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Radiological studies of LMNB1-related autosomal dominant leukodystrophy and Marinesco-Sjögren syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. (Neuroradiology)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are approximately 6000 to 8000 rare diseases, each with a prevalence of less than 1 / 10 000, but in aggregate affecting 6 to 8% of the population. It is important to evaluate disease development and progression to know the natural course of any disease. This information can be utilized in diagnostics and in assessing effects of therapeutic interventions as they become available. This thesis describes the natural clinical history and evolution of imaging findings of two rare diseases over approximately two decades.

Papers I, II and III present clinical, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings in LMNB1-related autosomal dominant leukodystrophy (ADLD). MRI was found to be very sensitive in finding pathology in patients with LMNB1-related ADLD, even before the onset of clinical symptoms. However, even patients with widespread MRI changes can have a relatively mild symptomatology and present only slight disturbances in metabolic examinations such as MRS and FDG-PET. This is compatible with relatively intact axons, even as myelin impairment is widespread.

Paper IV presents clinical and MRI findings in the brain and musculature in SIL1-positive Marinesco-Sjögren syndrome (MSS), and describes a new, mild phenotype of the disease with no intellectual disabilities and only slight motor disabilities. With a 19-year-long radiological follow-up, a slow progressive atrophic process in the cerebellum and brainstem could be demonstrated. MRI of the musculature shows early involvement of the quadriceps and gastrocnemii but not the tibialis anterior, progressing to widespread atrophy in the back and upper and lower limbs at the age of 20 years. In the mildest phenotype, the most severely affected muscles were the m gluteus maximus, m sartorius, m peroneus longus, and the lateral head of the m gastrocnemius.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1261
Keyword [en]
Leukoencephalopathies, hereditary central nervous system demyelinating diseases, autonomic dysfunction, adult-onset, neuromuscular disease, pediatric, neuro-ophtalmology, ataxia
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-303171ISBN: 978-91-554-9709-5OAI: oai:DiVA.org:uu-303171DiVA: diva2:1032893
Public defence
2016-11-22, Grönwallsalen, Ingång 70, Akademiska Sjukhuset, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2016-11-01 Created: 2016-09-15 Last updated: 2016-11-02
List of papers
1. 1H-MR spectroscopy of adult-onset autosomal dominant leukodystrophy with autonomic symptoms
Open this publication in new window or tab >>1H-MR spectroscopy of adult-onset autosomal dominant leukodystrophy with autonomic symptoms
2013 (English)In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 55, no 8, 933-939 p.Article in journal (Refereed) Published
Abstract [en]

Adult-onset ADLD with autonomic symptoms is a rare disease with a clinical course somewhat similar to chronic progressive MS but with different imaging findings consisting of extensive white matter changes in the cerebrum and cerebellar peduncles. Patients usually present in the fourth to sixth decade with autonomic symptoms, manifesting later symptoms from the pyramidal tracts and ataxia. Here, we present magnetic resonance spectroscopy (MRS) findings in this disease. Fourteen subjects, from two non-related families, with genetic linkage to the disease were studied with magnetic resonance imaging and single-voxel MRS. Clinically, they ranged from asymptomatic to wheelchair-using. Their results were compared to those of age- and sex-matched healthy controls. One MRS was excluded due to suboptimal quality. The remaining 13 subjects manifested characteristic evidence of pathology on MRI, 11 of them exhibited extensive changes. The metabolite concentrations of total Cr, total Cho, and total NAA measured in millimolars, using internal water as a reference, were significantly lower in these 11 subjects compared to controls, and we found linear correlations between all these metabolite levels. When total Cr was used as a reference, we found no difference between subjects and controls. No lactate was detected. The decreased metabolite concentrations measured using internal water as a reference are most likely due to increased water content in the tissues, diluting all metabolites to a similar degree. This is also in agreement with the high signal intensity exhibited in the white matter on T2-weighted MR images and with the reported histopathological findings of vacuolated myelin.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-204429 (URN)10.1007/s00234-013-1174-5 (DOI)000322020900002 ()23636437 (PubMedID)
Available from: 2013-08-05 Created: 2013-08-05 Last updated: 2016-10-04Bibliographically approved
2. LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course
Open this publication in new window or tab >>LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course
Show others...
2015 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 78, no 3, 412-25 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1-related ADLD.

METHODS: Twenty-three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years.

RESULTS: Pathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset.

INTERPRETATION: LMNB1-related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia. Ann Neurol 2015;78:412-425.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-261207 (URN)10.1002/ana.24452 (DOI)000360218800008 ()26053668 (PubMedID)
Note

Atle Melberg och Raili Raininko delar sistaförfattarskapet.

Available from: 2015-08-31 Created: 2015-08-31 Last updated: 2016-10-04Bibliographically approved
3. Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy; a PET study
Open this publication in new window or tab >>Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy; a PET study
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-303170 (URN)
Available from: 2016-09-15 Created: 2016-09-15 Last updated: 2016-11-19
4. Clinical and MRI evaluation of Marinesco-Sjögren syndrome with a 21-year-follow-up and a description of a mild form of the disease
Open this publication in new window or tab >>Clinical and MRI evaluation of Marinesco-Sjögren syndrome with a 21-year-follow-up and a description of a mild form of the disease
(English)Manuscript (preprint) (Other academic)
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-303168 (URN)
Available from: 2016-09-15 Created: 2016-09-15 Last updated: 2016-11-19

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