| 1. |
- Elbaz, Alexis, et al.
(author)
-
Independent and Joint Effects of the MAPT and SNCA Genes in Parkinson Disease
- 2011
-
In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 69:5, s. 778-792
-
Journal article (peer-reviewed)abstract
- Objective: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. Methods: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. Results: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 30 end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. Interpretation: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. ANN NEUROL 2011; 69: 778-792
|
|
| 2. |
- Gorcenco, Sorina, et al.
(author)
-
Ataxia-pancytopenia syndrome with SAMD9L mutations
- 2017
-
In: Neurology: Genetics. - 2376-7839. ; 3:5
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations.METHODS: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed.RESULTS: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.CONCLUSIONS: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.
|
|
| 3. |
- Behzadi, Arvin, 1994-
(author)
-
Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis
- 2024
-
Doctoral thesis (other academic/artistic)abstract
- Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to paresis, muscle atrophy, and respiratory failure. ALS can be difficult to diagnose and prognosticate early.Aim: To investigate the diagnostic and prognostic characteristics of biomarkers in cerebrospinal fluid (CSF), plasma, and skeletal muscle tissue in patients with ALS.Paper I: Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were analyzed in CSF using enzyme-linked immunosorbent assay (ELISA), and NFL in plasma was analyzed using single-molecule array (SIMOA). CSF NFL, CSF pNFH, and plasma NFL concentrations can differentiate ALS patients from ALS mimics, and were significantly negatively correlated with the disease duration in ALS patients.Paper II: Myosin heavy chain (MyHC) isoforms in extraocular muscles were investigated using immunofluorescence. Control donors had significantly higher proportion of myofibers containing MyHCIIa and significantly lower proportion of myofibers containing MyHCeom in the global layer compared to spinal-onset ALS and bulbar-onset ALS donors. Disease duration in the spinal-onset ALS donors was significantly correlated with the proportion of myofibers containing MyHCIIa in the global layer and MyHCeom in the orbital layer.Paper III: The study combined the neurofilament concentrations from Paper I, with cytokines previously analyzed in CSF and plasma using SIMOA, to investigate distinct molecular phenotypes in ALS. Patients with bulbar-onset ALS had significantly higher concentrations of CSF tumor necrosis factor α (TNF-α) compared to ALS mimics. TNF-α and NFL were significantly correlated with each other in both CSF and plasma in ALS patients. Combined analysis of NFL and IL-6 in plasma identified molecular prognostic subgroups in ALS patients.Paper IV: Creatine kinase (CK), high-sensitivity cardiac troponin T (hs-cTnT), hs-cTnI, and cystatin C (CysC) were analyzed in plasma in a fully accredited laboratory. CK and hs-cTnT concentrations were significantly elevated in limb-onset ALS compared to controls and bulbar-onset ALS. hs-cTnT concentrations were significantly elevated in truncal-onset ALS compared to controls and bulbar-onset ALS. Multivariable Cox proportional hazards models indicated elevated concentrations of CysC as a significant marker for worse prognosis in ALS.Conclusions: The papers report diagnostic and prognostic characteristics of biomarkers in CSF, plasma, and muscle tissue in ALS patients. The significant findings for biomarkers in plasma could be of value since plasma sampling does not involve a lumbar puncture.
|
|
| 4. |
- Ygland, Emil, et al.
(author)
-
Slowly progressive dementia caused by MAPT R406W mutations : longitudinal report on a new kindred and systematic review
- 2018
-
In: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 10
-
Research review (peer-reviewed)abstract
- Background: The MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer's disease-like clinical features. Methods: We compiled clinical data from a new Swedish kindred with R406W mutation. Seven family members were followed longitudinally for up to 22 years. Radiological examinations were performed in six family members and neuropathological examinations in three. We systematically reviewed the literature and compiled clinical, radiological, and neuropathological data on 63 previously described R406W heterozygotes and 3 homozygotes. Results: For all cases combined, the median age of onset was 56 years and the median disease duration was 13 years. Memory impairment was the most frequent symptom, behavioral disturbance and language impairment were less common, and Parkinsonism was rare. Disease progression was most often slow. The most frequent clinical diagnosis was Alzheimer's disease. R406W homozygotes had an earlier age at onset and a higher frequency of behavioral symptoms and Parkinsonism than heterozygotes. In the new Swedish kindred, a consistent imaging finding was ventromedial temporal lobe atrophy, which was evident also in early disease stages as a widening of the collateral sulcus with ensuing atrophy of the parahippocampal gyrus. Unlike previously published R406W carriers, all three autopsied patients from the novel family showed neuropathological similarities with progressive supranuclear palsy, with predominant four-repeat (exon 10+) tau isoform (4R) tauopathy and neurofibrillary tangles accentuated in the basal-medial temporal lobe. Amyloid-beta pathology was absent. Conclusions: Dominance of 4R over three-repeat (exon 10-) tau isoforms contrasts with earlier reports of R406W patients and was not sufficiently explained by the presence of H1/H2 haplotypes in two of the autopsied patients. R406W patients often show a long course of disease with marked memory deficits. Both our neuropathological results and our imaging findings revealed that the ventromedial temporal lobes were extensively affected in the disease. We suggest that this area may represent the point of origin of tau deposition in this disease with relatively isolated tauopathy.
|
|
| 5. |
|
|
| 6. |
- Hellberg, Clara, et al.
(author)
-
Nationwide prevalence of primary dystonia, progressive ataxia and hereditary spastic paraplegia
- 2019
-
In: Parkinsonism & Related Disorders. - : Elsevier BV. - 1353-8020. ; 69, s. 79-84
-
Journal article (peer-reviewed)abstract
- Objective: To determine the nationwide prevalence of primary dystonia, ataxia and hereditary spastic paraplegia (HSP) in Sweden. Methods: We extracted data on all patients who were registered in The National Patient Register (NPR) in Sweden (population 9.64 million) at least twice during five consecutive years with a diagnosis of primary dystonia, ataxia or HSP. We excluded patients with an additional diagnosis possibly indicating secondary causes, and determined the proportion of wrongly diagnosed patients at our own tertiary center by patient examination or chart review. We analyzed patients' age and disorder subtypes, geographical distribution of patients within Sweden and the country of birth of all patients. Results: Nationwide, we identified 4239 patients (31.6% male) with a diagnosis of primary dystonia. Of 347 patients with dystonia at our center, 20.2% may have had a different final diagnosis. Extrapolation of this uncertainty rate to the national population resulted in a prevalence for primary dystonia of 35.1/100,000. There were 672 patients (49.6% male) with ataxia in NPR, and the diagnostic uncertainty rate among 81 patients in our center was 13.6% (prevalence 6.0/100,000). HSP was diagnosed in 235 patients nationwide (52.3% male, prevalence 2.4/100,000). Patients were distributed relatively evenly throughout the country. The proportions of patients with these diagnoses who were born outside of Sweden were lower (8.0-12.7%) than the proportion of all Swedish residents born abroad (15.9%). Conclusions: In this large, nationwide study, the prevalence of dystonia was high compared to previous studies, which partly may be explained by the high coverage of NPR.
|
|
| 7. |
- Puschmann, Andreas, et al.
(author)
-
Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
- 2017
-
In: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 140:1, s. 98-117
-
Journal article (peer-reviewed)abstract
- SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.
|
|
| 8. |
- Heckman, Michael G., et al.
(author)
-
Population-specific Frequencies for LRRK2 Susceptibility Variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium
- 2013
-
In: Movement Disorders. - : Wiley. - 0885-3185. ; 28:12, s. 1740-1744
-
Journal article (peer-reviewed)abstract
- BackgroundVariants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. ConclusionsEstablishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. (c) 2013 International Parkinson and Movement Disorder Society
|
|
| 9. |
- Ilinca, Andreea, et al.
(author)
-
MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor
- 2021
-
In: Neurology: Genetics. - 2376-7839. ; 7:1
-
Journal article (peer-reviewed)abstract
- Objective: To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.Methods: We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.Results: Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.Conclusions: Our data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.
|
|
| 10. |
- Ilinca, Andreea, et al.
(author)
-
Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke
- 2020
-
In: Stroke. - 1524-4628. ; 51:4, s. 1056-1063
-
Journal article (peer-reviewed)abstract
- Backgrounds and Purpose- Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods- We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results- Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2:c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142:c.148C>G (p.Leu50Val), and PTPRN2:c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10c.1294dupG (p.Val432fs), IKBKB: c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions- Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
|
|
