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See detailTargeted next generation sequencing in SPAST-negative hereditary spastic paraplegia.
Kumar, Kishore R.; Blair, Nicholas F.; Vandebona, Himesha et al

in Journal of neurology (2013), 260(10), 2516-22

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We ... [more ▼]

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition. [less ▲]

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See detailLong-term follow-up of subthalamic nucleus stimulation in glucocerebrosidase-associated Parkinson's disease.
Weiss, Daniel; Brockmann, Kathrin; Srulijes, Karin et al

in Journal of neurology (2012), 259(9), 1970-2

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See detailCombined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson's disease.
Weiss, Daniel; Breit, Sorin; Wachter, Tobias et al

in Journal of neurology (2011), 258(6), 1183-5

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See detailEffective long-term subthalamic stimulation in PARK8 positive Parkinson's disease.
Breit, Sorin; Wachter, T.; Schmid-Bielenberg, D. et al

in Journal of neurology (2010), 257(7), 1205-7

Whether patients with genetically defined Parkinson's disease (PD) may be particularly eligible to benefit from deep brain stimulation of the nucleus subthalamicus (STN-DBS) is currently the subject of ... [more ▼]

Whether patients with genetically defined Parkinson's disease (PD) may be particularly eligible to benefit from deep brain stimulation of the nucleus subthalamicus (STN-DBS) is currently the subject of debate. We report on a patient with advanced PD due to R793M missense mutation in the LRRK2 gene successfully treated by STN-DBS. Disease onset was at age 42 with bradykinesia, rigidity and rest tremor. During the course of the disease he developed severe motor fluctuations, dyskinesias, postural instability with falls, but preserved levodopa responsiveness. At age 60 the patient was treated by bilateral DBS of the STN. At one year after surgery a 66% improvement of the UPDRS motor score in the off-medication state was determined. During the long-term follow-up there was sustained benefit with 56% improvement of motor score after 8 years. Our report adds evidence that patients with LRRK2 monogenetic Parkinsonism are well suited candidates for DBS treatment and may indicate a potential genetic predictor for positive long-term effect of STN-DBS treatment. [less ▲]

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See detailSevere orthostatic dysregulation associated with Wolfram syndrome.
Synofzik, Matthis; Weiss, Daniel; Erharhaghen, Jite et al

in Journal of neurology (2010), 257(10), 1751-3

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See detailImpaired performance on the Wisconsin Card Sorting Test under left- when compared to right-sided deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.
Lueken, Ulrike; Schwarz, Michaela; Hertel, Frank UL et al

in Journal of neurology (2008), 255(12), 1940-8

Over the past decade, deep brain stimulation (DBS) has become an effective treatment option for managing severe Parkinson's disease (PD). However, evidence is accumulating that DBS of target sites like ... [more ▼]

Over the past decade, deep brain stimulation (DBS) has become an effective treatment option for managing severe Parkinson's disease (PD). However, evidence is accumulating that DBS of target sites like the subthalamic nucleus (STN) can result in unintended cognitive effects that lie beyond motor control. The aim of the present study was to evaluate whether changes in executive task performance after chronic DBS might be predominantly associated with the stimulation of only one hemisphere. Eight patients with PD who had undergone DBS treatment of the STN were selected to participate in the study. Using a repeated measurements design, they underwent a neuropsychological examination under unilateral left- and right-sided stimulation in order to investigate laterality effects in their performance on the Wisconsin Card Sorting Test. All patients showed a significant improvement in motor symptoms postoperatively. Selected aspects of executive task performance were compromised under left- when compared to right-sided stimulation. Performance measures were unrelated to demographic, neurological, and behavioral characteristics of the patients. Findings are consistent with the emerging evidence that the STN is not only involved in motor control, but also participates in functions of the cognitive domain. Moreover, results raise the possibility that the left and right hemisphere might differ in their vulnerability to tolerate side effects on executive functions of DBS treatment. Potential consequences for future research questions and the management of cognitive side effects are discussed. [less ▲]

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See detailTranscranial ultrasound in different monogenetic subtypes of Parkinson's disease.
Schweitzer, Katherine J.; Brussel, Theresa; Leitner, Petra et al

in Journal of neurology (2007), 254(5), 613-6

Hyperechogenicity of the substantia nigra (SN) has been found to be a typical sign in idiopathic Parkinson's disease (PD), prevalent in more than 90% of affected individuals. To see whether SN ... [more ▼]

Hyperechogenicity of the substantia nigra (SN) has been found to be a typical sign in idiopathic Parkinson's disease (PD), prevalent in more than 90% of affected individuals. To see whether SN hyperechogenicity is also characteristic for monogenetically caused PD, we investigated PD patients with alpha-synuclein, LRRK2, parkin, PINK1 and DJ-1 mutations by transcranial sonography (TCS). In all these patients the area of SN echogenicity was significantly larger than in healthy controls, but smaller, than in idiopathic PD. As SN hyperechogenicity could be related to an increased iron content of the SN, these findings suggest that iron may play a less significant role in the pathogenesis of monogenetically caused compared to idiopathic PD. [less ▲]

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See detailAlteration of cerebral perfusion in patients with idiopathic normal pressure hydrocephalus measured by 3D perfusion weighted magnetic resonance imaging.
Walter, Christof; Hertel, Frank UL; Naumann, E. et al

in Journal of neurology (2005), 252(12), 1465-71

OBJECTIVE: It is controversial whether alteration of cerebral perfusion plays an important role in the pathophysiology of patients with idiopathic normal pressure hydrocephalus (NPH) and can help to ... [more ▼]

OBJECTIVE: It is controversial whether alteration of cerebral perfusion plays an important role in the pathophysiology of patients with idiopathic normal pressure hydrocephalus (NPH) and can help to predict the outcome after shunt surgery. MATERIALS AND METHODS: 28 patients with suspected NPH were examined clinically (Homburg Hydrocephalus Scale, walking test, incontinence protocol) and by 3D dynamic susceptibility based perfusion weighted magnetic resonance imaging (PWI-MRI) before and after cerebrospinal fluid release (spinal tap test, STT). The perfusion parameters (negative integral (NI), time of arrival (T0), time to peak (TTP), mean transit time, and the difference TTP-T0 were analysed. RESULTS: Three different groups of patients were identified preoperatively: In group 1 seven patients showed an increase in the cerebral perfusion and a clinical improvement after STT. The second group (9 patients) also revealed an increase of the cerebral perfusion, but no significant alteration of the clinical assessment could be found. In the third group neither the cerebral perfusion nor the clinical assessment changed. 14 of the 16 patients (group 1 and 2) were examined three months after shunt placement. 11 patients showed a good or excellent result, 2 patients revealed a fair assessment, and only 1 patient had transiently improved. No patient was downgraded after shunting. In the patient group 1 and 2 the NI increased significantly (effect size: 34%), whereas in group 3 no significant alteration of NI was observed. CONCLUSION: PWI-MRI improves the prediction of outcome after shunt placement in patients with NPH and can offer new insights into the pathophysiology. [less ▲]

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See detailGenes in familial parkinsonism and their role in sporadic Parkinson's disease.
Krüger, Rejko UL

in Journal of neurology (2004), 251 Suppl 6

For several decades there has been a controversy on the contribution of genetic factors to the pathogenesis of sporadic idiopathic Parkinson's disease (PD). The identification of families in which typical ... [more ▼]

For several decades there has been a controversy on the contribution of genetic factors to the pathogenesis of sporadic idiopathic Parkinson's disease (PD). The identification of families in which typical parkinsonism is inherited as an autosomal dominant or recessive trait sheds light on genes that cause phenotypes resembling sporadic PD. These genes are involved in molecular pathways leading to neurodegeneration and dysfunction of the nigrostriatal system. The present article gives insight into molecular pathways to neurodegeneration deciphered by the functional characterization of five genes identified in inherited forms of typical levodopa-responsive parkinsonism. There is increasing evidence that genes involved in monogenic forms of the disease may act as susceptibility factors also in the common sporadic form of PD. Transgenic animal models based on disease genes identified in monogenic forms of typical parkinsonism replicate important features of PD including protein aggregation and progressive motor symptoms. This implicates novel perspectives for neuroprotective therapeutic approaches that might be beneficial also to sporadic PD. [less ▲]

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See detailNew developments in diagnosis and treatment of Parkinson's disease--from basic science to clinical applications.
Storch, Alexander; Hofer, Anne; Krüger, Rejko UL et al

in Journal of neurology (2004), 251 Suppl 6

In this review we summarize new developments in early diagnosis, establishing surrogate markers, genetics, neuroprotection and cell replacement in Parkinson's disease. Furthermore, we discuss the major ... [more ▼]

In this review we summarize new developments in early diagnosis, establishing surrogate markers, genetics, neuroprotection and cell replacement in Parkinson's disease. Furthermore, we discuss the major problems in the translation of results from preclinical research into successful clinical trials. [less ▲]

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See detailTherapeutic strategies for Parkinson's disease based on data derived from genetic research.
Riess, Olaf; Berg, Daniela; Krüger, Rejko UL et al

in Journal of neurology (2003), 250 Suppl 1

Following the identification of mutations in alpha-synuclein as the cause of some rare forms of familial Parkinson's disease (PD), genetic research has uncovered numerous gene loci of PD. Meanwhile ... [more ▼]

Following the identification of mutations in alpha-synuclein as the cause of some rare forms of familial Parkinson's disease (PD), genetic research has uncovered numerous gene loci of PD. Meanwhile, several neurodegenerative diseases have been shown to accumulate a-synuclein in neuronal and glial cells summarizing this group of diseases as synucleinopathies. All currently known gene defects causing PD alter the ubiquitin-proteasomal pathway of protein degradation. Identification of these disease mutations allows studying the functional consequences which lead to cellular dysfunction and cell death in cell culture and transgenic animal models, to identify therapeutic targets and to test potential protective strategies in these models. [less ▲]

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See detailSpectrum of phenotypes and genotypes in Parkinson's disease.
Riess, Olaf; Krüger, Rejko UL; Schulz, Jorg B.

in Journal of neurology (2002), 249 Suppl 3

The pathogenesis of Parkinsons disease (PD) is currently unknown. Environmental and genetic factors might contribute to the neurodegenerative process. Genetic mapping approaches in rare familial cases ... [more ▼]

The pathogenesis of Parkinsons disease (PD) is currently unknown. Environmental and genetic factors might contribute to the neurodegenerative process. Genetic mapping approaches in rare familial cases with autosomal recessive and autosomal dominant inheritance of PD suggest wide genetic heterogeneity of the disease. These gene loci in turn allow now a more specific clinical investigation of affected families to study the clinical heterogeneity of PD. The recent identification of mutations in three genes involved in protein degradation and aggregation in familial PD does now facilitate the deciphering of other genes involved in the pathogenesis of the disease. [less ▲]

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See detailGenetic influence on the development of Parkinson's disease.
Riess, O.; Kuhn, W.; Krüger, Rejko UL

in Journal of neurology (2000), 247 Suppl 2

In the last few years, the genetic contribution to Parkinson's disease has gained major attention and resulted in the identification of four gene loci in autosomal dominant and autosomal recessive ... [more ▼]

In the last few years, the genetic contribution to Parkinson's disease has gained major attention and resulted in the identification of four gene loci in autosomal dominant and autosomal recessive Parkinson's disease. Several mutations in two genes have been shown to be responsible for neuronal cell death in Parkinson's disease. One of the gene products involved, alpha-synuclein, is a major component of Lewy bodies, the neuropathological feature of Parkinson's disease. In contrast, mutations in the parkin gene are associated with parkinsonism without Lewy body pathology. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and of xenobiotic metabolism is technically now possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of Parkinson's disease at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression. [less ▲]

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