A Novel Duplication Confirms the Involvement of 5q23.2 in Autosomal Dominant Leukodystrophy

Meijer, Inge A.; Simoes-Lopes, Ana A.; Laurent, Sandra B.; Katz, Tanya; St‐Onge, Judith; Verlaan, Dominique J.; Dupré, Nicolas; Thibault, Manon; Mathurin, Johanne; Bouchard, Jean‐Pierre; Rouleau, Guy A.

doi:10.1001/archneur.65.11.1496

Cited by 33 publications

(40 citation statements)

References 28 publications

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“…Interestingly, similar pseudoexacerbations are observed in MS, which shares several clinical features with LMNB1 ‐related ADLD. Life‐threatening hypothermia, previously reported in a Canadian patient having LMNB1 ‐related ADLD,9 occurred in 1 of our patients.…”

Section: Discussionsupporting

confidence: 53%

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: 53%

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

Finnsson

Sundblom

Dahl

et al. 2015

Annals of Neurology

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“…7 Similarly, duplications at the chromosome 5q23 locus containing three genes including the LMNB1 gene were identified in families with adult-onset autosomal dominant leukodystrophy. 26,27 The discrepant modes of inheritance of HDLS (autosomal dominant) and familial POLD (autosomal dominant or recessive) suggest both diseases are caused by distinct genetic defects. The implication of different genes in one clinicopathologic entity is not uncommon and is exemplified by Parkinson disease due to mutations in the LRRK2 and SNCA genes.…”

mentioning

confidence: 99%

Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD)

Wider¹,

Gerpen²,

DeArmond³

et al. 2009

Neurology

104

118

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Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

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“…To this date, ADLD had only been known for its progressive onset of autonomic, pyramidal and cerebellar symptoms [3,4]. We report of a 55 year-old ADLD patient with significant deficits in attention, memory, visuoconstruction and executive skills.…”

Section: Discussionmentioning

confidence: 91%

Neurocognitive deficits and diffusion MR imaging abnormalities in a case of adult-onset autosomal dominant leukodystrophy

Laforce¹,

Roy²,

Descoteaux³

et al. 2013

Translational Neuroscience

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Autosomal dominant adult-onset leukodystrophy (ADLD) is a progressive hereditary disease caused by duplication of Lamin B1 on chromosome 5q23.2. It is characterized by autonomic dysregulation, pyramidal signs, and cerebellar dysfunction. Since the first description in 1984, no authors have reported on its neurocognitive sequelae or attempted to quantify the severity of white matter changes. Herein we report a case of ADLD presenting with progressive cognitive changes leading to dementia and its associated white matter damage using diffusion MR imaging. Case reportA 55-year-old man was evaluated for a 10-year history of weakness of the legs (left > right) and gait disturbances. In the last three years, he also complained of significant changes in his cognition. A detailed history revealed changes in attention, memory and organizational skills. showed that compared to our control paired for age and education, FA was 12.5% lower in the patient, while ADC diffusivities (radial and axial) were 5% higher. Preliminary results from HARDI tractography robust to fiber crossing [2] showed chaotic and incoherently organized tracts (e.g., corticospinal tract; see Figure 2G-H). DiscussionTo this date, ADLD had only been known for its progressive onset of autonomic, pyramidal and cerebellar symptoms [3,4]. We report of a 55 year-old ADLD patient with significant deficits in attention, memory, visuoconstruction and executive skills. Deficits particularly affect frontal-subcortical pathways and give rise to

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A Novel Duplication Confirms the Involvement of 5q23.2 in Autosomal Dominant Leukodystrophy

Cited by 33 publications

References 28 publications

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

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

Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD)

Neurocognitive deficits and diffusion MR imaging abnormalities in a case of adult-onset autosomal dominant leukodystrophy

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