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From the Departments of Neurology (L.D.K., A.J.W.B., A.A., J.C.v.S.), Clinical Genetics (A.A.), and Epidemiology & Biostatistics (M.M.B.B.), Erasmus University Medical Center, Rotterdam; and Departments of Pathology (W.K.) and Human Genetics Section Medical Genomics and Center for Neurogenomics and Cognitive Research (B.A., P.H.), VU University Medical Center, Amsterdam, The Netherlands.
Address correspondence and reprint requests to Dr. L. Donker Kaat, Erasmus University Medical Center Rotterdam, Department of Neurology, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands l.donkerkaat{at}erasmusmc.nl
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.
Conclusion: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.
Abbreviations: CB = coiled bodies; CI = confidence interval; FTD = frontotemporal dementia; GRN = progranulin; LRRK2 = leucine-rich repeat kinase 2; MAPT = microtubule-associated protein tau; NFT = neurofibrillary tangles; NINDS-SPSP = National Institute for Neurological Diseases and Stroke–Society for Progressive Supranuclear Palsy; OR = odds ratio; PD = Parkinson disease; PSP = progressive supranuclear palsy; STN = subthalamic nucleus; TA = tufted astrocytes; Thr = threads.
Supplemental data at www.neurology.org
Editorial, page 86
e-Pub ahead of print on May 20, 2009, at www.neurology.org.
Supported by Prinses Beatrix Fonds (grant number 01-0128).
Disclosure: The authors report no disclosures.
Received October 16, 2008. Accepted in final form March 10, 2009.
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  P. Pastor Familial neurodegeneration in progressive supranuclear palsy: More frequent than expected? Neurology, July 14, 2009; 73(2): 86 - 87. [Full Text] [PDF]
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