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A report of 1 case with hereditary diffuse leukoencephalopathy with spheroids (HDLS) due to a new mutation of colony-stimulating factor 1 receptor (CSF1R)
XIELejing, CHENChunchun, MAYing, ZHUFeiqi
Chinese Journal of Alzheimer's Disease and Related Disorders ›› 2020, Vol. 3 ›› Issue (3) : 195-198.
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Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders
Editor in chief: Jun WANG
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A report of 1 case with hereditary diffuse leukoencephalopathy with spheroids (HDLS) due to a new mutation of colony-stimulating factor 1 receptor (CSF1R)
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare disease, which is very easy to be misdiagnosis as Alzheimer’s disease, frontotemporal demention, Parkinson’s syndrome, multiple sclerosis, depression and ischemic stroke etc.. The progress of HDLS is very quick and its prognosis is very severe. The etiology of HDLS is the mutation of colony stimulating factor 1 receptor gene in exon 12~22. At present, only a few cases of HDLS have been reported in China. Here we reported a case with HDLS who was a 68 year old female. At the age of 58, she began to have memory decline and movement discordance. She had been once diagnosed with Alzheimer’s disease and accepted the treatments of donepezil and memantine. Her disease continued to progress. In the fifth year, she began to have generalized seizures and accepted the treatment of sodium valproate. In the 7th year, she suffered with aphasia, walking disability, bedridden, family unknown, urinary incontinence, etc. In January 2020, due to frequent seizures, she were hospitalized in Luohu People’s Hospital. We found that her bilateral cerebral hemispheres had symmetrical abnormal signals and atrophy of white matter, enlargement of lateral ventricle and atrophy of brain by the brain magnetic resonance image (MRI). It was confirmed that she has a mutation in exon 3 of CSF1R (c.220G> A (guanine> adenine), p.A74T (alanine> threonine)) by whole exon gene sequencing. According to HGMDpro database, this mutation has not been reported. At present, her parents are still alive at the age of 90, without family history of dementia, and the siblings and children are healthy. However, the family refuses to detect the gene. The mutation of CSF1R gene in her immediate relatives is unclear, so she may be a HDLS patient caused by the mutation of exon 3 gene of CSF1R. It had been reported that the treatment of allogeneic hematopoietic stem cell transplantation is effective for the improvement and stability of HDLS, so it is very important to improve the understanding of the disease and carry out allogeneic hematopoietic stem cell transplantation as soon as possible to improve the prognosis of patients.
Hereditary Diffuse Leukoencephalopathy with Spheroids / Colony Stimulating Factor 1 Receptor Gene / Exon 3
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The 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.Clinical 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.In 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.The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.© 2016 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
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Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
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To 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.We 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.Among 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.These 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.© 2017 EAN.
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