Neuroimaging phenotypes of <i>CSF1R</i>‐related leukoencephalopathy: Systematic review, meta‐analysis, and imaging recommendations

Mickeviciute, Goda‐Camille; Valiuskyte, Monika; Plattén, Michael; Wszołek, Zbigniew K.; Andersen, Oluf; Karrenbauer, Virginija Danylaité; Ineichen, Benjamin Victor; Granberg, Tobias

doi:10.1111/joim.13420

Cited by 17 publications

(14 citation statements)

References 104 publications

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“…In the deeper cortex and cerebral white matter, the activated microglia were accumulated in the relatively preserved areas but not in the affected areas and exhibited abnormal morphologies and spatial restriction due to CSF1R mutation ( Tada et al, 2016 ). These pathological findings characterized by the region-specific distribution of the activated microglia were consistent with the structural brain MRI findings of the current and previous studies ( Mao et al, 2020 ; Mickeviciute et al, 2022 ), i.e., significant abnormal signals in the deep white matter of the frontoparietal lobe and corpus callosum, revealing the potential relationship between the number and functional changes in the microglia induced by CSF1R mutation and deep white matter degeneration.…”

Section: Discussionsupporting

confidence: 91%

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease.Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation.Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members.Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.

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Section: Discussionsupporting

confidence: 91%

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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“…Besides, sagittal reconstructions of CT and 7 T MRI are helpful to demonstrate calcifications. 33,34 In addition, the DWI sequences of all patients in this study showed constant high signals in bilateral abnormal white matter, suggesting that abnormalities on the DWI sequences are an important clue for the diagnosis and differential diagnosis of CRD. DWI is more sensitive to reflect the changes in the microstructure of the white matter and can detect the changes in the white matter at an earlier stage than the T2-FLAIR sequences.…”

Section: Discussionmentioning

confidence: 56%

“…In the retrospective study in Japan, the patients mostly received 1‐mm thin‐layer CT scans, whereas in this study, the CT scans conducted in the patients were all plain scans. Besides, sagittal reconstructions of CT and 7 T MRI are helpful to demonstrate calcifications 33,34 …”

Section: Discussionmentioning

confidence: 99%

The Phenotypic and Genotypic Spectrum of CSF1R‐Related Disorder in China

Wu,

Cheng,

et al. 2024

Movement Disorders

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BackgroundColony‐stimulating factor 1 receptor (CSF1R)‐related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated.ObjectiveThe objective of the study is to clarify the core features and influence factors of CRD patients in China.MethodsClinical and genetic‐related data of CRD patients in China were collected. Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations.ResultsA total of 103 patients were included, with a male‐to‐female ratio of 1:1.51. The average age of onset was (40.75 ± 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 ± 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 ± 7.89), and the white matter severity score (20.19 ± 8.47) of female patients was significantly higher than that of male patients (16.00 ± 7.62). There is no statistical difference in age of onset between male and female patients.ConclusionsThe core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. © 2024 International Parkinson and Movement Disorder Society.

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“…3 Although spinal cord involvement has only been reported in a few cases of CSF1R-related leukoencephalopathy, a systematic study of spinal cord findings in this disorder has not been undertaken to date. 9 Lesions may involve the lateral corticospinal tracts and diffusion restriction may be present in the spinal cord lesions as well. 9,10 In our case, spinal cord MRI was remarkable for short-segment focal hyperintensities in the right lateral cord at C2-3 and mid-C3 levels (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…9 Lesions may involve the lateral corticospinal tracts and diffusion restriction may be present in the spinal cord lesions as well. 9,10 In our case, spinal cord MRI was remarkable for short-segment focal hyperintensities in the right lateral cord at C2-3 and mid-C3 levels (Figure 2). Such spinal lesions are highly characteristic of MS and likely contributed to misdiagnosis in our case.…”

Section: Discussionmentioning

confidence: 99%

Pearls & Oy-sters: CSF1R -Related Leukoencephalopathy With Spinal Cord Lesions Mimicking Multiple Sclerosis

et al. 2023

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CSF1R-related leukoencephalopathy is an autosomal dominant neurological disorder causing microglial dysfunction with a wide range of neurologic complications, including motor dysfunction, dementia and seizures. This case report highlights an unusual presentation ofCSF1R-related leukoencephalopathy with radiographic spinal cord involvement initially diagnosed as multiple sclerosis. The case highlights the importance of considering adult-onset neurogenetic disorders in the setting of white matter disease. Genetic testing provides a confirmatory diagnosis for an expanding number of adult-onset leukoencephalopathies and informs therapeutic decision-making.

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Neuroimaging phenotypes of CSF1R‐related leukoencephalopathy: Systematic review, meta‐analysis, and imaging recommendations

Abstract: Benjamin V. Ineichen and Tobias Granberg shared the last authorship.

Cited by 17 publications

References 104 publications

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

The Phenotypic and Genotypic Spectrum of CSF1R‐Related Disorder in China

Pearls & Oy-sters: CSF1R -Related Leukoencephalopathy With Spinal Cord Lesions Mimicking Multiple Sclerosis

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