| 1. |
- Springer, W, et al.
(author)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Conference paper (peer-reviewed)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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| 2. |
- Appleton, Jason Philip, et al.
(author)
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The TOS2 study: An international multi-centre audit assessing the standard of neurological examination
- 2015
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 86:11
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Conference paper (peer-reviewed)abstract
- Having previously demonstrated that in-patients referred to neurology at two UK hospitals were not fully examined prior to referral, we designed an audit with 80% power to detect a 10% increase in tendon hammer or ophthalmoscope use following an educational intervention. In-patients referred to neurology over a 4 month period in the UK, Jordan, Sweden and the United Arab Emirates were asked whether they recalled examination with a Tendon hammer, Ophthalmoscope and Stethoscope since admission. Results were disseminated to local medical teams and data were collected for a further 4 months. Pre and post-intervention data were available for 11 centres with 407 and 391 patients in each arm. 264 patients (64.86%) recalled examination with a tendon hammer preintervention, which significantly improved to 298 (76.21%) (p
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| 3. |
- Rödström, E. Ygland, et al.
(author)
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Genomic analyses of a large Swedish multi-incident kindred with autosomal dominant Parkinson’s disease with dementia
- 2023
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In: Parkinsonism & Related Disorders. - 1353-8020. ; 113:Supp, s. 28-29
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Conference paper (peer-reviewed)abstract
- Background:The known genetic causes for Parkinson’s disease (PD) onlyexplain a small proportion of the familial aggregation of PD. Despiteintensive efforts by researchers internationally, identifying and confirmingadditional monogenic causes for PD has been difficult.Methods:We examined 16 members of a large family with multi-incidentPD and dementia. Eight members were examined by whole exome (WES)or whole genome sequencing. Rare variants co-segregating with the disease were evaluated based on their distribution in additional familymembers and known gene functions. WES data from 843 PD cases and 885controls were screened for the two most highly ranked candidate variantsand used for gene burden analysis.Results:Clinically, all affected family members had typical PD withcognitive decline. Two affected individuals showed typical PD neuropathology. Out of nine genetic variants identified, we highlighted two as goodcandidates for causing this family’s PD. However, co-segregation with PDwas imperfect and this study was complicated by the fact that somegenotyped family members showed mild motor symptoms of uncertaincause, or cognitive decline without apparent motor dysfunction. Geneburden analysis showed no difference between cases and controls in thefrequency of potentially deleterious variants in the top-candidate genes.Nonetheless, factors that could indicate an impact of either of the two topcandidate genetic variants were found as one of the variants was identifiedin one additional familial PD proband from the case series and geneticvariants in the other top-candidate gene had previously been associatedwith an increased risk for PD in humans.Conclusions: Our study was not able to determine a single high-impactvariant as the cause of PD with cognitive decline in the family despitedetailed clinical and genetic assessments, but we nominate two potentialcandidate variants. Reduced penetrance and phenocopies may complicategenomic studies of families with PD.
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| 4. |
- Perez-Soriano, Alexandra, et al.
(author)
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PBB3 Imaging in Parkinsonian disorders: Evidence for binding to abnormally aggregated proteins in addition to tau proteins
- 2017
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In: Movement Disorders. - : Wiley. - 1531-8257 .- 0885-3185. ; 32:Suppl 2, s. 585-587
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Conference paper (peer-reviewed)abstract
- Objective: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 ([11C]methylamino pyridin-3-yl buta-1,3-dienyl benzo[d]thiazol-6-ol) in tauopathies, and in conditions not typically associated with tauopathy. Background: Tau imaging is a promising tool to study the link between tau and neurodegeneration. The specificity of tracers in vivo however remains uncertain, and off target binding is frequently present, limiting its use in parkinsonian disorders. Methods: Dynamic PET scans were obtained for 70 min after the bolus injection of [11C]PBB3 (mean dose 518.97MBq) in five PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype,3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 7 healthy controls of similar age. The occipital cortex was used as reference region for the PSP , the DCTN1 mutation and the MSA subjects. The cerebellar white matter was used as a reference region for the SNCA duplication carriers. Tissue reference Logan analysis was applied to each region of interest (ROI) using the appropriate reference region. Results: In PSP subjects, the highest retention of [11C]PBB3 was observed in putamen, midbrain, globus pallidus and substantia nigra. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. The DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and globus pallidus. In SNCA duplication carriers there was a significant increase of [11C] PBB3 binding compared to controls in globus pallidus, putamen, thalamus, ventral striatum, substantia nigra, and pedunculopontine nucleus. The MSA case showed increased binding in comparison to the control group in frontal lobe, globus pallidus, midbrain, parietal lobe, putamen, temporal lobe, substantia nigra, thalamus and ventral striatum. Conclusions: All PSP patients showed increased retention of the tracer in the basal ganglia, as clinically expected. However, binding was also present in asymptomatic SNCA duplication carriers as well as the subject with MSA, which are not typically associated with pathological tau deposition. This suggests the possibility that [11C]PBB3 binds to alpha-synuclein or other proteins involved in neurodegeneration.
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| 5. |
- Dobloug, S., et al.
(author)
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A Swedish SCA34 family with late onset ataxia, cerebellar atrophy and ocular movement abnormalities with a novel mutation in ELOVL4
- 2023
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In: Parkinsonism & Related Disorders. - 1353-8020. ; 113:Suppl, s. 72-72
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Conference paper (peer-reviewed)abstract
- Background: To investigate the clinical and radiological presentation of anew ELOVL4mutation in a Swedish family.Methods:We compiled information on a Swedish family with 6 affectedmembers. Four of these had undergone neurological and radiological examinations. Two patients were independently analysed genetically bywhole exome or whole genome sequencing.Results: All examined affected family members showed slowly progressivecerebellar ataxia with balance impairment starting at between 42 and 70years, ocular movement disturbances with nystagmus, hypermetric saccades or vertical gaze palsy, and cerebellar atrophy on imaging. None of theaffected family members had erytrokeratodermia variabilis, but three haddry skin or psoriasis. Two members had seizures, one had intermittentmuscular cramps. One deceased obligate carrier had dementia and one ofthe members examined had mild cognitive dysfunction (MMSE 23/30). Oneindividual had poor night vision. One individual had a diagnosis ofschizophrenia since age 25 years. We identified a novel heterozygousvariant ELOVL4 c.511A>C, p.(Ile171Leu) (NM_022726.4) in affected individuals. When this was discovered in the first family member it was reported as a variant of uncertain significance (VUS). However, aftersegregation analysis and detailed clinical information for the entire family,the variant could be reclassified as likely pathogenic according to the ACMG classification system (PMID: 25741868) and Jarvik et al (PMID: 27236918).Conclusions: So far, including the present report, eight different ELOVL4-variants have been described in SCA34 patients. Our examinations provideadditional knowledge to the presentation of this rare neurodegenerativedisorder.
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| 6. |
- Dulski, J., et al.
(author)
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Neuroacanthocytosis - Clinical variability (a report on six cases)
- 2014
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 29:Suppl 1, s. 194-194
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Conference paper (peer-reviewed)abstract
- Objective: To provide clinical clues to differential diagnosis in patients with chorea and other movement disorders with blood acanthocytes. Background: Neuroacanthocytosis (NA) is an umbrella term for neurological conditions associated with acanthocytosis. Core NA syndromes, with basal ganglia involvement and in which acanthocytosis is a frequent finding, include autosomal recessive choreaacanthocytosis (Ch-Ac) and X-linked McLeod syndrome (MLS). Due to the very low prevalence, scarcity of data and high clinical variability they may be underdiagnosed. Methods: Six male patients (pts), three diagnosed with Ch-Ac: 33-y.o.(no.1), 35-y.o.(no.2), 42-y.o.(no.3), two diagnosed with MLS: 52-y.o.(no.4), 60-y.o.(no.5) and one 62-y.o.(no.6), a brother of no.5, with clinical suspicion of MLS. The patients had an unremarkable family history and were asymptomatic until adulthood. Pts no.1,2,4,5,6 developed generalized chorea and patient no.3 had predominant bradykinesia. Pts no.1,2,3 had phonic and motor tics, additionally pts no.1 and 2 exhibited peculiar oromandibular dystonia with tongue thrusting. In pts no.2 and 3 dystonic supination of feet was observed, patient no.3 subsequently developed bilateral foot drop. Pts no. 2 and 4 had signs of muscle atrophy. Tendon reflexes were decreased or absent and electroneurography demonstrated sensorimotor neuropathy in patients no. 1,2,3,4,5, except no. 6. Generalized seizures were seen in patients no.2,3,5,6 and myoclonic jerks in patient no 1. Cognitive deterioration was reported in patients no.1,2,3,5,6. Serum creatine kinase levels were elevated in all six patients. Results: Peripheral blood smears revealed acanthocytosis in patients no.1,2,3,5,6, except no. 4. In patients no. 1 and 3 reduced expression of chorein was detected on Western blot. In patient no. 2 genetic testing showed mutations in VPS13A gene and in no.4 and 5 genetic analysis confirmed mutations in XK gene (MLS). The time from the onset of symptoms till establishing the diagnosis in patients no. 1,2,3,4,5 was 11,5,7,6,32 years respectively. Patient no.4 suddenly developed multiple organ failure and died of cardiac arrhythmia at the age of 52. Conclusions: We highlight the variability of clinical presentation of NA syndromes and the long time from the onset to diagnosis with the need to screen the blood smears in uncertain cases, however, as in one of our cases acanthocytes may even be not found.
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| 7. |
- Gorcenco, S., et al.
(author)
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Patient perspective in hereditary ataxia
- 2023
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In: Parkinsonism & Related Disorders. - 1353-8020. ; 113:Supp, s. 9-9
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Conference paper (peer-reviewed)abstract
- Background: Hereditary ataxia is a group of rare disorders. Healthcareproviders and public authorities may have limited knowledge about thisdiagnosis. We asked the patients if they feel well-informed about thediagnosis and whom they usually turn to for support.Methods: Adult patients with a diagnosis of progressive cerebellar ataxiawere identified in the diagnosis register of Scania region or were recruitedthrough a patient organization. All patients were examined clinically. Asurvey with 32 multiple choice and open-ended questions was distributedthrough a secure online tool. Written and informed consent was obtainedfrom every participant. Our study is ethically approved.Results: Participants (N¼79) were aged between 22 and 80 years, onsetvaried from 1 to 73 years. The most common symptom at onset was“impaired balance”. The SARA score median was 10 (SD 9,06). Progress wasdescribed as slow by 87,3% (N¼69). Genetic testing was recalled by 56,9%(N¼45) of which 38% (N¼30) received a genetic diagnosis. Among patientswho had a genetic diagnosis, 76.7% felt “well-informed” (36.7%) or “partlywell informed” (40.0%) about their diagnosis. Among patients who did nothave a genetic diagnosis, 59.2% felt (fully: 22.4%; partly: 36.7%) wellinformed.This difference did not reach statistical significance (Pearson Chi-Square 0,17, Cramer’s V 0,2). On the question “what helps you feel better?”, “exercise” was the predominant answer 40,5% (N¼ 32) followed by “socialsupport from close family” and “medication”. Patients answered that closefamily and friends is the first instance they turn to for moral support (N¼62).Conclusions: This patient-perspective study on hereditary ataxia highlightsthe need to improve the disease-related information that healthservice providers give to their patients, even when the exact geneticsubtype has been established. Physiotherapy and support from closefamily are important for the wellbeing of patients with hereditary ataxia.
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| 8. |
- Kafantari, E., et al.
(author)
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Whole exome sequencing of familial, combined or complex dystonia
- 2023
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In: Parkinsonism & Related Disorders. - 1353-8020. ; 113:Supp, s. 65-66
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Conference paper (peer-reviewed)abstract
- Background: To determine the usefulness of whole exome sequencing(WES) in the diagnostic evaluation of patients and small families withfamilial, combined and/or complex forms of dystonia identified from anadult neurology clinic at a tertiary center, and to set up a computationalpathway for the bioinformatics analyses.Methods: By mail, we contacted all 347 patients from our department whoduring a 4-year period had an ICD-10 diagnosis of dystonia. Of these, 122were re-examined within our research study. Patients who had combinedand/or complex dystonia phenotypes and patients who reported closefamily members with dystonia were examined by WES. Differentcomputational approaches followed (co-segregation or trio analysis,filtering variants based on an in-house gene list with more than 500 dystonia nuclear and mitochondrial genes etc.). Copy number variants (CNVs)were also detected by using in-silico tools.Results: Re-examination revealed that 11 of 122 (9.0%) of patients hadother disorders. Of the remaining 111 patients, fourteen had familial, combined or complex dystonia phenotypes starting at mean 37.6 (SD 14.9)years and were analysed by WES. For 5 of these, a definite or candidatemonogenic disease cause was identified (table).The diagnostic yield in this project was 35,7% with positive or likely positive findings. Two of 5 patients had variants that had been described previously (40%) and the remaining 3 carried putatively pathogenic variants (60%).Conclusions: Candidate disease-causing variants were identified in 5 out of 14 cases investigated, all these had combined or complex dystonia and relatively young onset (mean 22.3, SD 11.3 years). CNV analysis is relevant in the genetic workup of familial/combined/complex dystonia.
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| 9. |
- Puschmann, Andreas J., et al.
(author)
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Familial late-onset focal dystonia in an African American family
- 2010
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 68:Suppl. S14, s. 69-69
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Conference paper (peer-reviewed)abstract
- Recent studies of THAP1 (DYT6) have pointed out that late-onset focal dystonia can have a genetic basis. Familial late-onset primary dystonia has not been described in African- Americans. Six members of an African American family were affected by focal or segmental dystonia with a mean age at onset of 47 years (range, 45-50). Two additional individuals with milder clinical signs were classified as probably affected. Clinical phenotypes included cervical, laryngeal and handforearm (writer's cramp) dystonia, following an autosomal dominant mode of inheritance. TOR1A (DYT1) and THAP1 (DYT6) were screened for sequence variants. There were no abnormalities in TOR1A. A novel THAP1 sequence variant (c.-237-3G>T) was found in both affected and unaffected family members and did not co-segregate with dystonia. This variant was also found in 1/212 African American control alleles. Another variant at the same site (c.-237-3G>A) was found in 2/212 African American control alleles and one African American subject with laryngeal dystonia (1/84 alleles). Therefore, these variants are unlikely to be pathogenic. Familial late-onset primary dystonia does occur in non-Caucasian populations. Future studies of THAP1 and other dystonia genes must take genetic background into consideration.
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| 10. |
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