A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings

Terlizzi, Rossana; Calandra-Buonaura, Giovanna; Zanigni, Stefano; Barletta, Giorgio; Capellari, Sabina; Guaraldi, Pietro; Donadio, Vincenzo; Cason, Ernesto; Contin, Manuela; Poda, Roberto; Tonon, Caterina; Sambati, Luisa; Gallassi, Roberto; Liguori, Rocco; Lodi, Raffaele; Cortelli, Pietro

doi:10.1016/j.autneu.2016.02.005

Cited by 10 publications

(15 citation statements)

References 30 publications

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“…The real prevalence of this ultra-rare pathology remains still uncertain [4] with sporadic new clinical case reports from different geographical areas, suggesting a possible heterogeneity in the first clinical manifestations and signs [5][6][7][8][9][10]. In majority of ADLD cases, the first clinical manifestations are related to autonomic dysfunction from bladder or bowel dysfunction to orthostatic hypotension, temperature dysregulation, and anhidrosis [11][12][13][14][15]. Usually, pyramidal and cerebellar dysfunction, muscle weakness, and spasticity appear after the autonomic dysfunction and before the cognitive impairment [1,2,16,17].…”

Section: Cellular and Molecular Life Sciencesmentioning

confidence: 99%

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Ratti

Rusciano

Mongiorgi

et al. 2020

Cell. Mol. Life Sci.

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Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.

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Section: Cellular and Molecular Life Sciencesmentioning

confidence: 99%

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Ratti

Rusciano

Mongiorgi

et al. 2020

Cell. Mol. Life Sci.

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“…Unlike these diseases, LMNB1 -related ADLD patients with tremor are extremely rare and ADLDs with tremor as the initial symptom have never been reported previously in China (Dai et al, 2017). There are four studies with patients presenting tremor of limbs or trunk from different countries, including Sweden and Italy (Schuster et al, 1984; Sundblom et al, 2009; Brussino et al, 2010; Terlizzi et al, 2016; Table 3). Analysis result showed that patients from Italy-2 (Schuster et al, 1984), Sweden (Sundblom et al, 2009), and Italy-3 (Terlizzi et al, 2016) were consistent with characteristics of this type of leukodystrophy.…”

Section: Discussionmentioning

confidence: 99%

“…The onset of ADLD often commences at the age of the fourth or fifth decade with autonomic dysfunction, occurring simultaneously with or followed by pyramidal abnormalities and cerebellar signs (Padiath and Fu, 2010; Lin et al, 2011; Brunetti et al, 2014; Finnsson et al, 2015; Terlizzi et al, 2016; Dai et al, 2017). In several atypical patients, however, autonomic dysfunction could occur after somatic motor dysfunction, or fail to be detected (Brussino et al, 2010; Giorgio et al, 2013; Potic et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

LMNB1-Related Adult-Onset Autosomal Dominant Leukodystrophy Presenting as Movement Disorder: A Case Report and Review of the Literature

Zhang

Bai

et al. 2019

Front. Neurosci.

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Adult-onset autosomal dominant leukodystrophy (ADLD) is a lately described rare form of leukodystrophy with only one family report from China. As the only disease associated with increased lamina B1 encoded by LMNB1, ADLDs have different clinical presentations, ranging from autonomic to pyramidal tract and cerebellar ataxia. Here, we report a case of ADLD that presented with positional tremor as the initial symptom. T2-weighted brain MRI showed brain atrophy and diffuse high signal intensity of the cerebral white matter and the brain stem. The precise diagnosis was made by identification of the mutated gene. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as tremor in China.

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“…ADLD starts clinically in the 4 th -5 th decades of life with 100% penetrance and no gender variation, and is fatal after a generally slow progression (Nahhas et al, 2016). Autonomic derangements, which may include constipation, bladder symptoms, erectile dysfunction, and orthostatic hypotension (Guaraldi et al, 2011; Terlizzi et al, 2016), are the first symptoms in most patients with ADLD. Orthostatic hypotension is particularly disabling, as it contributes to impair walking ability (Finnsson et al, 2015; Guaraldi et al, 2011; Terlizzi et al, 2016).…”

Section: Introduction2mentioning

confidence: 99%

Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD)

Martire

Alvente

Bastianini

et al. 2018

Experimental Neurology

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Autosomal dominant leukodystrophy (ADLD) is a rare adult-onset demyelinating disease caused by overexpression of lamin B1, a nuclear lamina filament. Early autonomic dysfunction involving the cardiovascular system before progressive somatic motor dysfunction is a striking feature of most cases of ADLD. In the Plp-FLAG-LMNB1 transgenic mouse model, lamin B1 overexpression in oligodendrocytes elicits somatic motor dysfunction and neuropathology akin to ADLD. Here, we investigate whether Plp-FLAG-LMNB1 mice also develop autonomic cardiovascular dysfunction before or after somatic motor dysfunction. We find that Plp-FLAG-LMNB1 mice have preserved cardiovascular responses to changes in wake-sleep state and ambient temperature and normal indexes of autonomic modulation at 37-42weeks of age despite a progressive somatic motor dysfunction, which includes impairments of walking ability (the ability to walk on a narrow path was impaired in 80% of mice at 34-38weeks of age) and subtle breathing derangements. Only late in the development of the disease phenotype did Plp-FLAG-LMNB1 mice develop a structural deficit of sympathetic noradrenergic fibers, with a 38% decrease in fiber profiles in the kidneys at 44-47weeks of age. We demonstrate that while the Plp-FLAG-LMNB1 mouse model recapitulates the age-dependent motor dysfunction of ADLD, it does not show signs of early autonomic cardiovascular dysfunction, raising the possibility that oligodendrocyte dysfunction may not be sufficient to cause the full spectrum of clinical features present in ADLD.

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A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings

Cited by 10 publications

References 30 publications

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

LMNB1-Related Adult-Onset Autosomal Dominant Leukodystrophy Presenting as Movement Disorder: A Case Report and Review of the Literature

Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD)

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