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MuSK Antibody(+) Versus AChR Antibody(+) Myasthenia Gravis: Clinical, Neurophysiological and Morphological Aspects
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder that causes fluctuating muscle weakness. MG may be divided into an ocular form and a generalized form based on the involved muscles. Treatment differs between these different MG forms. The majority (80%) of patients with generalized MG are seropositive for antibodies against the acetylcholine receptor (AChR-Ab). Recently a new antibody was detected against muscle specific tyrosine kinase (MuSK) in about 40% of patients who are AChR-Ab seronegative. A few patients with MuSK-Abs have muscular atrophies, as well as electrophysiological myopathy.

In this thesis we have characterized MuSK-Ab seropositive [MuSK(+)] patients using clinical parameters, including health-related quality of life (hrQoL), neurophysiology and muscle morphology, and compared them to patients with and without AChR-Abs. The question concerned which factors contribute to their muscle weakness. Additionally, we wanted to determine if single-fiber electromyography (SFEMG) in a limb muscle has any predictive value for generalization of ocular MG.

Our results suggest that MuSK(+) patients more often have a myopathic electromyography pattern, although this pattern is found also in other immunological subtypes of MG. The myopathic pattern may be associated with the frequently found mitochondrial abnormalities. However, disturbed neuromuscular transmission is the primary cause of muscle weakness in the majority of MuSK(+) patients, as well as in AChR-Ab seropositive patients. The disease-specific hrQoL MG questionnaire was successfully validated into Swedish and these scores correlated with disturbed neuromuscular transmission in a proximal arm muscle. Abnormal SFEMG findings occur also in muscles outside of the facial area in ocular MG, although this is not predictive of subsequent generalization.

MuSK (+) patients have little or no beneficial effect of acetylcholine esterase inhibitors (AChEI). On the contrary AChEI may produce profound adverse effects. We present the hypothesis that this effect of AChEI is due to abnormal receptor morphology in MuSK(+) patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2007. , p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 211
Keywords [en]
Neurosciences, myasthenia gravis, MuSK antibody, AChR antibody, myopathy, single-fiber EMG, mitochondria, Swedish MG questionnaire, quality of life
Keywords [sv]
Neurovetenskap
Identifiers
URN: urn:nbn:se:uu:diva-7408ISBN: 91-554-6752-0 (print)OAI: oai:DiVA.org:uu-7408DiVA, id: diva2:169410
Public defence
2007-02-02, Grönwallssalen, Akademiska sjukhuset, ingång 70, 75185 Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-12-15 Created: 2006-12-15Bibliographically approved
List of papers
1. Predictive value of single-fiber electromyography in the extensor digitorum communis muscle of patients with ocular myasthenia gravis: a retrospective study.
Open this publication in new window or tab >>Predictive value of single-fiber electromyography in the extensor digitorum communis muscle of patients with ocular myasthenia gravis: a retrospective study.
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2000 In: J Clinical Neuromuscular Disease, Vol. 2, no 1, p. 6-9Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-95257 (URN)
Available from: 2006-12-15 Created: 2006-12-15Bibliographically approved
2. Validation of the Swedish version of the disease- specific myasthenia gravis questionnaire.
Open this publication in new window or tab >>Validation of the Swedish version of the disease- specific myasthenia gravis questionnaire.
2006 (English)In: Neurological Sciences, ISSN 1590-1874, E-ISSN 1590-3478, Vol. 27, no 2, p. 91-96Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to translate and validate the disease-specific patient-derived Myasthenia Gravis (MG) Questionnaire to enable use among Swedish MG patients. The original Italian version of the MG Questionnaire (MGQ) was translated into Swedish and transculturally adapted. The validity and reliability was tested on 48 Swedish MG patients. We correlated MGQ scores with disease severity and with the Swedish version of the Short-Form 36-item general health survey (SF-36). Reproducibility was assessed on 18 clinically stable MG patients. A significant correlation regarding the MGQ scores was seen when correlated with physical scores of the SF-36 and the overall clinical status. Internal consistency and reproducibility was excellent. We conclude that the evaluation capacities of the Swedish MGQ are equivalent to those of the original Italian version of the MGQ. The questionnaire was successfully validated as an outcome measure also for Swedish MG patients, which is important for international multicentre clinical trials.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-95258 (URN)10.1007/s10072-006-0606-y (DOI)
Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2019-02-06Bibliographically approved
3. Correlation between a patient-derived functional questionnaire and abnormal neuromuscular transmission in myasthenia gravis patients.
Open this publication in new window or tab >>Correlation between a patient-derived functional questionnaire and abnormal neuromuscular transmission in myasthenia gravis patients.
2005 In: Clinical Neurophysiology, Vol. 116, no 9, p. 2058-2064Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-95259 (URN)
Available from: 2006-12-15 Created: 2006-12-15Bibliographically approved
4. Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes
Open this publication in new window or tab >>Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes
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2006 (English)In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 117, no 7, p. 1434-1443Article in journal (Refereed) Published
Abstract [en]

Objective: To compare the electrophysiological and histopathological features of immunological myasthenia gravis (MG) subtypes.Methods: Fifty MG patients underwent clinical examination, MuSK-Ab and AChR-Ab analysis. The majority underwent quantitative andsingle-fiber electromyography (QEMG, SFEMG), repetitive nerve stimulation and deltoid muscle biopsy. From muscle specimens withhistological mitochondrial dysfunction, we amplified mitochondrial DNA (mtDNA). In specimens with mtDNA deletions, the nuclear genePOLG1 was sequenced.Results: Five AChR-Ab seropositive [AChR(C)] and 5 seronegative [AChR(K)] patients were MuSK-Ab seropositive [MuSK(C)]. Five of7 neurophysiologically examined MuSK(C) patients (71%) had proximal myopathic pattern, compared to 7 of 31 MuSK(K)/AChR(C)patients (23%) (PZ0.012). SFEMG was abnormal in all examined MuSK(C) patients. All 7 biopsied MuSK(C) and 32 MuSK(K) patients(89%) had cytochrome c oxidase (COX) negative fibers. Three of five MuSK(C) and 13 of 20 MuSK(K) patients analyzed had multiplemtDNA deletions but no POLG1 mutations.Conclusions: Similar degree of SFEMG abnormalities was present in proximal muscles among MuSK(C) and AChR(C) patients. Proximalmyopathy was over-represented in MuSK(C) patients; however, both MuSK(C) and MuSK(K) patients had mild myopathy with frequentmitochondrial abnormalities.Significance: The weakness in MuSK(C) patients is most likely due to disturbed neuromuscular transmission. The frequently encounteredmitochondrial dysfunction in MG warrants further study.

Keywords
Myasthenia gravis, Quantitative EMG, Single-fiber EMG, MuSK, Myopathy, mtDNA deletions
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95260 (URN)10.1016/j.clinph.2006.03.028 (DOI)000239227100004 ()
Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2017-12-14Bibliographically approved
5. Cholinergic neuromuscular hyperactivity in patients with myasthenia gravis seropositive for MuSK antibody
Open this publication in new window or tab >>Cholinergic neuromuscular hyperactivity in patients with myasthenia gravis seropositive for MuSK antibody
2006 (English)In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 34, no 1, p. 111-115Article in journal (Refereed) Published
Abstract [en]

A 75-year-old man with severe oculobulbar myasthenia gravis (MG) treated with acetylcholine esterase inhibitors (AChEIs) was found to have muscle-specific tyrosine kinase (MuSK) antibodies. Neurophysiological examination displayed extra repetitive discharges after the compound motor action potential (CMAP) at low-frequency stimulation, possibly triggered by AChEI. This indicates an abnormal sensitivity to acetylcholine in patients with MuSK antibodies and may be a useful indicator of the adverse effect of AChEI treatment in these patients. Muscle Nerve, 2006

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95261 (URN)10.1002/mus.20515 (DOI)16453324 (PubMedID)
Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2017-12-14Bibliographically approved

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