| 1. |
- Fujioka, Shinsuke, et al.
(author)
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Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics.
- 2013
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In: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 8
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Research review (peer-reviewed)abstract
- Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.
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| 2. |
- Granberg, Tobias, et al.
(author)
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Hereditary diffuse leukoencephalopathy with spheroids - a volumetric and radiological comparison with multiple sclerosis patients and healthy controls.
- 2016
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 23:4, s. 817-822
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Journal article (peer-reviewed)abstract
- Background and purpose Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder caused by colony-stimulating factor 1 receptor (CSF1R) gene mutations, resulting in demyelination and axonal degeneration with spheroids. The clinical expression is variable, including behavioral changes, cognitive impairment, motor symptoms and parkinsonism. Magnetic resonance imaging (MRI) reveals white matter (WM) changes and atrophy. The indistinct phenotype has led to misdiagnoses. This study's aim was to compare brain volumetry and radiological ratings in HDLS with multiple sclerosis (MS) patients and controls. Methods Five HDLS patients with c.2562T>A p.Asn854Lys CSF1R mutation, five age- and gender-matched MS patients and five healthy controls were cross-sectionally studied. All patients were examined neurologically. HDLS patients underwent Mini-Mental State Examination (MMSE). Brain MRI scans were analyzed volumetrically with FreeSurfer and Lesion Segmentation Toolbox and neuroradiologically with the brain MRI scoring system for HDLS. Results Patients with HDLS had lower brain, grey matter and WM fractions (66.3%; 37.9%; 27.6%) compared with controls (78.5%, P = 0.008; 44.4%, P = 0.008; 32.0%, P = 0.008), but not compared with MS patients (65.7%, P = 0.7; 36.8%, P = 0.4; 27.3%, P = 0.7). Cerebellar WM changes and atrophy were not seen in the HDLS group. The HDLS lesion volume fraction correlated with MMSE scores (r = −0.90, P = 0.04). Conclusions Brain volume fractions in HDLS were lower than in controls and similar to those seen in MS. The cerebellum was relatively spared in HDLS, which may help in differentiating HDLS WM changes from MS. The strong relationship of HDLS lesions with MMSE scores indicates that accumulating WM pathology in HDLS is associated with cognitive decline.
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| 3. |
- Guerrero, A. L., et al.
(author)
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Need of guidance in disabling and chronic migraine identification in the primary care setting, results from the european MyLife anamnesis survey
- 2021
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In: Bmc Family Practice. - : Springer Science and Business Media LLC. - 1471-2296. ; 22:1
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Journal article (peer-reviewed)abstract
- Background Migraine affects 80.8 million people in Western Europe and is the first cause of disability among people between ages 15 and 49 worldwide. Despite being a highly prevalent and disabling condition, migraine remains under-diagnosed and poorly managed. Methods An international, online survey was conducted among 201 general practitioners (GPs) from 5 European countries (France, Germany, Italy, Spain and the UK) who are experienced in the management of headache disorders. Results The majority of GPs (82%) did not refer patients with chronic migraine (CM) to migraine specialists. Among those patients, the participants estimated that around 55% received preventive medication. Some differences between countries were observed regarding referral rate and prescription of preventive treatment. Most GPs (87%) reported a lack of training or the need to be updated on CM management. Accordingly, 95% of GPs considered that a migraine anamnesis guide could be of use. Overall, more than 95% of GPs favoured the use of a patient diary, a validated diagnostic tool and a validated scale to assess impact of migraine on patients' daily life. Similarly, 96% of the GPs considered that the inclusion of warning features (red flags) in an anamnesis guide would be useful and 90% favoured inclusion of referral recommendations. Conclusions The results from this survey indicate that more education on diagnosis and management of CM is needed in primary care. Better knowledge on the recognition and management of migraine in primary care would improve both prognosis and diagnosis and reduce impact of migraine on patients' lives, healthcare utilization and societal burden.
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| 4. |
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| 5. |
- Rademakers, Rosa, et al.
(author)
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Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:2, s. 200-5
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Journal article (peer-reviewed)abstract
- Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
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| 6. |
- Ryvlin, P., et al.
(author)
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Current clinical practice in disabling and chronic migraine in the primary care setting: results from the European My-LIFE anamnesis survey
- 2021
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In: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 21:1
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Journal article (peer-reviewed)abstract
- Background Migraine is a prevalent and disabling headache disorder that affects more than 1.04 billion individuals world-wide. It can result in reduction in quality of life, increased disability, and high socio-economic burden. Nevertheless, and despite the availability of evidence-based national and international guidelines, the management of migraine patients often remains suboptimal, especially for chronic migraine (CM) patients. Methods My-LIFE anamnesis project surveyed 201 General practitioners (GPs) from 5 European countries (France, Germany, Italy, Spain, and the UK) with the aim of understanding chronic migraine (CM) patients' management in the primary care setting. Results In our survey, GPs diagnosed episodic migraine (EM) more often than CM (87% vs 61%, p < 0.001). We found that many CM patients were not properly managed or referred to specialists, in contrast to guidelines recommendations. The main tools used by primary-care physicians included clinical interview, anamnesis guide, and patient diary. Tools used at the first visit differed from those used at follow-up visits. Up to 82% of GPs reported being responsible for management of patients diagnosed with disabling or CM and did not refer them to a specialist. Even when the GP had reported referring CM patients to a specialist, 97% of them were responsible for their follow-up. Moreover, the treatment prescribed, both acute and preventive, was not in accordance with local and international recommendations. GPs reported that they evaluated the efficacy of the treatment prescribed mainly through patient perception, and the frequency of follow-up visits was not clearly established in the primary care setting. These results suggest that CM is underdiagnosed and undertreated; thereby its management is suboptimal in the primary care. Conclusions There is a need of guidance in the primary care setting to both leverage the management of CM patients and earlier referral to specialists, when appropriate.
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| 7. |
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| 8. |
- Sundal, Christina, et al.
(author)
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A SCA7 premutation may be a novel Mendelian modifier of MS course: A case report
- 2019
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In: Multiple Sclerosis and Related Disorders. - : Elsevier BV. - 2211-0348. ; 31, s. 148-150
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Journal article (peer-reviewed)abstract
- A proportion of patients with the phenotype of complex genetic disorders carry dominantly inherited Mendelian traits, exemplified by hereditary spastic paraparesis influencing pyramidal symptoms in some MS cases. We here describe a mutable ATXN7 gene, a SCA7 premutation, in a patient fulfilling contemporary definitions of primary progressive MS. His onset age, and onset with a severely progressive cerebellar ataxia syndrome, was outside the reported range of symptoms in a representative MS material. We suggest that an ATXN7 premutation is a novel genetic modifier of the course of MS. © 2019
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| 9. |
- Sundal, Christina, et al.
(author)
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An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids
- 2019
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In: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7
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Journal article (peer-reviewed)abstract
- Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after asystematic and recent assessment of several family members. We also report the results from exome sequencing analysesindicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult onset CSF1R-negative leukoencephalopathies.
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| 10. |
- Sundal, Christina, et al.
(author)
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Autosomal dominant Parkinson's disease.
- 2012
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In: Parkinsonism & related disorders. - 1873-5126. ; 18 Suppl 1
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Research review (peer-reviewed)abstract
- Over the past two decades the understanding and classification of Parkinson's disease (PD) has been revolutionized by genetic research. Currently, sixteen PARK loci have been identified with autosomal dominant genes such as SNCA, and LRRK2, and autosomal recessive genes such as PRKN, DJ-1, and PINK1. Among these genes, LRRK2 is the most prevalent. Additionally, susceptibility variants located on some of these genes are widely recognized as risk factors for PD in certain ethnic populations. Alpha synuclein Lewy body (LB) pathology, the hallmark of sporadic PD, is predominantly seen in carriers of SNCA and LRRK2. Recently two new autosomal dominant PD genes have been discovered, eukaryotic translation initiation factor 4-gamma (EIF4G1) and vacuolar protein sorting 35 (VPS35). EIF4G1 is associated with LB pathology; however, only limited data currently exists on pathology of the VPS35. Thus, it remains to be seen if LB pathology can be identified on autopsy examination of carriers of VPS35 gene. The mechanism behind the cause of PD has yet to be elucidated; however, genetic studies on autosomal dominant PD have provided novel insights into the potential etiology of PD. Thus, paving the way for future targeted therapies aimed at disease prevention and cure.
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