MR Imaging Characteristics and Neuropathology of the Spinal Cord in Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms

Sundblom, Jimmy; Melberg, Atle; Kalimo, Hannu; Smits, Anja; Raininko, Raili

doi:10.3174/ajnr.a1354

Cited by 45 publications

(41 citation statements)

References 48 publications

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“…Tremor, previously reported in LMNB1 ‐related ADLD,2, 7 was present in less than half of the patients and caused major complaint in 1 patient. We found no signs of polyneuropathy, confirming earlier reports 2, 3, 4, 5, 24. A new observation in this follow‐up study is that sensory impairment started in the distal part of the legs and ascended over time to the thoracic level, consistent with myelopathy, and development of flaccid paralysis of the lower limbs.…”

Section: Discussionsupporting

confidence: 91%

“…This follow‐up study gives a strong indication that spinal cord involvement is clinically significant in this type of leukodystrophy and may also, at least partly, explain the autonomic dysfunction. Previous histopathological studies have verified involvement of the spinal cord in a patient already at 3 years after onset of symptoms5 and more‐severe changes in a patient with longer disease duration 24. In our study, clinical assessment, radiological findings, and neurophysiological examinations indicate myelopathy.…”

Section: Discussionsupporting

confidence: 74%

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LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

Finnsson

Sundblom

Dahl

et al. 2015

Annals of Neurology

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ObjectiveDuplication 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.MethodsTwenty‐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.ResultsPathological 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

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 74%

LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

Finnsson

Sundblom

Dahl

et al. 2015

Annals of Neurology

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“…Spinal atrophy has been observed in groups of individuals with pathologies such as autosomal dominant leukodystrophy, amyotrophic lateral sclerosis and hereditary paraplegia. [5][6][7] Good correlation between spinal cord area (SCA) and a number of global clinical scores has also been found in several studies of patients with multiple sclerosis in cross-sectional as well as longitudinal settings. 8 It is not known whether a similar quantitative relation between spinal cord atrophy and the extent of disability is found in individuals with SCI.…”

Section: Introductionmentioning

confidence: 94%

Independent spinal cord atrophy measures correlate to motor and sensory deficits in individuals with spinal cord injury

et al. 2010

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Study design: Cross-sectional descriptive analysis of magnetic resonance imaging (MRI) and clinical outcome. Objectives: The aim of this study was to present anatomically consistent and independent spinal cord atrophy measures based on standard MRI material and analyze their specific relations to sensory and motor outcome in individuals with chronic incomplete spinal cord injury (SCI). Setting: Danish study on human SCI. Methods: We included 19 individuals with chronic incomplete SCI and 16 healthy controls. Participants underwent MRI and a neurological examination including sensory testing for light touch and pinprick, and muscle strength. Antero-posterior width (APW), left-right width (LRW) and crosssectional spinal cord area (SCA) were extracted from MRI at the spinal level of C2. The angular variation of the spinal cord radius over the full circle was also extracted and compared with the clinical scores. Results: The motor score was correlated to LRW and the sensory scores were correlated to APW. The scores correlated also well with decreases in spinal cord radius in oblique angles in coherent and non-overlapping sectors for the sensory and motor qualities respectively. Conclusion: APW and LRW can be used to assess sensory and motor function independently. The finding is corresponding well with the respective locations of the main sensory and motor pathways.

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“…Both exhibited a vacuolar degenerative phenotype primarily involving the white matter tracts with a preservation of oligodendrocytes. 20,21 This suggested that the over expression of lamin B1 is not lethal to oligodendrocytes and that the demyelination is not the result of oligodendrocyte loss. Recent reports have linked lamin b1 to pathways of cellular proliferation and senescence.…”

mentioning

confidence: 99%

“…While patient brain sections exhibited a modest degree of reactive gliosis, no astrocytic proliferation was observed, although the astrocytes in affected regions were found to have abnormal and shortened processes. 20,21 It is unclear whether these differences represent species-specific responses to lamin B1 overexpression. However, it is important to remember that ADLD has a relatively slow disease progression with death occurring at least a 10-20 y after the onset of symptoms.…”

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confidence: 99%

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

Padiath

2016

Nucleus

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Autosomal Dominant Leukodystrophy (ADLD), a fatal adult onset demyelinating disorder, is the only human disease that has been linked to mutations of the nuclear lamina protein, lamin B1, and is primarily caused by duplications of the LMNB1 gene. Why CNS myelin is specifically targeted and the mechanisms underlying ADLD are unclear. Recent work from our group has demonstrated that over expression of lamin B1 in oligodendrocytes, the myelin producing cells in the CNS, resulted in age dependent epigenetic modifications, transcriptional down-regulation of lipogenic gene expression and significant reductions of myelin-enriched lipids. Given the high lipid content of meylin, we hypothesize that lipid loss is one of the primary drivers of the demyelination phenotype. These results can, at least partially, explain the age dependence and cell type specificity in ADLD and are discussed in the context of the existing literature, in an attempt to delineate potential pathways underlying the disease phenotype.

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MR Imaging Characteristics and Neuropathology of the Spinal Cord in Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms

Cited by 45 publications

References 48 publications

LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

LMNB1‐related autosomal‐dominant leukodystrophy: Clinical and radiological course

Independent spinal cord atrophy measures correlate to motor and sensory deficits in individuals with spinal cord injury

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

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