A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families. METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools. RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease. CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP.

Real-life long-term effectiveness of fingolimod in Swiss patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. METHODS: This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. RESULTS: Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naïve prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. CONCLUSION: In this Swiss cohort of naïve and pre-treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment.

Corticospinal output during muscular fatigue differs in multiple sclerosis patients compared to healthy controls.

BACKGROUND: In multiple sclerosis (MS), fatigue is a common and often disabling symptom. It has multiple causes with central motor fatigue playing an important role. OBJECTIVE: The objective of this study was to analyse the central motor conduction changes in relation to muscle contraction force during muscle fatigue and recovery in MS patients compared to healthy controls. METHODS: A total of 23 MS patients with fatigue and 13 healthy subjects were assessed during 2 minutes of fatiguing exercise of the abductor digiti minimi muscle of the hand and the subsequent 7 minutes of recovery. Central motor conduction was quantified by transcranial magnetic stimulation using the triple stimulation protocol and calculating a central conduction index (CCI). RESULTS: Force declined to 36% of the pre-exercise level (SD 16%; p < 0.01) in MS patients and to 44% (SD 9%, p < 0.01) in healthy subjects (group differences, not statistically significant). The decline of the CCI was significantly less marked in patients (-20%, SD 26%, p < 0.05) than in healthy subjects (-57%, SD 15%, p < 0.05; group differences, p < 0.05). The decline of force and CCI were not correlated in either group. CONCLUSIONS: During a fatiguing exercise, the decline in central motor conduction is significantly less pronounced in MS patients than healthy subjects, although the reduction of force is similar.

Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia.

DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of approximately 30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms. In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia. We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%. Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.

Infusion-related reactions during Natalizumab treatment: Do we still need a post-infusion observation period?

BACKGROUND: Natalizumab (NTZ) is a humanized monoclonal antibody used in the treatment of relapsing remitting multiple sclerosis. Although NTZ is usually well-tolerated, infusion-related reactions (IRRs) may occur, and the patients have to be monitored during the infusion and for one hour afterwards. OBJECTIVE: To identify frequency and severity of IRRs during NTZ infusions and one-hour post-infusion observation period in a clinical practice setting. METHODS: Multicenter, observational study involving three Swiss (Lugano, St. Gallen and Luzern) and two Italian (Milano and Napoli) tertiary MS centers. Predisposing factors to IRRs were investigated using multivariate Cox regression models. RESULTS: A total of 11'133 infusions received by 302 MS patients were analyzed (68.9% females, median age 33.6 years, median EDSS 2.5). IRRs occurred in 24 (8%) patients during NTZ infusions and in 7 (2%) during one-hour post-infusion. Only 8 patients needed pharmacological treatment, of whom 7 during NTZ infusion. Age, sex and history of allergies were not associated with risks for IRR. The frequency of post infusion IRRs after the fifth cycle was low compared to that during the first four infusions (0.83% vs 0.06%). CONCLUSION: In our cohort, NTZ associated IRR mainly occurred during the infusion period compared to the one-hour observational period. Also, the first IRR exclusively occurred within the first 4 NTZ administrations. However, further multi-center studies with a larger sample size are needed to capture rare and serious events that could emerge during the observational period and to make clinical recommendations.

[Genetics of dystonia]. / Genetik der Dystonien.

The dystonias comprise a heterogeneous group of movement disorders. In contrast to the frequent sporadic forms, a variety of rare familial forms are caused by genetic mutations with mendelian inheritance. In recent years, significant progress has been made with regard to the identification of genes causing dystonia, and to the molecular pathophysiology underlying dystonic symptoms. Currently, 18 gene loci have been described causing primary dystonia, dystonia-plus syndromes or paroxysmal dystonia. The most frequent form of inherited dystonia, according to current knowledge, is early-onset generalized DYT1 dystonia, caused by a deletion of three basepairs, GAG, in the DYT1 (TOR1A) gene. It is thought that the protein encoded by this gene, torsinA, participates in association of the endoplasmatic reticulum and the nuclear envelope with the cytoskeleton and hereby might influence the reaction of cells to various stresses and/or the development of specific neuronal populations involved in movement control in the brain. Other genes which have only recently been identified include: THAP1, causing adolescent-onset primary dystonia of mixed type (DYT6); ATP1A3, responsible for Rapid-Onset Dystonia-Parkinsonism (RDP, DYT12); PRKRA, causing young-onset dystonia-parkinsonism (DYT16); and SLC2A1, causing paroxysmal exertion-induced dystonia with haemolytic anemia (DYT18). Further, five other loci for primary dystonia (DYT2, DYT4, DYT7, DYT13 and DYT17) have been identified, for which the causative genes remain to be discovered.

TorsinA: movement at many levels.

TorsinA is the causative protein in the human neurologic disease early onset torsin dystonia, a movement disorder involving dysfunction in the basal ganglia without apparent neurodegeneration. Most cases result from a dominantly acting three-base pair deletion in the TOR1A gene causing loss of a glutamic acid near the carboxyl terminus of torsinA. Torsins are members of the AAA(+) superfamily of ATPases and are present in all multicellular organisms. Initial studies suggest that torsinA is an ER protein involved in chaperone functions and/or membrane movement.

The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group.

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.

Highly purified oligo-His tagged human recombinant alpha(1)-AChR is immunogenic in vivo and suitable for T cell stimulation in vitro in experimental and human myasthenia gravis.

Using recombinantly expressed proteins for selection of antigen-specific T cell lines carries a high risk of selecting T cells specific for contaminating proteins. This risk is especially high for very hydrophobic proteins which are notoriously difficult to purify, such as the integral membrane protein acetylcholine receptor (AChR). We prepared a highly purified recombinant AChR by adding an oligo-histidine affinity-tag to the human alpha(1)-AChR and expressing it in E. coli. This allowed purification by Ni-NTA chromatography and subsequent electroelution from preparative SDS gel as purification steps, resulting in complete purity as assessed by silver stain on SDS-PAGE. This protein preparation induced fatal experimental allergic myasthenia gravis in Lewis rats. Furthermore, the protein could be used to select T cell lines from immunized Lewis rats and patients with myasthenia gravis. However, even with this highly purified protein, one of 8 Lewis rat T cell lines and 3 of 7 human T cell lines cross-reacted to E. coli control proteins. The results show that oligo-histidine tagged, highly purified human alpha(1)-AChR is highly immunogenic in vivo and in vitro.

Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect.

OBJECTIVE: Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large German/Dutch pedigree has formerly been described as paroxysmal choreoathetosis/spasticity (DYT9) and linked close to but not including the SLC2A1 locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, in addition to PED, as described in DYT9, and 2) autosomal dominant forms of hereditary spastic paraparesis (HSP) without PED are caused by SLC2A1 defects. METHODS: The German/Dutch family and an Australian monozygotic twin pair were clinically (re-)investigated, and 139 index cases with dominant or sporadic HSP in which relevant dominant genes were partially excluded were identified from databanks. SLC2A1 was sequenced in all cases in this observational study and the functional effects of identified sequence variations were tested in glucose uptake and protein expression assays. RESULTS: We identified causative mutations in SLC2A1 in both families, which were absent in 400 control chromosomes, cosegregated with the affection status, and decreased glucose uptake in functional assays. In the 139 index patients with HSP without paroxysmal dyskinesias, we only identified one sequence variation, which, however, neither decreased glucose uptake nor altered protein expression. CONCLUSIONS: This study shows that DYT9 and DYT18 are allelic disorders and enlarges the spectrum of GLUT1 phenotypes, now also including slowly progressive spastic paraparesis combined with PED. SLC2A1 mutations were excluded as a cause of HSP without PED in our cohort.

Possible gender-dependent association of vascular endothelial growth factor (VEGF) gene and ALS.

Individuals homozygous for haplotypes -2578-A/-1154-A/-634-G or -2578-A/-1154-G/-634-G in the promoter/5'UTR of the VEGF gene have a 1.8-fold increased risk of ALS in several European populations. We did not observe any significant association with single markers, or haplotype pairs, in a German sample of 580 sporadic ALS patients and 628 controls. However, the promoter SNP-1154 (rs1570360) was associated with affection status in women (p = 0.036), suggesting that the VEGF effect may be dependent on the sex ratio of the sample.

Strong genetic evidence for association of TOR1A/TOR1B with idiopathic dystonia.

Recently, association of a TOR1A(DYT1)/TOR1B risk haplotype with common forms of idiopathic dystonia has been reported in the Icelandic population. Here we report a strong association of two single nucleotide polymorphisms within or in close proximity to the TOR1A 3'UTR, with the lowest p value being 0.000008, in a larger cohort of German and Austrian patients with predominantly focal sporadic dystonia.

The alpha-synuclein gene in multiple system atrophy.

BACKGROUND: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. METHOD: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. RESULTS AND CONCLUSION: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

User interfaces for voice applications.

This paper discusses some of the aspects of task requirements, user expectations, and technological capabilities that influence the design of a voice interface and then identifies several components of user interfaces that are particularly critical in successful voice applications. Examples from several applications are provided to demonstrate how these components are used to produce effective voice interfaces.

Psychometric functions for loudness discomfort and most comfortable loudness levels.

Adaptive procedures were used to determine psychometric functions for loudness discomfort level (LDL) and most comfortable loudness (MCL) for pure tones and speech using normal and hearing-impaired listeners. For the LDL, both groups demonstrated steeply rising functions with the 50% point at approximately 100 dB SPL. The MCL data resulted in two functions, one (Function A) differentiating MCL from less intense stimulus levels and the second (Function B) differentiating between MCL and more intense levels. Function A may be considered a lower bound and Function B an upper bound for MCL. For the normal listeners, the difference between the functions at 50% response ranged from 9.9 to 19.9 dB depending upon the experimental condition. For the hearing-impaired subjects, this range was restricted to approximately 4.5 dB, primarily as a result of a shift in Function A toward higher sound pressure levels.

Accuracy of adaptive procedure estimates of PF-max level.

A measure of maximum speech recognition ability (PB max) is often obtained in the clinical audiologic evaluation of patients. However, without developing a complete performance-intensity function (PIF), it is often difficult to determine an appropriate intensity level for measuring PB max. Levitt (1978) has described an adaptive procedure designed to estimate an intensity level at which maximum speech recognition performance could be measured. We have investigated the accuracy of this procedure by comparing speech recognition performance on a CNC word list presented at the level estimated by the adaptive procedure with maximum performance as measured on the listener's performance-intensity function. Using the presentation level indicated by the adaptive procedure, PB max scores were obtained for 12 of 16 normally hearing subjects and 19 of 25 listeners with mild-to-moderate sensorineural hearing loss. Similar accuracy was obtained for the hearing-impaired subjects using a single presentation level of 95 dB SPL, while use of a 40 dB SL speech level would have resulted in a lower proportion of PB-max measurements. Although PB max is most accurately estimated by delineating the entire performance-intensity function, the current results suggest that, if speech recognition is to be measured only at a single level, scores obtained at the level estimated by the adaptive procedure or at 95 dB SPL may serve as reasonable estimates of PB max for listeners with primarily cochlear hearing losses of less than or equal to 50 dB.

Effect of sensorineural hearing loss on loudness discomfort level and most comfortable loudness judgments.

A simple up-down adaptive procedure was used to estimate the 50% point on the psychometric function for loudness discomfort level (LDL) and the two functions describing the range of most comfortable loudness (MCL) for listeners with sensorineural hearing impairment. For pure tone and speech stimuli, median LDL and MCL levels were observed at relatively constant SPLs for subjects with hearing loss less than or equal to dB HL and at progressively higher SPLs with further increase in hearing loss. Correlation analysis verified a statistically significant relationship between LDL and magnitude of hearing loss. The nonlinear relationship between LDL and hearing loss together with the large intersubject variability in the data suggest that prediction of LDL from hearing threshold would often be highly inaccurate. These results also demonstrate that averaging LDL data across a group of subjects with a wide range of hearing loss may lead to inaccurate conclusions regarding the effects of sensorineural hearing loss on LDL.

Use of performance-intensity functions for diagnosis.

Performance-intensity (PI) functions for phonetically balanced (PB) word lists were obtained for a group of normal listeners (27 ears), and for two groups of patients with cochlear (89 ears) and retrocochlear disorders (eight ears). Listeners with normal hearing or cochlear disorders exhibited mild to moderate reductions in discrimination score as the speech level was raised above the PB maximum. In contrast, patients with retrocochlear disorders showed a pronounced rollover phenomenon, characterized by a rapid decline in performance as the speech level was raised above the maximum discrimination score.

Some effects of spectral shaping on recognition of speech by hearing-impaired listeners.

The effects of spectral shaping on speech recognition were investigated for hearing-impaired listeners with flat and steep audiometric configuration. Three frequency responses were tested: uniform frequency gain, high pass filtering, and a response shaped relative to each subject's loudness discomfort level curve. Speech-recognition performance was measured at four levels (from 80 to 95 dB SPL) using nonsense syllable (NST) and synthetic sentence (SSI) tests, presented against a background of "cafeteria noise." No significant differences in performance on the NST were observed between the two subject groups across all spectral shapes (frequency response) and presentation levels. On the SSI, performance of subjects with flat audiometric configuration was highest using the uniform frequency response, while performance of listeners with steep configuration was poorest for the uniform response. The recognition data were compared with predictions of relative performance using a modification of the Articulation index (AI). The AIs provided accurate estimates of relative performance across spectral shapes but were not consistent with relative performance as a function of presentation level. The results indicate that the selection of spectral shape for optimal performance is influenced by the particular speech task used to test recognition and also suggest that, with further validation, the AI may provide an objective technique for selecting optimal spectral shape.