Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients

Introduction: Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively. Methods: Molecular analyses were performed by PCR and the modified RP-PCR in patients, in their at-risk relatives and prenatal cases. Results: The analysis of Polish controls revealed the range of 5-31 CTG repeats for DM1 and 110-228 bp alleles for DM2. Among 318 confirmed probands - 196 (62%) were DM1 and 122 (38%) – DM2. Within DM1families, 10 subjects carried a low expanded CTG tract (< 100 repeats), which resulted in a full mutation in subsequent generations. Two related individuals had unstable alleles–188 bp and 196 bp without common interruptions. Conclusion: The relative frequencies of DM1/DM2 among Polish patients were 68% and 32%, respectively, with a relatively high proportion of DM2 mutations (1.6:1)

The personal experience of parenting a child with Juvenile Huntington’s Disease: perceptions across Europe

The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington’s disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington’s disease; living with the disease; other people’s knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe

Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.Acknowledgements: This work was supported by the Horizon 2020 research and innovation programme (grant 779257 Solve-RD to MS and RS), the National Ataxia Foundation (grant to CW and MS), the Wilhelm Vaillant Stiftung (grant to CW), the EU Joint Programme—Neurodegenerative Disease Research (JPND) through participating national funding agencies, and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417. BM was supported in part from the grant NKFIH 119540. HJ was funded by the Medical Faculty of the University of Heidelberg. CB was funded by the University of Basel (PhD Program in Health Sciences). The funding sources had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

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Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Pobudliwość kory ruchowej u pacjentów ze świeżo rozpoznaną chorobą Parkinsona

Background and purpose This study aimed to assess the indices of corticomotor excitability (CE) in drug-naive Parkinson disease (PD) patients and to investigate its relationship with asymmetry and severity of clinical symptoms. Material and methods Eleven (4 men) drug-naive PD patients (mean age: 53.1 ± 9.8 years) and 13 (7 men) healthy controls (mean age: 51.7 ± 4.2 years) were included. All PD patients were rated on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) with measurement of the side-specific score separately for arms and legs. Resting motor threshold (RMT), central silent period (CSP), amplitude of motor evoked potential (MEP) and central motor conduction time (CMCT) evoked by a single pulse of the transcranial magnetic stimulation were recorded in all subjects from the left and right abductor digiti minimi (ADM) and extensor digitorum brevis (EDB). Results Parkinson disease patients showed higher MEP (1.8 ± 0.9 vs. 1.1 ± 0.8 mV, p < 0.05) and shorter CMCT (6.1 ± 0.9 vs. 7.4 ± 1.0 ms, p < 0.05) recorded from the ADM on the more affected side. CSP recorded from the more affected ADM was under the normal range in five and from the less affected ADM in four PD patients. For CSP recorded from the EDB, respective values are four for the more affected side and three for the less affected side. The rigidity from the more affected arm and leg correlated negatively with the respective CSP recorded from the ADM (r = –0.74, p < 0.01) and EDB (r = –0.68, p < 0.04). Conclusions In the early stage of untreated PD the CE parameters are altered only on the more affected side. The shortening of CSP reflects the severity of rigidity on the more affected side

Pobudliwość kory ruchowej u pacjentów ze świeżo rozpoznaną chorobą Parkinsona

Background and purpose This study aimed to assess the indices of corticomotor excitability (CE) in drug-naive Parkinson disease (PD) patients and to investigate its relationship with asymmetry and severity of clinical symptoms. Material and methods Eleven (4 men) drug-naive PD patients (mean age: 53.1 ± 9.8 years) and 13 (7 men) healthy controls (mean age: 51.7 ± 4.2 years) were included. All PD patients were rated on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) with measurement of the side-specific score separately for arms and legs. Resting motor threshold (RMT), central silent period (CSP), amplitude of motor evoked potential (MEP) and central motor conduction time (CMCT) evoked by a single pulse of the transcranial magnetic stimulation were recorded in all subjects from the left and right abductor digiti minimi (ADM) and extensor digitorum brevis (EDB). Results Parkinson disease patients showed higher MEP (1.8 ± 0.9 vs. 1.1 ± 0.8 mV, p &lt; 0.05) and shorter CMCT (6.1 ± 0.9 vs. 7.4 ± 1.0 ms, p &lt; 0.05) recorded from the ADM on the more affected side. CSP recorded from the more affected ADM was under the normal range in five and from the less affected ADM in four PD patients. For CSP recorded from the EDB, respective values are four for the more affected side and three for the less affected side. The rigidity from the more affected arm and leg correlated negatively with the respective CSP recorded from the ADM (r = –0.74, p &lt; 0.01) and EDB (r = –0.68, p &lt; 0.04). Conclusions In the early stage of untreated PD the CE parameters are altered only on the more affected side. The shortening of CSP reflects the severity of rigidity on the more affected side.Wstęp i cel pracy Celem badania była ocena parametrów pobudliwości korowo-ruchowej (CE) u pacjentów ze świeżo rozpoznaną chorobą Parkinsona (ChP) oraz ich korelacji z nasileniem i asymetrią objawów klinicznych. Materiał i metody Badaniem objęto 11 (4 mężczyzn) pacjentów ze świeżo rozpoznaną ChP (średnia wieku: 53,1 ± 9,8 roku) oraz 13 (7 mężczyzn) osób zdrowych (grupa kontrolna) (średni wiek: 51,7 ± 4,2 roku). U wszystkich pacjentów dokonano oceny nasilenia objawów ruchowych według skali UPDRS z wyszczególnieniem kolejnych kończyn. U wszystkich badanych wykonano przezczaszkową stymulację magnetyczną pojedynczym impulsem z oceną: progu pobudliwości ruchowej (RMT), centralnego okresu ciszy (CSP), amplitudy wywołanego potencjału ruchowego (MEP) oraz centralnego ruchowego czasu przewodzenia (CMCT) w rejestracji z mięśni: odwodziciela palca V (ADM) i prostownika krótkiego palców (EDB) obustronnie. Wyniki W grupie chorych na ChP stwierdzono istotnie większą amplitudę MEP (1,8 ± 0,9 vs 1,1 ± 0,7; p &lt; 0,05) oraz krótszy CMCT (6,1 ± 0,9 vs 7,3 ± 1,0; p &lt; 0,05) w rejestracji z ADM po stronie bardziej zajętej. Centralny okres ciszy dla ADM był skrócony poniżej dolnego zakresu normy (&lt; 64,6 ms) po stronie bardziej zajętej u 5, a po stronie przeciwległej u 4 pacjentów. Skrócenie CSP dla EDB (&lt; 60,9 ms) zaobserwowano odpowiednio u 4 i 3 chorych. Stwierdzono ujemną korelację pomiędzy nasileniem sztywności w kończynach z przewagą objawów a CSP dla ADM (r = –0,74; p &lt; 0,008) i EDB (r = –0,68; p &lt; 0,04) po tej stronie. Wnioski We wczesnym stadium nieleczonej ChP zarejestrowano zmiany parametrów CE jedynie po stronie z przewagą objawów ruchowych. Skrócenie CSP korelowało z nasileniem sztywności po tej samej stronie