Dietrich Haubenberger

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

Variant in the sequence of the LINGO1 gene confers risk of essential tremor

We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 x 10(-9), odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. Increased axon integrity observed in Lingo1 mouse [corrected] knockout models highlights the potential role of LINGO1 in the pathophysiology of ET [corrected]We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 × 10−9, odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. Increased axon integrity observed in Lingo1 mouse knockout models highlights the potential role of LINGO1 in the pathophysiology of essential tremor.

Long‐term antidyskinetic efficacy of amantadine in Parkinson's disease

Several randomized placebo‐controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinsons disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LIDs) wear off after about 9 months of treatment. This randomized placebo‐controlled parallel‐group study was performed to assess the long‐term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year‐ were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patients diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1–4.03) at baseline to 4.28 (95% CI, 3.1–5.4) at three‐week follow‐up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1–4.4) to follow‐up 3.6 (95% CI, 2.3–4.8) in patients staying on amantadine. These findings argue for long‐term antidyskinetic efficacy of amantadine in PD patients with LIDs.

Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene

Mutations in the valosin-containing protein (VCP) on chromosome 9p13-p12 were recently found to be associated with hereditary inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). We identified a novel missense mutation in the VCP gene (R159H; 688G>A) segregating with this disease in an Austrian family of four affected siblings, who exhibited progressive proximal myopathy and Paget disease of the bone but without clinical signs of dementia.

Association of transcription factor polymorphisms PITX3 and EN1 with Parkinson's disease

The transcription factors PITX3 and Engrailed 1 (EN1), among others, have been shown to play a crucial role in the maturation and survival of midbrain dopaminergic neurons. The degeneration of those neurons is the pathological hallmark in Parkinsons disease (PD). In a hypothesis-driven candidate gene approach, it has been recently shown that polymorphisms in the genes coding for PITX3 and EN1 are associated with sporadic PD. In a study on 365 patients with PD and 418 controls, we genotyped nine single nucleotide polymorphisms spanning the entire genomic region of PITX3 and EN1. Furthermore, we analyzed whether the genotype of these SNPs associate with the age of onset in PD. We found a strong association between the PITX3 promoter rs3758549 polymorphism and PD (p=0.0001), as well as an association between EN1 rs1438852 and PD (p=0.046). In particular, our highly significant findings regarding the association of rs3758549 reproduce the results of the initial report on transcription factor gene variants, providing further evidence for PITX3 and EN1 polymorphisms as potential genetic risk factors for sporadic PD.

A novel mutation in the VCP gene (G157R) in a German family with inclusion-body myopathy with Paget disease of bone and frontotemporal dementia.

Mutations in the valosin‐containing protein (VCP) are known to cause autosomal‐dominant inclusion‐body myopathy with Pagets disease of bone and frontotemporal dementia (IBMPFD). We report a novel missense mutation (G157R) in the N‐terminal region of the VCP gene in a German family. Family members presented with mild to moderate proximal muscle weakness, Paget disease of bone, and signs of early cognitive decline, with onset in the fourth decade. Two family members also showed signs of early hearing impairment, which was confirmed to be sensorineural in one person, a symptom not yet described in the context of IBMPFD. Muscle Nerve 39: 389–391, 2009

Respective Potencies of Botox® and Dysport® in a Human Skin Model : A Randomized, Double-blind Study

Mouse units used to quantify the activity of botulinum A toxin preparations are not equivalent and issues concerning efficacy and safety remain with regard to their respective potencies and diffusion qualities in human tissue. We compared the effects of Botox® (BOT) and Dysport® (DYS) in different doses and dilutions in a human skin model. Eighteen (8 women, 10 men) healthy volunteers, aged 28.4 years ± 5.7 years were injected intradermally with pure saline, BOT and DYS at 16 points in the abdomen in random order and in a double‐blind condition, using two conversion ratios (1:3 and 1:4) and three different dilution schemes. For an objective outcome, the Ninhydrin sweat test was used to compare the anhidrotic areas. Both preparations showed a linear dose and dilution relationship with similar variances of responses for anhidrosis and hypohidrosis, indicating the same reliability of response. The dose equivalence conversion ratios (BOT: DYS) were 1:1.3 for anhidrosis and 1:1.6 for hypohidrosis (1:1.1‐1.5 and 1:1.4‐1.8 95% confidence intervals). The diffusion characteristics of both products were similar. A dose equivalence factor of more than 1:2 (BOT:DYS) is not supported by these objective and reproducible data.

Validation of Digital Spiral Analysis as Outcome Parameter for Clinical Trials in Essential Tremor

Essential tremor, one of the most prevalent movement disorders, is characterized by kinetic and postural tremor affecting activities of daily living. Spiral drawing is commonly used to visually rate tremor intensity, as part of the routine clinical assessment of tremor and as a tool in clinical trials. We present a strategy to quantify tremor severity from spirals drawn on a digitizing tablet. We validate our method against a well‐established visual spiral rating method and compare both methods on their capacity to capture a therapeutic effect, as defined by the change in clinical essential tremor rating scale after an ethanol challenge. Fifty‐four Archimedes spirals were drawn using a digitizing tablet by nine ethanol‐responsive patients with essential tremor before and at five consecutive time points after the administration of ethanol in a standardized treatment intervention. Quantitative spiral tremor severity was estimated from the velocity tremor peak amplitude after numerical derivation and Fourier transformation of pen‐tip positions. In randomly ordered sets, spirals were scored by seven trained raters, using Bain and Findleys 0 to 10 rating scale. Computerized scores correlated with visual ratings (P < 0.0001). The correlation was significant at each time point before and after ethanol (P < 0.005). Quantitative ratings provided better sensitivity than visual rating to capture the effects of an ethanol challenge (P < 0.05). Using a standardized treatment approach, we were able to demonstrate that spirography time‐series analysis is a valid, reliable method to document tremor intensity and a more sensitive measure for small effects than currently available visual spiral rating methods.

Analysis of four prevalent filaggrin mutations (R501X, 2282del4, R2447X and S3247X) in Austrian and German patients with atopic dermatitis.

Background  Recently, mutations in the filaggrin gene (FLG) have been shown to be a major predisposing factor for atopic dermatitis (AD).

PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease

The GIGYF2 (Grb10-Interacting GYF Protein-2) gene has recently been proposed to be the responsible gene for the PARK11 locus. Ten different putative pathogenic variants were identified in cohorts of Parkinsons disease (PD) patients from Italy and France. Among these variants Asn56Ser and Asn457Thr were found repeatedly. In the present study we screened 669 PD patients (predominantly of central European origin) and 1051 control individuals for the presence of these two variants. Asn56Ser was found in one patient with a positive family history of the disease and in one control individual. The affected sister of the patient did not carry this variant. Asn457Thr was found in one patient, who was exceptional for his Egyptian origin and in three control individuals. This variant was not found in 50 control individuals from Egypt. We conclude that neither of these two variants plays a major role in the pathogenesis of PD in our study population.