321 research outputs found
SPG10 is a rare cause of spastic paraplegia in European families
Background: SPG10 is an autosomal dominant form of hereditary spastic paraplegia (HSP), which is caused by mutations in the neural kinesin heavy chain KIF5A gene, the neuronal motor of fast anterograde axonal transport. Only four mutations have been identified to date.Objective: To determine the frequency of SPG10 in European families with HSP and to specify the SPG10 phenotype.Patients and methods: 80 index patients from families with autosomal dominant HSP were investigated for SPG10 mutations by direct sequencing of the KIF5A motor domain. Additionally, the whole gene was sequenced in 20 of these families.Results: Three novel KIF5A mutations were detected in German families, including one missense mutation (c.759G>T, p.K253N), one in frame deletion (c.768_770delCAA, p.N256del) and one splice site mutation (c.217G>A). Onset of gait disturbance varied from infancy to 30 years of age. All patients presented clinically with pure HSP, but a subclinical sensory--motor neuropathy was detected by neurophysiology studies.Conclusions: SPG10 accounts for approximately 3% of European autosomal dominant HSP families. All mutations affect the motor domain of kinesin and thus most likely impair axonal transport. Clinically, SPG10 is characterised by spastic paraplegia with mostly subclinical peripheral neuropathy
Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.
OBJECTIVE: To identify factors that determine disease severity and clinical
phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526
patients with SCA1, SCA2, SCA3. or SCA6.
METHODS: To measure the severity of ataxia we used the Scale for the Assessment
and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with
the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of
nonataxia symptoms in each patient.
RESULTS: An analysis of covariance with SARA score as dependent variable and
repeat lengths of the expanded and normal allele, age at onset, and disease
duration as independent variables led to multivariate models that explained 60.4%
of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in
SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the
expanded allele, age at onset, and disease duration. The only factors determining
the SARA score in SCA6 were age at onset and disease duration. The INAS count was
5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in
SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest
predictors of the INAS count. In SCA6, only age at onset and disease duration had
an effect on the INAS count.
CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and
SCA3 share a number of common biologic properties, whereas SCA6 is distinct in
that its phenotype is more determined by age than by disease-related factors
Износ кругов из СТМ при зубошлифовании
The problems of increasing the efficiency of grinding highly precision gearwheels of the 3–4
degree of precision using superhard material tools are discussed. The efficiency of cubic boron
nitride dish grinding wheels in various bonds has been studied. Recommendations how to use cubic
boron nitride wheels in gear grinding are given
Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.
Abstract: Onset of genetically determined neurodegenerative
diseases is difficult to specify because of their insidious and
slowly progressive nature. This is especially true for spinocerebellar
ataxia (SCA) because of varying affection of many
parts of the nervous system and huge variability of symptoms.
We investigated early symptoms in 287 patients with
SCA1, SCA2, SCA3, or SCA6 and calculated the influence
of CAG repeat length on age of onset depending on (1) the
definition of disease onset, (2) people defining onset, and (3)
duration of symptoms. Gait difficulty was the initial symptom
in two-thirds of patients. Double vision, dysarthria, impaired
hand writing, and episodic vertigo preceded ataxia in 4% of
patients, respectively. Frequency of other early symptoms did
not differ from controls and was regarded unspecific. Data
about disease onset varied between patients and relatives for
1 year or more in 44% of cases. Influence of repeat length
on age of onset was maximum when onset was defined as
beginning of permanent gait disturbance and cases with
symptoms for more than 10 years were excluded. Under
these conditions, CAG repeat length determined 64% of
onset variability in SCA1, 67% in SCA2, 46% in SCA3, and
41% in SCA6 demonstrating substantial influence of nonrepeat
factors on disease onset in all SCA subtypes. Identification
of these factors is of interest as potential targets for
disease modifying compounds. In this respect, recognition of
early symptoms that develop before onset of ataxia is mandatory
to determine the shift from presymptomatic to affected
status in SCA
Spinocerebellar Ataxia Type 23: A Genetic Update
The spinocerebellar ataxia type 23 locus was identified in 2004 based on linkage analysis in a large, two-generation Dutch family. The age of onset ranged 43–56 years and the phenotype was characterized by a slowly progressive, isolated ataxia. Neuropathological examination revealed neuronal loss in the Purkinje cell layer, dentate nuclei, and inferior olives. Ubiquitin-positive intranuclear inclusions were found in nigral neurons, but were considered to be Marinesco bodies. The disease locus on chromosome 20p13-12.3 was found to span a region of approximately 6 Mb of genomic DNA, containing 97 known or predicted genes. To date, no other families have been described that also map to this SCA locus. Direct sequencing of the coding regions of 21 prioritized candidate genes did not reveal any disease-causing mutation. Apparently, the SCA23 gene is a disease gene with a different function than the genes that have been associated with other known SCA types. Work to elucidate the chromosomal organization of the SCA23 locus will eventually discover the responsible disease gene
Mutations in Potassium Channel KCND3 Cause Spinocerebellar Ataxia Type 19
OBJECTIVE: To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21-q21. METHODS: Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high-resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild-type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch-clamping. RESULTS: We detected a T352P mutation in the third extracellular loop of the voltage-gated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild-type Kv4.3 that was localized on the plasma membrane. The regulatory β subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane-located mutant Kv4.3 complexes or restored it only partially. INTERPRETATION: KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function
Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1-disease
OBJECTIVE: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of RFC1-repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS: Multimodal RFC1 repeat screening (PCR, southern blot, whole-exome/genome (WES/WGS)-based approaches) combined with cross-sectional and longitudinal deep-phenotyping in (i) cross-European cohort A (70 families) with ≥2 features of CANVAS and/or ataxia-with-chronic-cough (ACC); and (ii) Turkish cohort B (105 families) with unselected late-onset ataxia. RESULTS: Prevalence of RFC1-disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1-disease was also identified in Western and Eastern Asians, and even by WES. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (=overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea and/or dystonia (11%). Ataxia progression was ∼1.3 SARA points/year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1]), but also included early falls, variable non-linear phases of MSA-C-like progression (SARA 2.5-5.5/year), and premature death. Treatment trials require 330 (1-year-trial) and 132 (2-year-trial) patients in total to detect 50% reduced progression. CONCLUSIONS: RFC1-disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes, yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1-treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RFC1-repeat expansions are associated with CANVAS and ACC
Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease
Objective To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).
Methods Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing?based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ?2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.
Results Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ?1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ?9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C?like progression (SARA points 2.5?5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.
Conclusions RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.
Classification of Evidence This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.FUNDING: Study Funding This work was supported via the European Union’s Horizon 2020 research and innovation program by the BMBF under the frame of the E-Rare-3 network PREPARE (01GM1607; to M. Synofzik,M.A., H.P., B.P.v.d.W.), by the DFG under the frame of EJP-RD network PROSPAX (No. 441409627; M. Synofzik, B.P.v.d.W., A.N.B.), and grant 779257 “Solve-RD” (toM. Synofzik, B.P.v.d.W.). B.P.v.d.W. receives additional research support from ZonMW, Hersenstichting, Gossweiler Foundation, uniQure, and Radboud University Medical Centre. T.B.H. was supported by the DFG (No 418081722). A.T. receives funding from the University of T¨ubingen, medical faculty, for the Clinician Scientist Program grant 439-0-0. A.C. thanks Medical Research Council, MR/T001712/1) and Fondazione CARIPLO (2019-1836) for grant support. L.S., T.K., B.P.v.d.W., and M. Synofzik are members of the European Reference Network for Rare Neurological Diseases, project 739510. A.N.B. is supported by the Suna and Inan Kirac Foundation and Koç University School of Medicine
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