| 1. |
|
|
| 2. |
|
|
| 3. |
- af Edholm, Karolina, et al.
(författare)
-
Clinical Reasoning : Leg weakness and stiffness at the emergency room
- 2019
-
Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 92:6, s. E622-E625
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A 48-year-old woman from the Maghreb came to the emergency department with insidious gait difficulties, urgency, and constipation starting 6 months prior to the visit. The patient's complaints consisted of weakness, stiffness, and pain in her legs. Her medical history consisted of Hashimoto thyroiditis and breast cancer, with the latter having motivated surgery 4 months prior to admission. Histopathologic examination had demonstrated ductal cancer sensitive to estrogen and mapping with sentinel node biopsy ruled out metastasis. For that reason, the patient was treated with local radiation given weekly over 1 month and treatment with tamoxifen was started. Physical examination upon admission demonstrated weakness and spasticity in both legs. Reflexes were brisk; bilateral nonsustained foot clonus and Babinski sign were also present. Bilateral dorsal flexion was reduced, but vibration and sensation to touch and pinprick were normal. Sphincter tonus was reduced; systemic manifestations such as myalgias, fever, skin rashes, uveitis, sicca, and arthritic joints were absent.
|
|
| 4. |
- Bieder, Andrea, et al.
(författare)
-
Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia : a case report
- 2020
-
Ingår i: BMC Medical Genetics. - : Springer. - 1471-2350. ; 21:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies. Case presentation Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified. Conclusions We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.
|
|
| 5. |
- Keller, Annika, et al.
(författare)
-
Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:9, s. 1077-
-
Tidskriftsartikel (refereegranskat)abstract
- Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait ( idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor beta (PDGF-R beta) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R beta. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
|
|
| 6. |
- Korpela, Sara, et al.
(författare)
-
Cerebrospinal fluid glial fibrillary acidic protein, in contrast to amyloid beta protein, is associated with disease symptoms in Huntington's disease
- 2024
-
Ingår i: Journal of the Neurological Sciences. - : Elsevier. - 0022-510X .- 1878-5883. ; 459
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Huntington's disease (HD) is a hereditary neurodegenerative disease, currently lacking disease-modifying treatments. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (Aβ42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers.Methods: CSF from participants was obtained from three sites in Sweden. Clinical symptoms were graded with the composite Unified Huntington's disease rating scale (cUHDRS). Protein concentrations were measured using ELISA. Pearson correlations were calculated to assess disease progression association. Results were adjusted for age and collection site.Results: The study enrolled 28 manifest HD patients (ManHD), 13 premanifest HD gene-expansion carriers (PreHD) and 20 controls. Aβ42 levels did not differ between groups and there was no correlation with measures of disease progression. GFAP concentration was higher in ManHD (424 ng/l, SD 253) compared with both PreHD (266 ng/l, SD 92.4) and controls (208 ng/l, SD 83.7). GFAP correlated with both cUHDRS (r = -0.77, p < 0.001), and 5-year risk of disease onset (r = 0.70, p = 0.008).Conclusion: We provide evidence that indicates CSF Aβ42 has limited potential as a biomarker for HD. GFAP is a potential biomarker of progression in HD. Validation in larger cohorts measuring GFAP in blood and CSF would be of interest.
|
|
| 7. |
- Lindahl, Hannes, et al.
(författare)
-
The clinical spectrum of ataxia telangiectasia in a cohort in Sweden
- 2024
-
Ingår i: Heliyon. - 2405-8440. ; 10:4
-
Tidskriftsartikel (refereegranskat)abstract
- Ataxia telangiectasia (A-T), caused by biallelic variants in the ATM gene, is a multisystemic and severe syndrome characterized by progressive ataxia, telangiectasia, hyperkinesia, immunodeficiency, increased risk of malignancy, and typically death before the age of 30. In this retrospective study we describe the phenotype of 14 pediatric and adult A-T patients evaluated at the Karolinska University Hospital in Sweden during the last 12 years. Most of the patients in this cohort were severely affected by ataxia and wheelchair use started at a median age of 9 years. One patient died before the age of 30 years, but five patients had survived beyond this age. Four patients received prophylactic immunoglobulin replacement therapy due to hypogammaglobulinemia and respiratory complications ranged from mild to moderate severity. Three patients developed type 2 diabetes in young adulthood and nine patients (64%) had a history of elevated liver function tests. Four patients were diagnosed with cancer at ages 7, 41, 47, and 49 years. All the ATM variants in these patients were previously reported as pathogenic except one, c.6040G > A, which results in a p.Glu2014Lys missense variant. With increased life expectancy, A-T complications such as diabetes type 2 and liver disease may become more common. Despite having severe neurological presentations, the A-T patients in this case series had relatively mild infectious and respiratory complications.
|
|
| 8. |
- Lindstrand, Anna, et al.
(författare)
-
Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability
- 2022
-
Ingår i: Genetics in Medicine. - : ELSEVIER SCIENCE INC. - 1098-3600 .- 1530-0366. ; 24:11, s. 2296-2307
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
|
|
| 9. |
- Machaczka, Maciej, et al.
(författare)
-
Impact of imiglucerase supply shortage on clinical and laboratory parameters in norrbottnian patients with Gaucher disease type 3.
- 2015
-
Ingår i: Archivum Immunologiae et Therapiae Experimentalis. - : Springer Science and Business Media LLC. - 0004-069X .- 1661-4917. ; 63:1, s. 65-71
-
Tidskriftsartikel (refereegranskat)abstract
- A viral contamination of the production plant producing imiglucerase (Cerezyme™) resulted in an unpredicted worldwide shortage of global supplies during 2009-2010. The aim of the study was to describe the effects of dose reduction of enzyme replacement therapy (ERT) in adults with Norrbottnian form of Gaucher disease type 3 (N-GD3). There were ten adults with N-GD3 treated with imiglucerase in the county of Norrbotten in June 2009. Analyzed variables included plasma chitotriosidase activity and concentration of CCL18/PARC, whole blood hemoglobin concentration (Hb) and platelet count (PLT), as well as patients' body weight, subjective complaints and health status measured by the EuroQoL-5D questionnaire. The median duration of ERT shortage lasted for 14 months (10-20 months). The median percentage reduction of imiglucerase dose was 36 % (26-59 %). Hb decreased in four patients, PLT decreased in three patients, chitotriosidase increased in three patients (max. +22 % of baseline), and CCL18/PARC increased in six patients (+14 % to +57 %). The body weight was moderately decreased in one patient. No new bone events were noted. Self-assessment of individual patient's health status was stable in all but one patient. Our results suggest that moderate reduction of ERT dosage lasting for relatively short period of time can lead to worsening in biomarkers of adults with N-GD3. However, this worsening is infrequently translated to clinical worsening of patients. It is possible that CCL18/PARC has a higher sensitivity than chitotriosidase in monitoring of ERT dosing in GD3.
|
|
| 10. |
- Machaczka, Maciej, et al.
(författare)
-
Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients
- 2018
-
Ingår i: Blood Cells, Molecules & Diseases. - San Diego : Academic Press. - 1079-9796 .- 1096-0961. ; 68:S1, s. 86-92
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1.METHODS: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken.RESULTS: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations.CONCLUSIONS: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD.
|
|
| 11. |
- Niemelä, Valter, et al.
(författare)
-
CSF Proenkephalin decreases with the progression of Huntington's disease
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 presymptomatic gene expansion carriers (pGEC) and 38 controls. In ManHD compared to pGEC 10 proteins were downregulated, and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin along with upregulated proteins (VASN, STC2, SGCE and C7) were all closely linked to HD symptom severity. The decreased PENK levels were replicated in a separate cohort of 23 ManHD and 23 controls where absolute quantitation was performed. We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK, and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD.
|
|
| 12. |
- Niemelä, Valter, et al.
(författare)
-
Huntingtons sjukdom – kliniska prövningar inger nu optimism
- 2020
-
Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518.
-
Forskningsöversikt (refereegranskat)abstract
- Huntingtons sjukdom är en autosomalt dominant neurodegenerativ sjukdom, som leder till förtidig död. Orsaken är expansion av en CAG-triplett i huntingtingenen.Sjukdomen är vanligast i västerländska befolkningar. Den debuterar typiskt i medelåldern och orsakar framskridande motoriska, kognitiva och psykiska symtom.I dag finns endast symtomlindrande mediciner tillgängliga, men ny molekylärgenetisk teknologi kan komma att möjliggöra behandlingar som minskar nivåerna av muterat huntingtin.
|
|
| 13. |
|
|
| 14. |
- Niemelä, Valter, et al.
(författare)
-
Phenotypic variability in chorea-acanthocytosis associated with novel VPS13A mutations
- 2020
-
Ingår i: NEUROLOGY-GENETICS. - : LIPPINCOTT WILLIAMS & WILKINS. - 2376-7839. ; 6:3
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo perform a comprehensive characterization of a cohort of patients with chorea-acanthocytosis (ChAc) in Sweden.MethodsClinical assessments, targeted genetic studies, neuroimaging with MRI, [F-18]-fluorodeoxyglucose (FDG) PET, and dopamine transporter with I-123 FP-CIT (DaTscan) SPECT. One patient underwent magnetic resonance spectroscopy (MRS).ResultsFour patients living in Sweden but with different ethnical backgrounds were included. Their clinical features were variable. Biallelic VPS13A mutations were confirmed in all patients, including 3 novel mutations. All tested patients had either low or absent chorein levels. One patient had progressive caudate atrophy. Investigation using FDG-PET revealed severe bilateral striatal hypometabolism, and DaTscan SPECT displayed presynaptic dopaminergic deficiency in 3 patients. MRS demonstrated reduced N-acetylaspartate/creatine (Cr) ratio and mild elevation of both choline/Cr and combined glutamate and glutamine/Cr in the striatum in 1 case. One patient died during sleep, and another was treated with deep brain stimulation, which transiently attenuated feeding dystonia but not his gait disorder or chorea.ConclusionsLarger longitudinal neuroimaging studies with different modalities, particularly MRS, are needed to determine their potential role as biomarkers for ChAc.
|
|
| 15. |
- Nordenvall, Anna Skarin, et al.
(författare)
-
Hypospadias as a novel feature in spinal bulbar muscle atrophy
- 2016
-
Ingår i: Journal of Neurology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0340-5354 .- 1432-1459.
-
Tidskriftsartikel (refereegranskat)abstract
- Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repeat expansions in the androgen receptor (AR) gene. The SBMA phenotype consists of slowly progressive neuromuscular symptoms and undermasculinization features as the result of malfunction of the AR. The latter mainly includes gynecomastia and infertility. Hypospadias is also a feature of undermasculinization with an underdeveloped urethra and penis; it has not been described as part of the SBMA phenotype but has been suggested to be associated with a prolonged CAG repeat in the AR gene. This study includes the first epidemiologic description of the co-occurrence of hypospadias and SBMA in subjects and their male relatives in Swedish population-based health registers, as well as an additional clinical case. One boy with severe hypospadias was screened for mutations in the AR gene and was found to have 42 CAG repeats in it, which is in the full range of mutations causing SBMA later in life. We also detected a maximum of four cases displaying the combination of SBMA and hypospadias in our national register databases. This is the third case report with hypospadias in association with CAG repeat expansions in the AR gene in the full range known to cause SBMA later in life. Our findings suggest that hypospadias may be an under diagnosed feature of the SBMA phenotype and we propose that neurologists working with SBMA further investigate and report the true prevalence of hypospadias among patients with SBMA.
|
|
| 16. |
|
|
| 17. |
- Paucar, Martin, et al.
(författare)
-
Genetic screening for Huntington disease phenocopies in Sweden : A tertiary center case series focused on short tandem repeat (STR) disorders
- 2023
-
Ingår i: Journal of the Neurological Sciences. - : Elsevier. - 0022-510X .- 1878-5883. ; 451
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo perform a screening for Huntington disease (HD) phenocopies in a Swedish cohort.MethodsSeventy-three DNA samples negative for HD were assessed at a tertiary center in Stockholm. The screening included analyses for C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis (C9orf72-FTD/ALS), octapeptide repeat insertions (OPRIs) in PRNP associated with inherited prion diseases (IPD), Huntington's disease-like 2 (HDL2), spinocerebellar ataxia-2 (SCA2), spinocerebellar ataxia 3 (SCA3) and spinocerebellar ataxia-17 (SCA17). Targeted genetic analysis was carried out in two cases based on the salient phenotypic features.ResultsThe screening identified two patients with SCA17, one patient with IPD associated with 5-OPRI but none with nucleotide expansions in C9orf72 or for HDL2, SCA2 or SCA3. Furthermore, SGCE-myoclonic-dystonia 11 (SGCE-M-D) and benign hereditary chorea (BHC) was diagnosed in two sporadic cases. WES identified VUS in STUB1 in two patients with predominant cerebellar ataxia.ConclusionsOur results are in keeping with previous screenings and suggest that other genes yet to be discovered are involved in the etiology of HD phenocopies.
|
|
| 18. |
- Paucar, Martin, et al.
(författare)
-
Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation.
- 2013
-
Ingår i: Prion. - : Informa UK Limited. - 1933-6896 .- 1933-690X. ; 7:6, s. 501-10
-
Tidskriftsartikel (refereegranskat)abstract
- A minority of inherited prion diseases (IPD) are caused by four to 12 extra octapeptide repeat insertions (OPRI) in the prion protein gene (PRNP). Only four families affected by IPD with 8-OPRI have been reported, one of them was a three-generation Swedish kindred in which four of seven affected subjects had chorea which was initially attributed to Huntington's disease (HD). Following the exclusion of HD, this phenotype was labeled Huntington disease-like 1 (HDL1). Here, we provide an update on the Swedish 8-OPRI family, describe the clinical features of one of its affected members with video-recordings, compare the four 8-OPRI families and study the effect of PRNP polymorphic codon 129 and gender on phenotype. Surprisingly, the Swedish kindred displayed the longest survival of all of the 8-OPRI families with a mean of 15.1 years from onset of symptoms. Subjects with PRNP polymorphic codon 129M in the mutated allele had significantly earlier age of onset, longer survival and earlier age of death than 129V subjects. Homozygous 129MM had earlier age of onset than 129VV. Females had a significantly earlier age of onset and earlier age of death than males. Up to 50% of variability in age of onset was conferred by the combined effect of PRNP polymorphic codon 129 and gender. An inverse correlation between early age of onset and long survival was found for this mutation.
|
|
| 19. |
- Paucar, Martin
(författare)
-
Genotype-phenotype characterization of familial hyperkinetic movement disorders : emphasis on ataxia and brain calcifications
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Differential diagnosis of familial chorea encompasses Huntington’s disease along with a group of conditions referred to as Huntington’s disease-like (HDL). One such HDL is an inherited prion disorder (IPD) caused by pathological insertions of 8 additional OPRIS in the prion protein gene (PRNP). Only four 8-OPRI families have been reported, one of which was Swedish. Polymorphism in codon 129 of the PRNP gene, alternating between methionine (M) and valine (V), is the primary modulator of prion diseases. The Swedish family had the longest survival of any 8-OPRI family. Patients carrying 129M in the mutated allele demonstrated earlier age of onset (AO), longer survival and earlier age of death than those with 129V. PRNP polymorphism in codon 129 together with gender determined as much as 50% of the variability in AO. An inverse correlation between early AO and length of survival was observed (Paper I). Ataxia with oculomotor apraxia type 4 (AOA4) is caused by mutations in the gene encoding polynucleotide kinase 3-prime phosphatase (PNKP) gene. A Swedish patient withAOA4 due to compound PNKP mutations, progressive symptoms and cerebellar atrophy was characterized (Paper II). Novel AOA4 features in this case were chorea during childhood, slower disease progression than previously described and low levels of the PNKP protein in her lymphocytes. Spinocerebellar ataxia type 4 (SCA4), a rare disease first described in a Scandinavian family in the American Midwest in 1996 has been found to be linked to chromosome 16q22.1. A second SCA4 family was later identified in Germany. Two Swedish SCA4 families with novel symptoms such as dystonia and dysautonomia are described here. Symptom onset was at middle age and anticipation was suggested in one family. Variable infratentorial atrophy and spinal cord atrophy was evident in all the tested patients. Flumazenil-PET revealed reduced binding in several brain regions including the insula, thalamus, hypothalamus and cerebellum. The candidate region was sequenced but no pathogenic variants were found. Widespread neurodegeneration was exhibited by two cases (Paper III). Primary familial brain calcifications (PFBC) are heterogeneous diseases. One Swedish-Finnish family (F13) with such calcifications and associated migraine, hyperkinesias and psychiatric symptoms associated is described along with five other PFBC families. The F13 family harbors the L9R mutation in the platelet-derived growth factor beta polypetide (PDGFB) gene. Other PDGFB mutations were identified in the remaining families. A hypomorphic PDGFB ret/ret mouse model displays brain calcifications and an impaired blood-brain barrier (BBB). Paper IV established mutations in PDGFB as the second most common cause of PFBC, after mutations in SLC20A2. Later, cognitive deficits, progressive hyperkinesias and calcifications in the F13 family were documented; CSF-NfL was elevated, but oxysterol levels were normal in all tested patients indicating that the BBB was intact (Paper V). One patient harboring the R467X mutation in SLC20A2 and affected by ataxia, dementia, and progressive brain calcifications is described (Paper VI). SLC20A2 encodes sodium-dependent phosphate transporter 2. As in SLC20A2 knockout mouse models, the level of phosphate in her CSF was elevated as was her CSF-NfL. In both the F13 family and the carrier of SLC20A2 mutation a coregistration was employed to evaluate the progression of calcification. GBA1 mutations and variants are risk factors for Parkinson’s disease (PD) and other types of parkinsonism. The GBA1 gene is mutated in connection with Gaucher disease (GD). A GD1 cohort (n =13) and a GD3 cohort (n=12) were examined. In the GD1 cohort two PD cases were identified but none in the GD3 cohort. Abnormal DAT scan was found in 1 GD3 patient and hyposmia was present in 44%. Six GD3 patients have lived beyond 40 years of age. Dystonia was documented as a novel feature in GD3. Neither group had detectable neurological progression during 3 years (Paper VII).
|
|
| 20. |
- Paucar, Martin, et al.
(författare)
-
V374A KCND3 Pathogenic Variant Associated With Paroxysmal Ataxia Exacerbations
- 2021
-
Ingår i: Neurology Genetics. - : American Academy of Neurology. - 2376-7839. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Ataxia channelopathies share common features such as slow motor progression and variable degrees of cognitive dysfunction. Mutations in potassium voltage-gated channel subfamily D member 3 (KCND3), encoding the K+ channel, Kv4.3, are associated with spinocerebellar ataxia (SCA) 19, allelic with SCA22. Mutations in potassium voltage-gated channel subfamily C member 3 (KCNC3), encoding another K+ channel, Kv3.3, cause SCA13. First, a comprehensive phenotype assessment was carried out in a family with autosomal dominant ataxia harboring 2 genetic variants in KCNC3 and KCND3. To evaluate the physiological impact of these variants on channel currents, in vitro studies were performed.Methods: Clinical and psychometric evaluations, neuroimaging, and genotyping of a family (mother and son) affected by ataxia were carried out. Heterozygous and homozygous Kv3.3 A671V and Kv4.3 V374A variants were evaluated in Xenopus laevis oocytes using 2-electrode voltage-clamp. The influence of Kv4 conductance on neuronal activity was investigated computationally using a Purkinje neuron model.Results: The main clinical findings were consistent with adult-onset ataxia with cognitive dysfunction and acetazolamide-responsive paroxysmal motor exacerbations in the index case. Despite cognitive deficits, fluorodeoxyglucose (FDG)-PET displayed hypometabolism mainly in the severely atrophic cerebellum. Genetic analyses revealed the new variant c.1121T>C (V374A) in KCND3 and c.2012T>C (A671V) in KCNC3. In vitro electrophysiology experiments on Xenopus oocytes demonstrated that the V374A mutant was nonfunctional when expressed on its own. Upon equal co-expression of wild-type (WT) and V374A channel subunits, Kv4.3 currents were significantly reduced in a dominant negative manner, without alterations of the gating properties of the channel. By contrast, Kv3.3 A671V, when expressed alone, exhibited moderately reduced currents compared with WT, with no effects on channel activation or inactivation. Immunohistochemistry demonstrated adequate cell membrane translocation of the Kv4.3 V374A variant, thus suggesting an impairment of channel function, rather than of expression. Computational modeling predicted an increased Purkinje neuron firing frequency upon reduced Kv4.3 conductance.Conclusions: Our findings suggest that Kv4.3 V374A is likely pathogenic and associated with paroxysmal ataxia exacerbations, a new trait for SCA19/22. The present FDG PET findings contrast with a previous study demonstrating widespread brain hypometabolism in SCA19/22.
|
|
| 21. |
- Siebzehnrübl, Florian A., et al.
(författare)
-
Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition
- 2018
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:37, s. 8765-8774
-
Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
|
|
| 22. |
- Ågren, Richard, et al.
(författare)
-
An E280K Missense Variant in KCND3/Kv4.3—Case Report and Functional Characterization
- 2023
-
Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:13
-
Tidskriftsartikel (refereegranskat)abstract
- A five-year-old girl presented with headache attacks, clumsiness, and a history of transient gait disturbances. She and her father, mother, twin sister, and brother underwent neurological evaluation, neuroimaging, and exome sequencing covering 357 genes associated with movement disorders. Sequencing revealed the new variant KCND3 c.838G>A, p.E280K in the father and sisters, but not in the mother and brother. KCND3 encodes voltage-gated potassium channel D3 (Kv4.3) and mutations have been associated with spinocerebellar ataxia type 19/22 (SCA19/22) and cardiac arrhythmias. SCA19/22 is characterized by ataxia, Parkinsonism, peripheral neuropathy, and sometimes, intellectual disability. Neuroimaging, EEG, and ECG were unremarkable. Mild developmental delay with impaired fluid reasoning was observed in both sisters, but not in the brother. None of the family members demonstrated ataxia or parkinsonism. In Xenopus oocyte electrophysiology experiments, E280K was associated with a rightward shift in the Kv4.3 voltage-activation relationship of 11 mV for WT/E280K and +17 mV for E280K/E280K relative to WT/WT. Steady-state inactivation was similarly right-shifted. Maximal peak current amplitudes were similar for WT/WT, WT/E280K, and E280K/E280K. Our data indicate that Kv4.3 E280K affects channel activation and inactivation and is associated with developmental delay. However, E280K appears to be relatively benign considering it does not result in overt ataxia.
|
|
| 23. |
- Thomas, HS, et al.
(författare)
-
- 2019
-
swepub:Mat__t
|
|
