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| 3. |
- af Edholm, Karolina, et al.
(författare)
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Clinical Reasoning : Leg weakness and stiffness at the emergency room
- 2019
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 92:6, s. E622-E625
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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.
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| 4. |
- Machaczka, Maciej, et al.
(författare)
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Impact of imiglucerase supply shortage on clinical and laboratory parameters in norrbottnian patients with Gaucher disease type 3.
- 2015
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Ingår i: Archivum Immunologiae et Therapiae Experimentalis. - : Springer Science and Business Media LLC. - 0004-069X .- 1661-4917. ; 63:1, s. 65-71
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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.
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| 5. |
- Machaczka, Maciej, et al.
(författare)
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Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients
- 2018
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Ingår i: Blood Cells, Molecules & Diseases. - San Diego : Academic Press. - 1079-9796 .- 1096-0961. ; 68:S1, s. 86-92
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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.
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| 6. |
- Nordenvall, Anna Skarin, et al.
(författare)
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Hypospadias as a novel feature in spinal bulbar muscle atrophy
- 2016
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Ingår i: Journal of Neurology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0340-5354 .- 1432-1459.
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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.
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| 7. |
- Paucar, Martin
(författare)
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Genotype-phenotype characterization of familial hyperkinetic movement disorders : emphasis on ataxia and brain calcifications
- 2017
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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).
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| 8. |
- Siebzehnrübl, Florian A., et al.
(författare)
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Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition
- 2018
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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
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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.
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| 9. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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