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Autosomal Dominant Leukodystrophy with Autonomic Symptoms and Rippling Muscle Disease: Translational Studies of Two Neurogenetic Diseases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a large variety of diseases caused by single-gene mutations. Although most of these conditions are rare, together they impose a significant burden to the population. This thesis describes clinical and genetic studies of two single-gene diseases:

1) Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD) caused by LMNB1 gene duplications, and characterized by autonomic, pyramidal and cerebellar symptoms. Spinal cords of patients with ADLD were studied by MRI and found to be thin, with high signal intensity in white matter. Histopathology showed loss of myelinated fibres with some reactive gliosis. DNA samples from four different families with ADLD were obtained, and the LMNB1 gene was screened for duplications. Single nucleotide polymorphism array revealed LMNB1 duplications in all ADLD families. LMNB1 mRNA and protein levels were assessed in white blood cells using quantitative polymerase chain reaction and Western blot, and increased levels of LMNB1 mRNA and lamin B1 protein could be demonstrated. We concluded that spinal cord atrophy in patients with ADLD is a valuable differential diagnostic sign, and that increased levels of LMNB1 can be detected in peripheral blood.

2) Rippling muscle disease (RMD) is caused by CAV3 gene mutations. Clinical features are percussion-induced muscle mounding, –rapid contractions and undulating muscle contractions (rippling). The CAV3 gene was sequenced in 38 members of a family with RMD. Twenty-two individuals had clinical features of RMD. No muscle weakness was seen. All patients with signs of RMD carried the p.A46T CAV3 mutation, showing that the p.A46T mutation was benign and that the diagnosis can be made clinically. In vitro contracture test results from 10 of the subjects were collected, but no association between pathological test results and RMD was found.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 726
Keyword [en]
Inborn genetic diseases, Leukoencephalopathies, Lamin type B, Muscular disease, Caveolin 3
National Category
Neurology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-162048ISBN: 978-91-554-8230-5 (print)OAI: oai:DiVA.org:uu-162048DiVA: diva2:458955
Public defence
2012-01-13, Grönwallsalen, Akademiska sjukhuset, Ing 70, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-12-20 Created: 2011-11-23 Last updated: 2012-01-03Bibliographically approved
List of papers
1. MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms
Open this publication in new window or tab >>MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms
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2009 (English)In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 30, no 2, p. 328-335Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE:

MR imaging findings in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms have been described in the brain, but no descriptions of MR imaging findings in the spinal cord have been published. Here, we describe MR imaging findings in the spinal cord in adult-onset ADLD with autonomic symptoms and histopathologic investigations of the spinal cord.

MATERIALS AND METHODS:

Twelve subjects from 2 families with adult-onset ADLD with autonomic symptoms identified by clinical investigation underwent MR imaging examination of the spinal cord. Sagittal and transverse sections were obtained. MR imaging examination of the brain was performed in 11 patients. One of the patients underwent postmortem examination, and the spinal cord was subjected to histopathologic analysis.

RESULTS:

In all family members with adult-onset ADLD with autonomic symptoms, even in the asymptomatic person, the spinal cord was thin. All examined family members also had a slight general white matter signal intensity (SI) increase in the whole spinal cord, mainly visible in T2-weighted transverse images. The pathologic examination revealed a discrete demyelination in the spinal cord. Brain MR imaging also showed increased T2 SI in the white matter.

CONCLUSIONS:

The spinal cord is affected in adult-onset ADLD with autonomic symptoms. Findings consist of atrophy and a diffuse T2 SI increase in the white matter. Transverse images are needed to assess these findings. The typical SI changes of the spinal cord are also present in subjects without clinical symptoms of the disease and with very limited changes in the brain.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-98169 (URN)10.3174/ajnr.A1354 (DOI)000263491200020 ()18945794 (PubMedID)
Available from: 2009-02-16 Created: 2009-02-16 Last updated: 2017-12-13Bibliographically approved
2. Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
Open this publication in new window or tab >>Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
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2011 (English)In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, no 1, p. 65-72Article in journal (Refereed) Published
Abstract [en]

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

Keyword
Autonomic symptoms, Autosomal dominant leukodystrophy (ADLD), Duplication, Lamin B1, LMNB1
National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-144612 (URN)10.1007/s10048-010-0269-y (DOI)000286664500009 ()21225301 (PubMedID)
Available from: 2011-02-01 Created: 2011-02-01 Last updated: 2017-12-11Bibliographically approved
3. Bedside diagnosis of rippling muscle disease in CAV3 p.A46T mutation carriers
Open this publication in new window or tab >>Bedside diagnosis of rippling muscle disease in CAV3 p.A46T mutation carriers
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2010 (English)In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 41, no 6, p. 751-757Article in journal (Refereed) Published
Abstract [en]

Thirty-nine members, ages 1 to 67 years, of a Swedish family with rippling muscle disease (RMD) were investigated to assess genotype-phenotype correlations. Clinical, neurophysiological, and muscle morphological examinations were performed. Genetic analysis was performed in 38 individuals. Twenty-three patients had percussion-induced muscle mounding (PIMM) and percussion-induced rapid contractions (PIRC). Rippling and hyperCKemia were not found in all patients. Weakness was minor or absent. The electromyogram showed absence of electrical activity in ripples and PIMM, and muscle biopsy specimens confirmed caveolin-3 deficiency and absence of caveolae. Genetic analysis revealed a CAV3 c.G136A transition resulting in a p.A46T missense mutation in affected family members. The phenotype in these 23 cases of RMD with this mutation appears to be homogenous, benign, and nonprogressive. The presence of PIMM and PIRC seems to be diagnostic at all ages, whereas the absence of hyperCKemia and rippling does not exclude the diagnosis.

Keyword
Caveolin-3, electromyogram, mutation, rippling, stiffness
National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-126255 (URN)10.1002/mus.21589 (DOI)000278285300004 ()20229577 (PubMedID)
Available from: 2010-06-07 Created: 2010-06-07 Last updated: 2017-12-12Bibliographically approved
4. A family with discordance between Malignant hyperthermia susceptibility and Rippling muscle disease
Open this publication in new window or tab >>A family with discordance between Malignant hyperthermia susceptibility and Rippling muscle disease
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2013 (English)In: Journal of Anesthesia, ISSN 0913-8668, E-ISSN 1438-8359, Vol. 27, no 1, p. 128-131Article in journal (Refereed) Published
Abstract [en]

Rippling muscle disease (RMD) is a benign disorder affecting striated muscle.Malignant hyperthermia (MH) susceptibility is a potentially lethal disorder in which otherwise healthy individuals can develop an extreme hypermetabolism and muscle rigidity/rhabdomyolysis during anesthesia with potent inhalational agents and/or succinylcholine. Disturbed calcium homeostasis has been suggested as the cause of RMD symptoms. Uncontrolled increase in intracellular calcium concentration starts a MH reaction.

Purpose

To investigate if there is a relation between RMD and MH susceptibility in a family with both RMD and MH susceptibility.

Materials and methods

Ten members of a family segregating RMD had, prior to RMD diagnosis, been investigated for MH susceptibility. Results from MH and RMD investigations and anesthesia outcomes were cross-referenced and evaluated to find connections or phenotype variations predicted by in vitro contracture test results.

Results

There was no relation between RMD and MH susceptibility. There were no adverse anesthesia reactions recorded in this family.

Conclusions

RMD and MH susceptibility did not co-segregate. RMD patients should probably not be considered at risk for MH reactions.

Keyword
Caveolin 3, Malignant Hyperthermia, Rippling muscle disease, Calcium, Anesthesia
National Category
Anesthesiology and Intensive Care Neurology
Research subject
Anaesthesiology and Intensive Care; Neurology
Identifiers
urn:nbn:se:uu:diva-162047 (URN)10.1007/s00540-012-1482-7 (DOI)000315042200021 ()22976939 (PubMedID)
Available from: 2011-11-23 Created: 2011-11-23 Last updated: 2017-12-08Bibliographically approved

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