Benjamin Bereznai

Chronic high-frequency globus pallidus internus stimulation in different types of dystonia: a clinical, video, and MRI report of six patients presenting with segmental, cervical, and generalized dystonia.

The results of deep brain stimulation (DBS) of the globus pallidus internus (Gpi) in six patients with generalized, focal, and segmental dystonia are presented. Pre‐ and postoperative assessments are given for one patient with generalized inherited dystonia and for five patients with idiopathic segmental or cervical dystonia. Clinical symptoms were evaluated before and 3–12 months after surgery using the Burke‐Fahn‐Marsden (BFM) dystonia rating scale for primary torsion dystonia and the Tsui scale for cervical dystonia. The Short‐Form Health Survey (SF‐36) was completed by each patient to document preoperative and postoperative health status. Also, neurological status was documented by video before and during chronic stimulation. Magnetic resonance imaging studies were performed to show the anatomical localization of the electrode leads. Five patients showed a progressive improvement within 7 days. One patient with cervical dystonia and Meiges syndrome showed no improvement for 3 months, but beneficial effects were observed after 12 months. On average, the BFM movement scale scores decreased by 72.5% and Tsui scale scores by 63%. SF‐36 showed an improvement in health status by an average of 36% according to eight different health categories. We conclude that chronic high‐frequency Gpi stimulation in different types of dystonia is a very effective and safe treatment.

The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease

Recently an Ile93Met mutation in the ubiquitin-carboxy-terminal-hydrolase-L1 gene (UCH-L1) has been described in a German family with Parkinsons disease (PD). The authors showed that this mutation is responsible for an impaired proteolytic activity of the UCH-L1 protein and may lead to an abnormal aggregation of proteins in the brain. In order to determine the importance of this or any other mutation in the coding region of the UCH-L1 gene in PD, we performed mutation analysis on Caucasian families with at least two affected sibs. We did not detect any mutations in the UCH-L1 gene, however, we cannot exclude mutations in the regulatory or intronic regions of the UCH-L1 gene since these regions were not sequenced. We conclude that the UCH-L1 gene is not a major gene responsible for familial PD.

Ultrasonography of MADSAM neuropathy: Focal nerve enlargements at sites of existing and resolved conduction blocks

Using the emerging technique of peripheral nerve ultrasonography, multiple focal nerve swellings corresponding to sites of existing conduction blocks have been described in demyelinating polyneuropathies. We report two cases of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). In the first, multiple focal nerve enlargements were detected by ultrasound at sites of previous conduction blocks, well after complete clinical and electrophysiological resolution. In the second case, existing proximal conduction blocks could be localized by ultrasound. Our cases highlight the importance of nerve ultrasound in identifying conduction blocks and demonstrate that ultrasonographic morphological changes may outlast functional recovery in demyelinating neuropathies.

Point mutations in exon 1 of the NR4A2 gene are not a major cause of familial Parkinson′s disease

Sirs, Parkinson’s disease (PD) is a neurodegenerative disorder, clinically characterized by a triad of rigidity, resting tremor, and bradykinesia. To date, mutations in four separate PD genes have been identified: the genes for alpha-synuclein and for ubiquitin C-terminal hydrolase L1 both cause autosomal dominant forms of PD, whereas mutations in the parkin gene and DJ-1 are associated with early onset recessive parkinsonism [1, 2]. Recently, two variants (-245T!G and 291Tdel) in exon1 of the NR4A2 gene were identified in 2 and 8 patients, respectively of 107 patients with familial PD [3]. Neither of these two variants was found in 94 sporadic PD patients or age-matched controls (n=221). NR4A2 is a member of the superfamily of “zinc finger” transcription factors and has been shown to be an absolute requirement for the development of dopaminergic neurons [4]. Although both described variants are located in the 5́UTR of exon 1 and do not change the amino acid composition of the protein, they resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. We aimed to replicate this study by sequencing exon 1 of 44 cases of familial PD. All index patients of Caucasian ethnicity were diagnosed with PD according to United Kingdom brain bank criteria. The mean age at onset was 58€9.3 years (range 35–73 years). Family history was regarded positive in all cases, since levodopa-responsive rest tremor and/or hyopkinetic symptoms were reported in at least one first-degree relative (sibling or parent). Of 44 cases (32 male, 12 female), 14 had one or more affected siblings and 30 showed a parent-child transmission. All patients were parkin negative. A 269-bp PCR fragment of NR4A2 exon 1 was generated and directly sequenced using genomic DNA (NR4A2Ex1F: cgc aag cca cat aaa caa ag and Nurrex1R: act gca tgg gct gca tct act). Neither the 291Tdel nor the 245T!G mutation occurred in any of our PD patients. No other sequence variants relative to the published sequence in the exon 1 region were identified. The mutations found by Le et al. [3] were present in a heterozygous state, suggesting an autosomal dominant transmission. Therefore the most-significant result in our study was that no mutations were found in the 30 families with known parent-child transmission. The 14 affected siblings might either be associated with recessive mutations or with a dominant inheritance with reduced penetrance. Our findings show that sequence alterations in exon 1 of the NR4A2 gene are not a major cause of familial PD in central Europe. The NR4A2 mutations associated with familial PD reported by Le et al. [3] are apparently caused by strong A. Zimprich · F. Asmus · P. Leitner · T. Gasser ()) Center of Neurology, University of Tuebingen, Department of Neurology and Hertie-Institute of Clinical Brain Research, Section for Neurodegenerative Diseases, Hoppe-Seyler Strasse 3, 72076 Tuebingen, Germany e-mail: Thomas.Gasser@med.uni-tuebingen.de Tel.: +49-7071-2986529 Fax: +49-7071-294839

Psychiatric symptoms of patients with primary mitochondrial DNA disorders.

BackgroundThe aim of our study was to assess psychiatric symptoms in patients with genetically proven primary mutation of the mitochondrial DNA.Methods19 adults with known mitochondrial mutation (MT) have been assessed with the Stanford Health Assessment Questionnaire 20-item Disability Index (HAQ-DI), the Symptom Check List-90-Revised (SCL-90-R), the Beck Depression Inventory-Short Form (BDI-SF), the Hamilton Depression Rating Scale (HDRS) and the clinical version of the Structured Clinical Interview for the the DSM-IV (SCID-I and SCID-II) As control, 10 patients with hereditary sensorimotor neuropathy (HN), harboring the peripheral myelin protein-22 (PMP22) mutation were examined with the same tools.ResultsThe two groups did not differ significantly in gender, age or education. Mean HAQ-DI score was 0.82 in the MT (range: 0-1.625) and 0.71 in the HN group (range: 0-1.625). Level of disability between the two groups did not differ significantly (p = 0.6076). MT patients scored significantly higher on the BDI-SF and HDRS than HN patients (12.85 versus 4.40, p = 0.031, and 15.62 vs 7.30, p = 0.043, respectively). The Global Severity Index (GSI) of SCL-90-R also showed significant difference (1.44 vs 0.46, p = 0.013) as well as the subscales except for somatization. SCID-I interview yielded a variety of mood disorders in both groups. Eight MT patient (42%) had past, 6 (31%) had current, 5 (26%) had both past and current psychiatric diagnosis, yielding a lifetime prevalence of 9/19 (47%) in the MT group. In the HN group, 3 patients had both past and current diagnosis showing a lifetime prevalence of 3/10 (30%) in this group. SCID-II detected personality disorder in 8 MT cases (42%), yielding 3 avoidant, 2 obsessive-compulsive and 3 personality disorder not otherwise specified (NOS) diagnosis. No personality disorder was identified in the HN group.ConclusionsClinicians should be aware of the high prevalence of psychiatric symptoms in patients with mitochondrial mutation which has both etiologic and therapeutic relevance.

Different Patterns of Nerve Enlargement in Polyneuropathy Subtypes as Detected by Ultrasonography

The purpose of our study was to examine how the pathologic type of polyneuropathy affects nerve size as assessed by high-resolution ultrasonography with a 15 MHz transducer. Cross-sectional area (CSA) of the C5-C7 nerve roots and several upper and lower limb nerves at multiple sites was measured in 38 patients with acquired diffuse sensorimotor demyelinating or axonal polyneuropathy and in 34 healthy control subjects. Significant differences were found among the groups for all nerve and root segments: Both types of polyneuropathy are characterized by nerve enlargement in comparison to controls, but in different patterns. In demyelinating polyneuropathies, an additional degree of nerve thickening appears in proximal upper limb nerves and cervical nerve roots compared with axonal polyneuropathies. With respect to the other nerves, a similar degree of nerve enlargement was observed in both patient groups. These results highlight that ultrasonography may be a complementary tool in differentiating polyneuropathies.

The role of SCARB2 as susceptibility factor in Parkinson's disease

Genetic variation in the glucocerebrosidase (GBA) gene is strongly associated with Parkinsons disease (PD). Transport of glucocerebrosidase to the lysosome involves the protein encoded by the SCARB2 gene. An association between the common SNP rs6812193, upstream of SCARB2, and PD has been reported previously. The role of exonic variants in the SCARB2 gene in PD has not been examined.

Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease

Recently, mutations in eukaryotic translation initiation factor 4G1 (EIF4G1) were reported as a rare cause of familial Parkinson’s disease (PD). We screened the 33 exons of EIF4G1 by high-resolution melting curve analysis for variants in our Central European cohort of 376 PD cases. Variant frequency was assessed in a total of 975 PD cases and 1,014 general population controls. Eight novel nonsynonymous and four synonymous variants were identified. In our cohort, novel and previously identified nonsynonymous variants were very rare. Although it is possible that our general population controls also comprise individuals who have or could develop PD in the future, the presence of the original mutation (EIF4G1 p.Arg1205 His) in three controls only, raises questions about the causality of this variant with regard to PD.

A novel SOD1 mutation in an Austrian family with amyotrophic lateral sclerosis.

We report on an Austrian pedigree with autosomal dominant amyotrophic lateral sclerosis (ALS), diagnosed in six patients from two generations. The only surviving clinically affected family member was examined in our ALS clinic. Historical information on other affected individuals was obtained from knowledgeable family members. The mean +/- S.D. age of onset of the disease was 54 +/- 6.9 years, with a range of 43-66 years. The duration of the index patients disease until death was 8 months. Using single strand conformational polymorphism (SSCP) analysis, we studied the index patients exons 1, 2 and 4 of the Cu/Zn superoxide dismutase gene (SOD1) on chromosome 21. A variant banding pattern was observed for exon 1. Sequencing studies showed a previously undescribed T to A missense mutation at position 8 in exon 1 of the SOD1 gene. This mutation results in the elimination of an Eco57I restriction site. Whereas the index patient was heterozygous for this restriction site, 50 unrelated healthy controls and an unaffected brother were not. The mutation lies in a region involved in dimer contact in the three-dimensional structure of the SOD1 protein. This region comprises other known sites for ALS-causing mutations.

Rare variants in β- Amyloid precursor protein (APP) and Parkinson’s disease

Many individuals with Parkinson’s disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer’s disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.