title: Familial aggregation of parkinsonism in progressive supranuclear palsy.
abstract: BACKGROUND
  Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group.
  
  
  METHODS
  Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases.
  
  
  RESULTS
  Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas.
  
  
  CONCLUSIONS
  This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.
authors.affiliation: Erasmus University Medical Center Rotterdam, Department of Neurology, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. l.donkerkaat@erasmusmc.nl
authors.forename: L
authors.initials: L
authors.lastname: Donker Kaat
authors.forename: A J W
authors.initials: AJ
authors.lastname: Boon
authors.forename: A
authors.initials: A
authors.lastname: Azmani
authors.forename: W
authors.initials: W
authors.lastname: Kamphorst
authors.forename: M M B
authors.initials: MM
authors.lastname: Breteler
authors.forename: B
authors.initials: B
authors.lastname: Anar
authors.forename: P
authors.initials: P
authors.lastname: Heutink
authors.forename: J C
authors.initials: JC
authors.lastname: van Swieten
mesh_terms: D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D003704:Dementia / Q000235:genetics; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D016017:Odds Ratio; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000077153:Progranulins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D013494:Supranuclear Palsy, Progressive / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014202:Tremor / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases