Adult-onset Leukoencephalopathy Research Articles

Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.

ObjectiveTo characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1).MethodsNinety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed.ResultsWe identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region.ConclusionsWe identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

NfL is a biomarker for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a devastating disease characterized by rapidly progressing motor impairment and dementia with a mean age at onset of 43 years and a mean survival of 7 years.1 It is caused by autosomal dominant mutations in the CSF1R gene with almost complete penetrance, posing a 50% risk to each patient's descendant to carry the mutation.1,2

Identification and functional characterization of novel mutations including frameshift mutation in exon 4 of CSF1R in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

ObjectiveAdult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12–22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants.MethodsSixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants.ResultsWe identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic.ConclusionsThe detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases.

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.

Colony-Stimulating Factor 1 Receptor (CSF1R) Regulates Microglia Density and Distribution, but Not Microglia Differentiation In Vivo

Microglia are brain-resident macrophages with trophic and phagocytic functions. Dominant loss-of-function mutations in a key microglia regulator, colony-stimulating factor 1 receptor (CSF1R), cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a progressive white matter disorder. Because it remains unclear precisely how CSF1R mutations affect microglia, we generated an allelic series of csf1r mutants in zebrafish to identify csf1r-dependent microglia changes. We found that csf1r mutations led to aberrant microglia density and distribution and regional loss of microglia. The remaining microglia still had a microglia-specific gene expression signature, indicating that they had differentiated normally. Strikingly, we also observed lower microglia numbers and widespread microglia depletion in postmortem brain tissue of ALSP patients. Both in zebrafish and in human disease, local microglia loss also presented in regions without obvious pathology. Together, this implies that CSF1R mainly regulates microglia density and that early loss of microglia may contribute to ALSP pathogenesis.

Generation of an induced pluripotent stem cell line from a patient with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): HIHCNi003-A

An induced pluripotent stem cell line, HIHCNi003-A (iPSC-ALSP), was created from a skin biopsy of a patient with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) caused by a heterozygous c.2512G>C, p.Val838Leu mutation in the CSF1R gene. Skin fibroblasts were reprogrammed using episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC, and hLIN28. The iPSC-ALSP line exhibits chromosomal stability with conservation of the CSF1R mutation, expresses pluripotency markers and differentiates into endo-, meso-, and ectodermal cells in vitro.

Identification and Functional Assay of Novel CSF1R Mutations in Patients with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (P2.190)

Identification and Functional Assay of Novel CSF1R Mutations in Patients with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (P2.190)

Mutational Analysis of AARS2 in Japanese Patients with Adult-Onset Leukoencephalopathy Lacking CSF1R Mutation (P2.189)

Mutational Analysis of AARS2 in Japanese Patients with Adult-Onset Leukoencephalopathy Lacking CSF1R Mutation (P2.189)

Partial loss of function of colony-stimulating factor 1 receptor in a patient with white matter abnormalities.

Mutations in colony-stimulating factor 1 receptor (CSF1R) cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Patients with ALSP can be misdiagnosed as having acute ischemic stroke due to hyperintensity lesions on diffusion-weighted magnetic resonance imaging. Mutant CSF1R proteins identified in ALSP show a complete loss of autophosphorylation of CSF1R. We conducted mutation screening of CSF1R in 123 patients with definite acute ischemic cerebrovascular syndrome and positive family history of stroke. The pathogenicity of identified variants was evaluated using functional analyses. The levels of autophosphorylation of CSF1R in response to treatment with ligands of CSF1R were examined in cells transfected with wild-type and mutant CSF1R. We identified eight CSF1R variants, six were known non-pathogenic polymorphisms, whereas the other two were missense variants inducing substitution of amino acid residues (p.Glu573Lys and p.Gly747Arg). Functional assay showed that the levels of autophosphorylation of p.Gly747Arg were similar to those of wild-type when treated with ligands. The autophosphorylation of p.Glu573Lys was detectable, but significantly decreased compared with those of wild-type CSF1R (P < 0.001, two-way anova with Bonferroni). The clinical presentation of the patient with p.Glu573Lys was consistent with cerebral embolism. The patient did not have typical clinical findings of ALSP. However, periventricular white matter abnormalities, unrelated to the recent infarct, were evident on brain magnetic resonance imaging. In contrast to ALSP-associated missense mutations, CSF1R p.Glu573Lys variant in a patient with acute ischemic cerebrovascular syndrome showed a partial loss of autophosphorylation of CSF1R; its clinical significance warrants further investigation.

Study of Genetic Mutation CSF1R and EPM2A Genes in Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Syndrome, Iran

Study of Genetic Mutation CSF1R and EPM2A Genes in Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Syndrome, Iran

Adult-Onset Leukoencephalopathy with Vanishing White Matter

Leukoencephalopathy with vanishing white matter (LEVWM) is one of the most common hereditary leukoencephalopathies with characteristic MRI picture of diffuse white matter lesions with cystic degeneration. The disease is associated with EIF2B1-5 genes, encoding five subunits of translation initiation factor EIF2B. There are infantile, Childhood (the most frequent one), and adult-onset forms. Adult-onset LEVWM accounts for 15–20% of all cases and is characterized by significant clinical variability. In addition to neurological and cognitive disorders, this disease is characterized by ovarian failure. The review presents the clinical and molecular genetic aspects of adult-onset LEVWM.

Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation.

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.

Pathologic Correlation of Paramagnetic White Matter Lesions in Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia.

It has been proposed that susceptibility-weighted imaging is a sensitive magnetic resonance imaging (MRI) technique for identifying white matter (WM) pathologic changes involving demyelination and iron accumulation. We identified the tree silhouette-like configuration with a paramagnetic phase shift in the frontal subcortical WM lesions of 4 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia who underwent 3T MRI. According to our postmortem 7T MRI and histologic correlation study to investigate the origin of the susceptibility-related phase contrast, changes in the subcortical WM architecture and central WM loss with the relative preservation of iron-rich U-fibers may contribute to the paramagnetic susceptibility.

Identification and functional assay of novel missense mutations of CSF1R in patients with HDLS/ALSP

Background: Hereditary diffuse leukoencephalopathy with spheroids (HDLS)/Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) is an adult-onset leukoencephalopathy with variable clinical presentations. Colony stimulating factor 1 receptor (CSF1R) has been identified as the causative gene of HDLS/ALSP. To date, more than 50 pathological mutations in CSF1R have been identified.

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu-Hakola disease: Lesion staging and dynamic changes of axons and microglial subsets

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu-Hakola disease: Lesion staging and dynamic changes of axons and microglial subsets

Dynamic changes of axons and microglial subsets in corpus callosum in patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

Background: ALSP is characterized by loss of axons in the white matter with spheroids. CSF1R has been reported as causative gene of ALSP, and CSF1R is expressed on microglia in brain. Microglia are involved in the pathogenesis of ALSP. Remarkable atrophy of corpus callosum (CC) even in the early stages of brain lesion among four was elucidated by the present authors (2014, 2017). However, the neuropathological features in CC in ALSP are poorly understood.

Cognitive dysfunction and symptoms of movement disorders in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Adult-onset leukoencephalopathies are clinically and genetically heterogeneous disorders that affect predominantly the cerebral white matter of the central nervous system. Clinical and neuroimaging-based approaches have been developed to improve diagnostic processes for adult-onset leukoencephalopathies. However, the differential diagnosis is often challenging. Recently, knowledge of the genetic basis of leukoencephalopathies has been accumulated rapidly, which provides powerful diagnostic approaches. The article provides an overview of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), focusing on the clinical presentations of cognitive impairment and symptoms of movement disorders. ALSP is a subtype of dominantly inherited leukoencephalopathy caused by CSF1R mutations. ALSP typically develop in adulthood, with cognitive decline, psychiatric symptoms, and motor symptoms of movement disorders. Cognitive symptoms in ALSP are characterized by frontal lobe dysfunctions such as executive dysfunction, attention deficits and indifference. The cardinal motor symptoms of movement disorders ALSP were gait disturbance and bradykinesia, which may appear as the initial symptoms. Thus, ALSP should be recognized as both a cognitive disorder and a movement disorder.

Letter re: Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy.

Ayrignac et al.1 presented an interesting case that highlighted the importance of CSF-1R in adult-onset leukoencephalopathies. However, we are concerned that the discussion by Dr. Ganesh in the Mystery Case Responses section confused 2 different diseases as the same.1 This case clearly described a typical presentation of CSF-1R-related disease with apparent autosomal dominant inheritance. However, Dr. Ganesh described this as a case of Labrune syndrome (leukoencephalopathy with calcifications and cysts), an autosomal recessive disorder caused by mutations in SNORD118 .2 While calcifications occur in both syndromes, they are far more widespread and severe in Labrune syndrome and the imaging appearance of both conditions is distinctive. Dr. Ganesh incorrectly attributed 11% of adult-onset leukoencephalopathy to Labrune syndrome by referencing Guerreiro et al.,3 who clearly referred to CSF-1R-related disease.

Clinical and genetic characterisation of adult onset leukoencephalopathy (P6.102)

Clinical and genetic characterisation of adult onset leukoencephalopathy (P6.102)

A case of sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia presenting as fronto-temporal dementia (P4.190)

A case of sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia presenting as fronto-temporal dementia (P4.190)