A Swedish family with de novo α-synuclein A53T mutation: Evidence for early cortical dysfunction

Received 15 March 2009; received in revised form 22 May 2009; accepted 19 June 2009.

Abstract

A de novo α-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria, and cognitive decline. Longitudinal clinical follow-up, EEG, SPECT and CSF biomarker examinations suggested an underlying encephalopathy with cortical involvement. The mutated allele (c.209A) was present within a haplotype different from that shared among mutation carriers in the Italian (Contursi) and the Greek-American Family H kindreds. One unaffected family member carried the mutation haplotype without the c.209A mutation, strongly suggesting its de novo occurrence within this family. Furthermore, a novel mutation c.488G > A (p.Arg163His; R163H) in the presenilin-2 (PSEN2) gene was detected, but was not associated with disease state.

Keywords: Parkinson disease, Parkinsonian conditions, Autosomal dominant parkinsonism, Alpha-synuclein, A53T mutation, Ala53Thr, A53T, Biomarkers, CSF examination, Cerebrospinal fluid, Neuroimaging, Longitudinal clinical follow-up, Haplotype analysis, SPECT, Single-photon emission computed tomography, Myoclonus, Electroencephalogram, Magnetic resonance imaging

a Department of Neurology, Lund University Hospital, Sweden

b Department of Clinical Science, Section of Geriatric Psychiatry, Lund University, Sweden

c Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

d Division of Neurogenetics, Rigshospitalet Copenhagen University Hospital, Denmark

e Institute of Cellular and Molecular Medicine, Section of Neurogenetics, University of Copenhagen, The Panum Institute, Denmark

f Memory Disorders Research Unit, Rigshospitalet, Copenhagen University Hospital, Denmark

g Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

h Department of Radiology, Lund University Hospital, Sweden

i Department of Clinical Neurophysiology, Lund University Hospital, Sweden

j University of Thessaly, Medical School, Larissa, Greece

k Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA

l Department of Cognitive Medicine, Lund University Hospital, Sweden

Corresponding author. Department for Neurology, Lund University Hospital, Getingevägen 4, 22185 Lund, Sweden. Tel.: +46 46 175421/+46 46 171000; fax: +46 46 177940.

PII: S1353-8020(09)00152-7

doi:10.1016/j.parkreldis.2009.06.007

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