Department of Neuro-logical Sciences, Federico II University, via Pansini 5, 80131 Naples,Italy. E-mail: sky569@libero.itReceived 7 August 2005; Revised 4 January 2006; Accepted 6January 2006Published online 12 May 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mds.20933PINK1 HOMOZYGOUS W437X MUTATION IN PD 1265Movement Disorders, Vol. 21, No. 8, 2006by PD (Fig. 1). Both parents of the proband were clini-cally examined and sampled, whereas the only affectedliving relative (a proband’s cousin) refused to participatein the study. The W437X mutation was detected in theheterozygous state in both parents, who did not carry anyother pathogenic changes or gene rearrangements.CASE REPORTSBoth parents of the proband originated from a smallvillage in Southern Italy, but consanguinity was denied.The proband, a 51-year-old woman, first noted bradyki-nesia and tremor in the left leg at age 22. Over the nextyear, symptoms spread to the left arm and subsequentlyto the right side. Neither dystonia at onset nor sleepbenefit were reported. L-Dopa was started approximately1 year after disease onset, with marked clinical benefit.However, after approximately 2 years of L-dopa therapy,wearing-off occurred leading to compulsive automedica-tion (up to 2,000 mg daily) and painful leg dyskinesias.At the same time, a depressive disorder with severehistrionic and paranoid personality disturbances was di-agnosed. Drug withdrawal at 48 years of age causedsevere off state (Hoehn & Yahr stage 5; UPDRS-IIIscore, 85). Apomorphine was added to L-dopa when shewas 50 years of age. On the last examination, she wastaking 100 mg of L-dopa and 1 mg of subcutaneousapomorphine 10 times a day. In on state, very mildbradykinesia and rigidity were observed (UPDRS-IIIscore, 8). After approximately 2 hours, the patient pro-gressed to an on–off transition state characterized bymarked axial rigidity and bradykinesia, hypomimia, andmild postural and action bilateral tremor (UPDRS-IIIscore, 44). Tendon reflexes were brisk. Dementia andautonomic disturbances were absent. A brain magneticresonance imaging scan revealed slight supratentorialand infratentorial atrophy. [123I]FP-CIT single-photonemission computed tomography (SPECT) scan showedthat striatal DAT density was reduced by 62% in thecaudate and 76% in the putamen compared with averagecontrol values. The right striatum was more affected,with a posterior to anterior gradient of DAT decline.The 73-year-old mother of the proband had onset at 53years of age, with left arm rest tremor and bradykinesia.L-Dopa was started from the beginning. On the lastexamination, she was taking 800 mg of L-dopa daily withgood response, but motor fluctuations, peak dyskinesias,and early-morning dystonia were present. Examinationin off state revealed flexed posture, mild postural insta-bility, diffuse bradykinesia and rigidity prevalent on theleft side (Hoehn & Yahr stage III, UPDRS-III score: 42),mild dyskinesias, and normal tendon reflexes. She re-ported urinary urgency and was not demented. Neuro-logical examination of the proband’s father at age 79 wasentirely normal. None of the subjects on the paternal linewas reported to be affected by PD. Both parents refusedto undergo further diagnostic procedures, such as[123I]FP-CIT SPECT scanning. The 3 other affected rel-atives of the family were reported by history to presenttremor, difficulties in gait, and slow movements.DISCUSSIONWe detected a homozygous mutation (W437X) in thePINK1 gene in 1 of 58 EOP patients. The patient re-ported here carries the same homozygous W437X as the6 patients from the 2 Italian families originally linked toPARK6.3 All these patients, including the present one,share the same haplotype for markers surrounding thegene (data not shown). Recently, W437X was found inanother Italian patient with EOP.13 Conversely, this mu-tation was never identified in EOP patients of differentnationality,14 strongly suggesting a founder effect in It-aly. The 7 previously described patients homozygote forW437X presented a fairly typical parkinsonian pheno-type, with asymmetric onset in the fourth or fifth decade(range, 30–48 years of age), wearing-off and L-dopa–induced dyskinesias of variable severity, and absence ofpsychiatric problems. The distinctive features in our pa-tient are earlier age of onset (22 years) and presence ofmajor psychiatric disturbances. Cognitive or autonomicabnormalities were absent in all W437X mutation carri-ers, whereas dystonia at onset and diurnal fluctuationswere rarely observed.In the family reported here, both parents were het-erozygous for the W437X mutation, but only the motherwas affected by PD. DNA from the remaining threeaffected relatives was not available. An increasing num-ber of patients carrying single heterozygous mutations inone of the three EOP genes has been reported.1,2,4,7,9,11The presence of a heterozygous mutation may be coin-cidental to the disease, or alternatively a second mutationFIG. 1. Pedigree of the family. Black symbols denote definitely af-fected individuals, half-black symbols denote family members affectedby history. A diagonal slash across symbols indicates a deceasedindividual. The arrow indicates the proband.1266 C. CRISCUOLO ET AL.Movement Disorders, Vol. 21, No. 8, 2006(for instance, within regulatory untranslated regions)may be missed, despite extensive screening. A third,appealing hypothesis is that a single mutation could leadto a nigrostriatal subclinical dopaminergic defect, whichwould reach the threshold of disease only in the presenceof other genetic or environmental factors. The strongestevidence in favor of this hypothesis comes from positronemission tomographic studies, which concordantly dem-onstrate a significant decrease of 18F-dopa uptake inParkin and PINK1 heterozygous healthy carriers.15,16Moreover, some heterozygous carriers present mild signsof Parkinsonism, further supporting the existence of aborderline dopaminergic dysfunction.Acknowledgments: This work was partially supported bygrants from the Italian Ministry of Health (to A.F. and to B.D.),and by Telethon grant GGP04291 (to E.M.V.).REFERENCES1. Periquet M, Latouche M, Lohmann E, et al. Parkin mutations arefrequent in patients with isolated early-onset parkinsonism. Brain2003;126:1271–1278.2. Abou-Sleiman PM, Healy DG, Wood NW. Causes of Parkinson’sdisease: genetics of DJ-1. Cell Tissue Res 2004;318:185–188.3. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science2004;304:1158–1160.4. Valente EM, Salvi S, Ialongo T, et al. PINK1 mutations areassociated with sporadic early-onset parkinsonism. Ann Neurol2004;56:336–341.5. Hatano Y, Li Y, Sato K, et al. Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 2004;56:424–427.6. Hatano Y, Sato K, Elibol B, et al. PARK6-linked autosomalrecessive early-onset parkinsonism in Asian populations. Neurol-ogy 2004;63:1482–1485.7. Rogaeva E, Johnson J, Lang AE, et al. Analysis of the PINK1 genein a large cohort of cases with Parkinson Disease. Arch Neurol2004;61:1898–1904.8. Rohe CF, Montagna P, Breedveld G, et al. Homozygous PINK1C-terminus mutation causing early-onset parkinsonism. Ann Neu-rol 2004;56:427–431.9. Klein C, Djarmati A, Hedrich K, et al. PINK1, Parkin, and DJ-1mutations in Italian patients with early-onset parkinsonism. Eur JHum Genet 2005;13:1086–1093.10. Lucking CB, Durr A, Bonifati V, et al. Association betweenearly-onset Parkinson’s disease and mutations in the parkin gene.French Parkinson’s Disease Genetics Study Group. N Engl J Med2000;342:1560–1567.11. West A, Periquet M, Lincoln S, et al. Complex relationship be-tween Parkin mutations and Parkinson disease. Am J Med Genet2002;114:584–591.12. Hedrich K, Eskelson C, Wilmot B, et al. Distribution, type, andorigin of Parkin mutations: review and case studies. Mov Disord2004;19:1146–1157.13. Bonifati V, Rohe CF, Breedveld GJ, et al. Early-onset parkinson-ism associated with PINK1 mutations: frequency, genotypes, andphenotypes. Neurology 2005;65:87–95.14. Deng H, Le WD, Zhang X, et al. G309D and W437OPA PINK1mutations in Caucasian Parkinson’s disease patients. Acta NeurolScand 2005;111:351–352.15. Khan NL, Scherfler C, Graham E, et al. Dopaminergic dysfunctionin unrelated, asymptomatic carriers of a single parkin mutation.Neurology 2005;64:134–136.16. Khan NL, Valente EM, Bentivoglio AR, et al. Clinical and sub-clinical dopaminergic dysfunction in PARK6-linked parkinsonism:an 18F-dopa PET study. Ann Neurol 2002;52:849–853.Diffusion-Weighted MagneticResonance Imaging in theSyndrome of Acute BilateralBasal Ganglia Lesions in DiabeticUremiaTaik-Kun Kim, MD,1* Sang Il Seo, MD,1Jung Hyuck Kim, MD,1 Nam Joon Lee, MD,1and Hae Young Seol, MD1Department of Diagnostic Radiology, Korea University,College of Medicine, Seoul, KoreaAbstract: In this report, we have presented a diabetic pa-tient with uremia, in which acute Parkinsonism occurred,coupled with acute mental confusion, after a sudden in-crease in blood urea nitrogen and serum creatinin levels.Diffusion-weighted magnetic resonance imaging revealed aunique cytotoxic-type edema in the bilateral basal gangliaduring the acute phase. Signal alterations were shown toregress in accordance with the normalized apparent diffu-sion coefficient (ADC) values, but irreversible cystic degen-eration developed in the globus pallidus, with the very lowpreceding ADC values. © 2006 Movement Disorder SocietyKey words: diffusion MRI; basal ganglia; diabetes mellitus;uremiaThe syndrome of acute bilateral basal ganglia lesionsin patients with diabetic uremia is a rare illness, whichnormally affects Asian patients. Recently, several casesof acute movement disorders with bilateral basal gangliainvolvement have been described in uremic–diabetic pa-tients. This syndrome is characterized by reversible,acute-onset Parkinsonism or dyskinesia, together with avariety of symptoms, including disturbances of con-*Correspondence to: Dr. Taik-Kun Kim, Department of DiagnosticRadiology, Korea University College of Medicine, Ansan Hospital,#516 Kojan-Dong, Ansan City, Kyungki-Do 425-020, Korea. E-mail:tkkim@kumc.or.krReceived 23 October 2005; Revised 27 December 2005; Accepted 6January 2006Published online 12 May 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mds.20932DWI AND ACUTE BILATERAL BASAL GANGLIA LESIONS IN DIABETIC UREMIA 1267Movement Disorders, Vol. 21, No. 8, 2006

PINK1 homozygous W437X mutation in a patient with apparent dominant  transmission of parkinsonism.

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PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism.

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