No abstract

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 as the associated clinical and MRI findings are nonspecific. We present nine cases with intracranial calcifications distributed in two brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-slice (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 two 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 its pathogenesis.

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.Electronic supplementary materialThe online version of this article (10.1007/s00415-018-9017-2) contains supplementary material, which is available to authorized users.

BackgroundAlthough human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP.ResultsThe subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p < 0.001) and s-HAM/TSP (p < 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5α in HAM/TSP patients. The patients with TRIM5α 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/104 PBMC, p = 0.003). The patients with the 304L variant of TRIM5α had significantly higher PVLs than those with 304H (1669 vs. 595 copies/104 PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors.ConclusionsTranscontinental subtype is susceptible to HAM/TSP, especially in familial cases. Ten common mutations causing amino acid changes in the HTLV-1 gene were specific to the transcontinental subtype. TRIM5α polymorphisms were associated with PVLs, indicating that TRIM5α could be implicated in HTLV-1 replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0350-9) contains supplementary material, which is available to authorized users.

Our results suggest that age and virus mediated inflammation are correlated with disease phenotypes while additional factors such as host or HTLV-1 genetics and gender may influence disease susceptibility.