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ARTICLES: T.-B. Ahn, S. Y. Kim, J. Y. Kim, S.-S. Park, D. S. Lee, H. J. Min, Y. K. Kim, S. E. Kim, J.-M. Kim, H.-J. Kim, J. Cho, and B. S. Jeon -Synuclein gene duplication is present in sporadic Parkinson disease Neurology 2007; 0: 01.wnl.0000271080.53272.c7v1 [Abstract]

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{Alpha}- Synuclein gene duplication is present in sporadic Parkinson disease

André R. Troiano, Cécile Cazeneuve, Isabelle Le Ber, Anne-Marie Bonnet, Suzanne Lesage and Alexis Brice   (28 February 2008)

Reply from the authors

Beom S. Jeon, Tae B. Ahn, Sung S. Park   (28 February 2008)

alpha--Synuclein gene duplication is present in sporadic Parkinson disease

Norbert Brueggemann, Per Odin, Anne Gruenewald, Vera Tadic, Johann Hagenah, Guenter Seidel, Katja Lohmann, Christine Klein, Ana Djarmati   (26 November 2007)

Reply from the authors

Beom S. Jeon, Tae-Beom Ahn, Sung S. Park   (26 November 2007)

{Alpha}- Synuclein gene duplication is present in sporadic Parkinson disease 28 February 2008
André R. Troiano, Hôpital Pitié-Salpêtrière - Paris U679, Batiment Nouvelle Pharmacie, 4eme etage. 41 blvd de l'Hôpital, 75013, Paris, Cécile Cazeneuve, Isabelle Le Ber, Anne-Marie Bonnet, Suzanne Lesage and Alexis Brice Send Correspondence to journal: Re: {Alpha}- Synuclein gene duplication is present in sporadic Parkinson disease andretroiano{at}gmail.com André R. Troiano, et al.	Ahn et al. [1] reported that alpha-synuclein gene (SNCA) multiplications were present in 2/878 patients with sporadic Parkinson Disease (PD), a frequency of approximately 0.2%. Previous investigations of SNCA mutations were performed primarily in PD families with autosomal dominant inheritance [2-5]. We searched for SNCA multiplications in 101 patients with early onset sporadic PD, mostly of European (84%) and North African (4%) origin. The molecular analysis was performed with the SALSA MLPA kit P051 (MRC Holland, Amsterdam, the Netherlands), as recommended by the supplier. Peak areas representing exons 1, 3-6 of SNCA (Figure 1a) were approximately 1.5 larger in one of the patients (1%), compared to the control, suggesting that the entire SNCA gene was duplicated. This was confirmed by dosage of microsatellites within the SCNA gene (Fig 1b). [2] The patient, a 41-year-old woman with early onset sporadic PD, first noted bradykinesia and rest tremor in the right arm at 35 years of age. PD was diagnosed and she was treated with ropinirole, up to 18 mg/day. She responded favorably to the medication and was able to continue working as a secretary. A few years later, levodopa was added. When she was seen at our center, she was taking ropinirole 15 mg/d and had recently been started on levodopa 50 mg/ entacapone 200 mg/ carbidopa 12.5mg. No falls were reported and no cognitive impairment was observed (MMS = 30). Postural hypotension developed after the introduction of levodopa, but other symptoms of autonomic dysfunction were absent. On follow-up, motor fluctuations and dyskinesias worsened, without other complications. The patient is currently undergoing a work up for deep brain stimulation. Our series, which included another patient with a duplication of the SNCA gene without a family history of the disease, extends the findings of Ahn et al. This emphasizes the importance of mutations in what otherwise appear to be patients with sporadic PD. It also shows that genes other than those involved in autosomal recessive parkinsonism can be associated with early onset PD. References 1. Ahn TB, Kim SY, Kim JY, et al. {alpha}-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology. 2007 Jul 11; [Epub ahead of print] 2. Ibanez P, Bonnet AM, Debarges B, et al. Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 2004;364:1169-1171. 3. Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004;364:1167-1169. 4. Nishioka K, Hayashi S, Farrer MJ, et al. Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol 2006;59:298-309. 5. Fuchs J, Nilsson C, Kachergus J, et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 2007;68:916-922. Figure Figure. (A) Heterozygous SNCA duplication in a patient with “sporadic” PD. Electrophoregrams of MLPA analysis of patient carrying a duplication of SNCA gene. MLPA analysis was performed using the SALSA® MLPA® kit P051. The peak areas of probes corresponding to SNCA exons (exons 1, 3 to 6) are approximately 1.5 times larger for the patient (black) than for the normal control (grey). After PCR, samples were loaded on 3730 DNA Analyzer and analyzed using GeneMapper® software (AppliedBiosystems). (B) Chromatograms for two representative microsatellite markers, D4S3460 and D4S3456, demonstrating allele dosage in the patient. Microsatellite alleles size (in bp) are indicated below the peak and the copy number (in bold) next to the peak. Disclosure: The authors report no conflicts of interest.
Reply from the authors 28 February 2008
Beom S. Jeon, Seoul National University Hospital Seoul 110-744, Korea, Tae B. Ahn, Sung S. Park Send Correspondence to journal: Re: Reply from the authors brain{at}snu.ac.kr Beom S. Jeon, et al.	Troiano et al. report a 41 year-old woman with apparently sporadic Parkinson’s disease (PD) with onset at the age of 35 and alpha synuclein (AS) duplication. Their case confirms our findings. Firstly, AS duplication is present in sporadic PD, and it also has a wide phenotypic variability. There is certainly a gene dose effect and a tendency that AS duplication has a typical PD picture with late onset, slow progression, and no dementia whereas AS triplication has a rather aggressive course with young onset and dementia. [5] The case of Troiano et al. resembles our first case including the young onset age, postural hypotension, and development of dyskinesia and motor fluctuation necessitating deep brain stimulation. One difference is the absence of cognitive decline in the case of Troiano et al. Future investigation is needed to determine whether there are genetic and environmental risk factors in the penetrance and phenotypic variability of AS multiplication. Disclosure: The authors report no conflicts of interest.
alpha--Synuclein gene duplication is present in sporadic Parkinson disease 26 November 2007
Norbert Brueggemann, Department of Neurology, University of Luebeck Ratzeburger Allee 160, 23538 Luebeck, Germany, Per Odin, Anne Gruenewald, Vera Tadic, Johann Hagenah, Guenter Seidel, Katja Lohmann, Christine Klein, Ana Djarmati Send Correspondence to journal: Re: alpha--Synuclein gene duplication is present in sporadic Parkinson disease christine.klein{at}neuro.uni-luebeck.de Norbert Brueggemann, et al.	We read the article by Ahn et al. with great interest. [1] As part of a similar study, we recently tested 403 patients with a diagnosis of PD (234 men, mean age of onset: 48.0+/-11.6 years) for gene dosage changes of SNCA by quantitative duplex PCR (n=292) or MLPA (n=111). [2] We detected one SNCA duplication in a 38-year old woman with a two-year history of parkinsonism (1/403; 0.25%; Figure 1) [see link below], which is comparable to the number reported by Ahn et al. in a Korean PD population (3/906=0.3%). Neurological examination of our patient revealed generalized bradykinesia, rigidity predominantly of her right limbs, and mild postural instability but no rest tremor (UPDRSIII score: 32/108). We also found frontal release signs and bilateral horizontal gaze-evoked nystagmus. Dopaminergic treatment resulted in a dramatic improvement of motor symptoms. Olfactory function was severely impaired (UPSIT: 18/40). The Montreal Cognitive Assessment test (MoCA) was normal (28+1/30). There was a marked increase of substantia nigra hyperechogenicity of 0.46 cm² on the right side (cut-off 0.27 cm²), whereas the left side was normal at 0.12 cm². A J123-Ioflupan SPECT scan showed a decreased signal in the posterior basal ganglia bilaterally, consistent with nigrostriatal dysfunction. Family history was negative. Despite genetically proven paternity, the SNCA duplication was not present in either parent of our patient, suggesting that this mutation arose de novo. As described for several carriers of SNCA duplications [1,3], our patient’s parkinsonism could not be distinguished from early-onset idiopathic PD or parkinsonism due to mutations in the Parkin, PINK1 or DJ- 1 genes. Although they are rare and tend to be associated with a later age of onset [4,5], our findings confirm that SNCA duplications should be considered as a cause of early-onset parkinsonism. Our patient may represent the first description of a de novo SNCA mutation. While the two mutation carriers with a negative family history of PD from the Ahn et al. study appeared sporadic on the basis of reduced penetrance in unaffected mutation-positive family members [1], we report a de novo SNCA mutation as the cause of true sporadic occurrence of SNCA-associated parkinsonism. References 1. Ahn TB, Kim SY, Kim JY et al. a-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology 2007; 0: 01.wnl.0000271080.53272.c7v1 2. 2. Djarmati A, Guzvic M, Grunewald A, et al. Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation-dependent probe amplification. Mov Disord 2007. e-pub ahead of print. 3. Nishioka K, Hayashi S, Farrer MJ, et al. Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol 2006;59:298-309. 4. Hofer A, Berg D, Asmus F, et al. The role of alpha-synuclein gene multiplications in early-onset Parkinson's disease and dementia with Lewy bodies. J Neural Transm 2005;112:1249-1254. 5. Johnson J, Hague SM, Hanson M et al. SNCA multiplication is not a common cause of Parkinson disease or dementia with Lewy bodies. Neurology 2004;63:554-556. Figure Figure 1: Normalized MLPA analysis results of the DNA of our index patient (A) and a non-affected control subject (B). Values between 1.3 and 1.7 are considered duplications, whereas values between 0.8 and 1.2 are in the normal range. The asterisks in figure A mark the six duplicated SNCA exons (Exon 1-6). Note the artificially modified ratios of nearest- neighbor probes because of the normalization process. Disclosure: The authors report no conflicts of interest. Acknowledgments: We thank the family who participated in this study and furthermore Dr. I. Steck for the excellent collaboration. This work was supported by the Deutsche Forschungsgemeinschaft and the Volkswagen Foundation.
Reply from the authors 26 November 2007
Beom S. Jeon, Department of Neurology and Movement Disorder Center, Seoul National University Hospital #28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Korea, Tae-Beom Ahn, Sung S. Park Send Correspondence to journal: Re: Reply from the authors brain{at}snu.ac.kr Beom S. Jeon, et al.	Klein et al. report a German sporadic case of alpha-Synuclein gene duplication. This finding confirms our finding that alpha-Synuclein gene duplication is present in sporadic Parkinson disease (PD). [1] One remarkable finding by Klein et al. is that the patient had the de novo mutation. Patients 1 and 3 in our report were mutation positive but had asymptomatic siblings so are not de novo mutation. [5] Both parents of Patient 2 are deceased so presence of the mutation cannot be determined. Klein et al’s findings confirm that alpha-Synuclein multiplication needs to be considered in studying sporadic PD. Disclosure: The authors report no conflicts of interest.