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: 3.97). 07/2009; 15(9):627-32. DOI: 10.1016/j.parkreldis.2009.06.007
Source: PubMed


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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    ABSTRACT: Neurodegenerative diseases are (i) characterized by a selective neuronal vulnerability to degeneration in specific brain regions; and (ii) likely to be caused by disease-specific protein misfolding. Parkinson's disease (PD) is characterized by the presence of intraneuronal proteinacious cytoplasmic inclusions, called Lewy Bodies (LB). α-Synuclein, an aggregation prone protein, has been identified as a major protein component of LB and the causative for autosomal dominant PD. Lysosomes are responsible for the clearance of long-lived proteins, such as α-synuclein, and for the removal of old or damaged organelles, such as mitochondria. Interestingly, PD-linked α-synuclein mutants and dopamine-modified wild-type α-synuclein block its own degradation, which result in insufficient clearance, leading to its aggregation and cell toxicity. Moreover, both lysosomes and lysosomal proteases have been found to be involved in the activation of certain cell death pathways. Interestingly, lysosomal alterations are observed in the brains of patients suffering from sporadic PD and also in toxic and genetic rodent models of PD-related neurodegeneration. All these events have unraveled a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. In this review, we emphasize the pathophysiological mechanisms connecting α-synuclein and lysosomal dysfunction in neuronal cell death.
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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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    ABSTRACT: Mutations in seven genes are robustly associated with autosomal dominant (SNCA, LRRK2, EIF4G1, VPS35) or recessive (parkin/PARK2, PINK1, DJ1/PARK7) Parkinson's disease (PD) or parkinsonism. Changes in a long list of additional genes have been suggested as causes for parkinsonism or PD, including genes for hereditary ataxias (ATXN2, ATXN3, FMR1), frontotemporal dementia (C9ORF72, GRN, MAPT, TARDBP), DYT5 (GCH1, TH, SPR), and others (ATP13A2, CSF1R, DNAJC6, FBXO, GIGYF2, HTRA2, PLA2G6, POLG, SPG11, UCHL1). This review summarizes the clinical features of diseases caused by mutations in these genes, and their frequencies. Point mutations and multiplications in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system. LRRK2 mutations may lead to a clinical phenotype closely resembling idiopathic PD with a puzzling variety in neuropathology. Mutations in parkin/PARK2, PINK1 or DJ1/PARK7 may cause early-onset parkinsonism with a low risk for cognitive decline and a pathological process usually restricted to the brainstem. Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD. The pathogenicity of several mutations remains unconfirmed. Although some mutations occur with high frequency in specific populations, worldwide all are very rare. The genetic cause of the majority of patients with sporadic or hereditary PD remains unknown in most populations. Clinical genetic testing is useful for selected patients. Testing strategies need to be adapted individually based on clinical phenotype and estimated frequency of the mutation in the patient's population.
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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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