Clinical and genetic characterization of leukoencephalopathies in adults

Lynch, David S.; Paiva, Anderson Rodrigues Brandão de; Zhang, Wei Jia; Bugiardini, Enrico; Freua, Fernando; Lucato, Leandro Tavares; Macedo‐Souza, Lúcia Inês; Lakshmanan, Rahul; Kinsella, Justin A.; Merwick, Áine; Rossor, Alexander M.; Bajaj, Nin; Herron, Brian; McMonagle, Paul; Morrison, Patrick J.; Hughes, Deborah; Pittman, Alan; Laurá, Matilde; Warren, Jason D.; Mummery, Catherine J.; Schott, Jonathan M.; Adams, Matthew; Fox, Nick C.; Murphy, Elaine; Davagnanam, Indran; Kok, Fernando; Chataway, Jeremy; Houlden, Henry

doi:10.1093/brain/awx045

Cited by 77 publications

(109 citation statements)

References 13 publications

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“…[1][2][3][4] and an additional eight histopathologically confirmed cases from which only formalin-fixed material was available (no. [5][6][7][8][9][10][11][12]. The genotypes at the TSEN54:c.371G>A variant were perfectly associated with the phenotype (P Fisher = 6.1 x 10 −22 ; Table 2).…”

Section: Genetic Analysismentioning

confidence: 99%

“…Twelve closely related dogs presented clinically and/or histopathologically with leukodystrophy were designated as cases (no. [1][2][3][4][5][6][7][8][9][10][11][12]. The remaining 369 Standard Schnauzers represented population controls, for which there were no records of neurological disease.…”

Section: Animal Selection For Genetic Analysismentioning

confidence: 99%

“…In human medicine, hypomyelination, also known as hypomyelinogenesis or dysmyelinogenesis, is mostly associated with genetic, rarely viral or toxic disorders leading to insufficient or delayed formation of myelin [3,4]. On the other hand, the term leukodystrophy refers to progressive disorders of glial cells and myelin maintenance [1,5] resulting in bilateral symmetric lesions in selective areas of the CNS white matter [4]. The diagnosis is accomplished via a combination of the clinical course of the disease, magnetic resonance imaging (MRI), pathology and genetic testing [1,4].…”

Section: Introductionmentioning

confidence: 99%

“…The diagnosis is accomplished via a combination of the clinical course of the disease, magnetic resonance imaging (MRI), pathology and genetic testing [1,4]. Abnormal formation, turnover and destruction of the myelin are often caused by a lack of specific enzymes and inborn errors of metabolism [1,4,5].…”

Section: Introductionmentioning

confidence: 99%

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TSEN54 missense variant in Standard Schnauzers with leukodystrophy

et al. 2019

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We report a hereditary leukodystrophy in Standard Schnauzer puppies. Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect. Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy. Combined linkage analysis and homozygosity mapping in two related families delineated critical intervals of approximately 29 Mb. The comparison of whole genome sequence data of one affected Standard Schnauzer to 221 control genomes revealed a single private homozygous protein changing variant in the critical intervals, TSEN54:c.371G>A or p.(Gly124Asp). TSEN54 encodes the tRNA splicing endonuclease subunit 54. In humans, several variants in TSEN54 were reported to cause different types of pontocerebellar hypoplasia. The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds. These results suggest that TSEN54:c.371G>A causes the leukodystrophy. The identification of a candidate causative variant enables genetic testing so that the unintentional breeding of affected Standard Schnauzers can be avoided in the future. Our findings extend the known genotype-phenotype correlation for TSEN54 variants.

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Section: Genetic Analysismentioning

confidence: 99%

Section: Animal Selection For Genetic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TSEN54 missense variant in Standard Schnauzers with leukodystrophy

et al. 2019

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“…1,2 The clinical phenotype of CARASAL continues to be defined. Here, we report a British patient with CARASAL with brainstem dysfunction as a leading clinical issue.…”

mentioning

confidence: 99%

Brainstem phenotype of cathepsin A–related arteriopathy with strokes and leukoencephalopathy

et al. 2017

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Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations

Tsai

Fuh

Yang

et al. 2021

Ann Clin Transl Neurol

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Objective: Mutations in the colony-stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult-onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult-onset leukoencephalopathy. Methods: Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1-induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results: Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1-induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin-like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3-4 years. Diffusion-restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation: CSF1R mutations account for 3.5% (5/149) of the adult-onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.

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Clinical and genetic characterization of leukoencephalopathies in adults

Cited by 77 publications

References 13 publications

TSEN54 missense variant in Standard Schnauzers with leukodystrophy

TSEN54 missense variant in Standard Schnauzers with leukodystrophy

Brainstem phenotype of cathepsin A–related arteriopathy with strokes and leukoencephalopathy

Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations

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