An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia.
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SUBMITTER: Wu J
PROVIDER: S-EPMC10142409 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia.
Wu Jingying J Liu Taotao T Zhang Benyan B Liu Chang C Luan Xinghua X Cao Li L
Translational neurodegeneration 20230428 1
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Project description:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) leads to rapidly progressive dementia and is caused by mutations in the gene CSF1R. Neurodegeneration is driven by dysfunction of microglia, the predominant cell type expressing CSF1R in the brain. We assessed chitotriosidase, an enzyme secreted by microglia, in serum and cerebrospinal fluid of patients with ALSP. Chitotriosidase activity was highly increased in cerebrospinal fluid of patients and correlated inversely with disease duration. Of interest, presymptomatic CSF1R mutation carriers did not show elevated chitotriosidase levels. This makes chitotriosidase a promising new biomarker of disease activity for this rare disease.
| S-EPMC9639634 | biostudies-literature
Project description:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare neurodegenerative disease resulting from mutations in the colony stimulating factor 1 receptor gene. Accurate diagnosis can be difficult because the associated clinical and MR imaging findings are nonspecific. We present 9 cases with intracranial calcifications distributed in 2 brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-section (1-mm) CT scans are particularly helpful in detection due to the small size of the calcifications. These calcifications had a symmetric "stepping stone appearance" in the frontal pericallosal regions, which was clearly visible on reconstructed sagittal CT images. Intrafamilial variability was seen in 2 of the families, and calcifications were seen at birth in a single individual. These characteristic calcification patterns may assist in making a correct diagnosis and may contribute to understanding of the pathogenesis of leukoencephalopathy.
| S-EPMC5233547 | biostudies-literature
Project description:BackgroundAdult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare neurodegenerative disorder with characteristic clinicopathological features. Identification of pathogenic mutations in CSF1R, AARS1, and AARS2 genes led to increased recognition and diagnosis of the ALSP.ObjectivesThis paper presents the first family with typical clinical, radiological, and pathological features of ALSP, yet negative for CSF1R, AARS1, and AARS2 mutations.MethodsThe index case was a 30-year-old male who presented with gait difficulty, followed by cognitive decline and incontinence.ResultsNeurological examination evidenced progressive dementia, dysarthria, spasticity, parkinsonism, and severe gait disturbances. Brain MRI showed confluent white matter abnormalities with scattered foci of restricted diffusion, and atrophy of the corpus callosum. He was suspected of ALSP; however, the extensive genetic work-up did not find pathogenic mutation. He died at 33 years, and brain autopsy was performed. He had myelin staining pallor and axonal swellings, spheroids, and pigmented glia in affected white matter. His father developed similar symptoms in his early 40s and died at 46 years. Neuropathological examination also confirmed ALSP diagnosis. We found two similar cases in the literature with typical ALSP features but negative for CSF1R mutation; however, none were tested for AARS1 and AARS2 mutations.ConclusionsWe draw attention to a new entity within the ALSP disease spectrum that needs further investigation. As the disease-modifying therapy is already available for ALSP-CSF1R, there is a strong need to identify the genetic cause of patients such as these in the ALSP spectrum, enabling research toward implementing effective treatment.
| S-EPMC9941916 | biostudies-literature
Project description:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.
| S-EPMC7655300 | biostudies-literature
Project description:Background and purposeTo establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation.MethodsWe developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide 'probable' and 'possible' designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations.ResultsAmong the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as 'probable' and 32 (39%) were diagnosed as 'possible,' leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled 'probable' or 'possible' to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria.ConclusionsThese diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.
| S-EPMC5741468 | biostudies-literature
Project description:We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the Colony-Stimulating Factor 1 Receptor gene (CSF1R). Neuropathology of two affected family members showed cerebral white matter degeneration with axonal swellings and pigmented macrophages. The few recently reported families with CSF1R mutations had been previously labelled "hereditary diffuse leukencephalopathy with axonal spheroids" (HDLS) and "pigmentary orthochromatic leukodystrophy" (POLD), disorders which now appear to form a disease continuum. The term "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP) has been proposed to encompass this spectrum. As CSF1R regulates microglia this mutation implies that dysregulation of microglia is the primary cause of the disease.
| S-EPMC4432561 | biostudies-literature
Project description:Background and purposeThe clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated.MethodsClinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data.ResultsIn all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18-78 years), the mean age at death was 53 years (range 23-84 years) and the mean disease duration was 6.8 years (range 1-29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158-11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype-genotype correlations.ConclusionsThe characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.
| S-EPMC5215554 | biostudies-literature
Project description:A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.
| S-EPMC8850408 | biostudies-literature
Project description:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant disorder that is caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. Functional haplo-insufficiency of the CSF1R gene has been considered for the underlying genetic mechanisms. A novel mutation of CSF1R and its effects on CSF1R expression or clinical characteristics were explored in an ALSP family. Clinical data and imaging data were collected from the family members with ALSP. Peripheral blood samples were collected for DNA and RNA extraction. Whole-exome sequencing and quantitative PCR were used to identify mutations and to determine the expression of CSF1R. The family had a history of a dominant hereditary pattern. Patients in this family presented motor symptoms, emotional abnormality, or memory impairment at onset. MRI findings showed high hyperintensity signals of T2-weighted imaging in the white matter and atrophy of the corpus callosum. NOTCH3 gene sequencing ruled out the diagnosis of CADASIL. Whole-exome sequencing identified a novel splice-site mutation (c.2319+1C>A) in intron 16 of the CSF1R gene. CSF1R mRNA was significantly decreased (~15%) in the peripheral blood samples of affected patients, which was much lower than the expected 50%. Our findings not only supported the pathological implication of this splice-site mutation but also demonstrated for the first time a dominant-negative effect on CSF1R expression. This report extends the genetic spectrum of ALSP with CSF1R mutations and provides evidence for the clinical heterogeneity of ALSP.
| S-EPMC6789214 | biostudies-literature
Project description:IntroductionBecause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive, debilitating, and ultimately fatal neurodegenerative disease, a rapid and accurate diagnosis is critical. This analysis examined the frequency of initial misdiagnosis of ALSP via comprehensive review of peer-reviewed published cases.MethodsData were extracted from a MEDLINE search via PubMed (January 1, 1980, through March 22, 2022) from eligible published case reports/series for patients with an ALSP diagnosis that had been confirmed by testing for the colony-stimulating factor-1 receptor gene (CSF1R) mutation. Patient demographics, clinical symptoms, brain imaging, and initial diagnosis data were summarized descriptively. Categorical data for patient demographics, symptoms, and brain imaging were stratified by initial diagnosis category to test for differences in initial diagnosis based on each variable.ResultsData were extracted from a cohort of 291 patients with ALSP from 93 published case reports and case series. Mean (standard deviation) age of symptom onset was 43.2 (11.6) years. A family history of ALSP was observed in 59.1% of patients. Cognitive impairment (47.1%) and behavioral and psychiatric abnormalities (26.8%) were the most frequently reported initial symptoms. Of 291 total cases, an accurate initial diagnosis of ALSP was made in 72 cases (24.7%) and the most frequent initial misdiagnosis categories were frontotemporal dementia (28 [9.6%]) and multiple sclerosis (21 [7.2%]). Of the 219 cases (75.3%) that were initially mis- or undiagnosed, 206 cases (94.1%) were later confirmed as ALSP by immunohistology, imaging, and/or genetic testing; for the remaining 13 cases, no final diagnosis was reported. Initial diagnosis category varied based on age, family history, geographic region, mode of inheritance, and presenting symptoms of pyramidal or extrapyramidal motor dysfunction, behavioral and psychiatric abnormalities, cognitive impairment, and speech difficulty. Brain imaging abnormalities were common, and initial diagnosis category was significantly associated with white matter hyperintensities, white matter calcifications, and ventricular enlargement.DiscussionIn this literature analysis, ALSP was frequently misdiagnosed. Improving awareness of this condition and distinguishing it from other conditions with overlapping presenting symptoms is important for timely management of a rapidly progressive disease such as ALSP.
| S-EPMC10962389 | biostudies-literature