Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD

Prominent White Matter Involvement in Multiple System Atrophy of Cerebellar Type

Background Sporadic degenerative ataxia patients fall into 2 major groups: multiple system atrophy with predominant cerebellar ataxia (MSA‐C) and sporadic adult‐onset ataxia (SAOA). Both groups have cerebellar volume loss, but little is known about the differential involvement of gray and white matter in MSA‐C when compared with SAOA. Objectives The objective of this study was to identify structural differences of brain gray and white matter between both patient groups. Methods We used magnetic resonance imaging to acquire T1‐weighted images and diffusion tensor images from 12 MSA‐C patients, 31 SAOA patients, and 55 healthy controls. Magnetic resonance imaging data were analyzed with voxel‐based‐morphometry, tract‐based spatial statistics, and tractography‐based regional diffusion tensor images analysis. Results Whole‐brain and cerebellar‐focused voxel‐based‐morphometry analysis showed gray matter volume loss in both patient groups when compared with healthy controls, specifically in the cerebellar areas subserving sensorimotor functions. When compared with controls, the SAOA and MSA‐C patients showed white matter loss in the cerebellum, whereas brainstem white matter was reduced only in the MSA‐C patients. The tract‐based spatial statistics revealed reduced fractional anisotropy within the pons and cerebellum in the MSA‐C patients both in comparison with the SAOA patients and healthy controls. In addition, tractography‐based regional analysis showed reduced fractional anisotropy along the corticospinal tracts in MSA‐C, but not SAOA. Conclusion Although in our cohort extent and distribution of gray and white matter loss were similar between the MSA‐C and SAOA patients, magnetic resonance imaging data showed prominent microstructural white matter involvement in the MSA‐C patients that was not present in the SAOA patients. Our findings highlight the significance of microstructural white matter changes in the differentiation between both conditions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Characterization of Cerebellar Atrophy and Resting State Functional Connectivity Patterns in Sporadic Adult-Onset Ataxia of Unknown Etiology (SAOA)

Sporadic adult-onset ataxia of unknown etiology (SAOA) is a non-genetic neurodegenerative disorder of the cerebellum of unknown cause which manifests with progressive ataxia without severe autonomic failure. Although SAOA is associated with cerebellar degeneration, little is known about the specific cerebellar atrophy pattern in SAOA. Thirty-seven SAOA patients and 49 healthy controls (HCs) were included at two centers. We investigated the structural and functional characteristics of SAOA brains using voxel-based morphometry (VBM) and resting-state functional imaging (rs-fMRI). In order to examine the functional consequence of structural cerebellar alterations, the amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and then assessed their relation with disease severity, disease duration, and age of onset within these regions. Group differences were investigated using two-sample t tests, controlling for age, gender, site, and the total intracranial volume. The VBM analysis revealed a significant, mostly bilateral reduction of local gray matter (GM) volume in lobules I-V, V, VI, IX, X, and vermis VIII a/b in SAOA patients, compared with HCs. The GM volume loss in these regions was significantly associated with disease severity, disease duration, and age of onset. The disease-related atrophy regions did not show any functional alternations compared with HCs but were functionally characterized by high ALFF and poor DC compared with intact cerebellar regions. Our data revealed volume reduction in SAOA in cerebellar regions that are known to be involved in motor and somatosensory processing, corresponding with the clinical phenotype of SAOA. Our data suggest that the atrophy occurs in those cerebellar regions which are characterized by high ALFF and poor DC. Further studies have to show if these findings are specific for SAOA, and if they can be used to predict disease progression

Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia

Item does not contain fulltextOBJECTIVE: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations. METHODS: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing. RESULTS: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 +/- 0.74, p 10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 +/- 6.0 vs 16.0 +/- 5.8, p = 0.0200) and a slower annual SARA increase (1.1 +/- 2.3 vs 3.3 +/- 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made. CONCLUSIONS: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort. CLINICALTRIALSGOV REGISTRATION: NCT02701036