Article

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

Department of Clinical Science, Section of Geriatric Psychiatry, Lund University, Sweden.
Parkinsonism & Related Disorders (Impact Factor: 4.13). 07/2009; 15(9):627-32. DOI: 10.1016/j.parkreldis.2009.06.007
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ABSTRACT A de novo alpha-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.

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    • "THE HARMFUL α-SYNUCLEIN α-Syn has a central role in the pathogenesis of PD and other synucleinopathies, as dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA; Spillantini and Goedert, 2000). In 1997, the first link between PD and α-syn was described with the identification of point mutations -A53T-in the SNCA gene in autosomal-dominant forms of PD (Polymeropoulos et al., 1997; Athanassiadou et al., 1999; Spira et al., 2001; Ki et al., 2007; Choi et al., 2008; Puschmann et al., 2009). To date, the list of missense mutations continues to grow with A30P, E46K, H50Q, G51D, A53E (all classified as PARK1 locus) (Krüger et al., 1998; Zarranz et al., 2004; Appel-Cresswell et al., 2013; Lesage et al., 2013; Proukakis et al., 2013; Pasanen et al., 2014). "
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    • "A Korean family with a different haplotype [8] [9] was reported, as well as one sporadic case of Polish origin [10]. The mutation occurred de novo within a Swedish family [11]. "
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    • "Apart from the Italian Contursi family, p.Ala53Thr was also identified in several families of Greek descent [Athanassiadou et al., 1999; Papadimitriou et al., 1999; Polymeropoulos et al., 1996, 1997; Spira et al., 2001]. More recently, p.Ala53Thr was also detected in two other unrelated families from Asia and Sweden [Choi et al., 2008; Ki et al., 2007; Puschmann et al., 2009] as well as in one seemingly sporadic PD patient of Polish origin [Michell et al., 2005]. With only two other missense mutations identified in SNCA—p.Ala30Pro [Kruger et al., 1998] and p.Glu46Lys [Zarranz et al., 2004] (see Supp. "
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