Cheshire, William P.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Objectives Multiple system atrophy (MSA) is classified into parkinsonian (MSA‐P) and cerebellar (MSA‐C) phenotypes based on predominant motor features, with corresponding pathological classifications of striatonigral (SN) degeneration and olivopontocerebellar (OPC) atrophy; however, disease progression patterns remain poorly understood. We aimed to identify novel MSA subtypes based on neuronal loss patterns using unsupervised machine learning. Methods We applied the Subtype and Stage Inference (SuStaIn) algorithm to analyze neuronal loss patterns in 167 autopsy‐confirmed MSA. Neuronal loss was semi‐quantitatively assessed in 5 brain regions: putamen, substantia nigra, pontine nucleus, inferior olivary nucleus, and cerebellar Purkinje cells. Obtained subtypes were validated by clinicopathological information. Results Three distinct subtypes were identified: SN‐early subtype (54% [86/160]) with initial SN neuronal loss, OPC‐early subtype (28% [44/160]) with early OPC involvement, and SN‐OPC‐synchronous subtype (19% [30/160]) with concurrent early neuronal loss in both systems. These subtypes corresponded well with clinical phenotypes. The SN‐OPC‐synchronous subtype exhibited significantly shorter survival (median 6.2 years vs 6.9 and 7.4 years in SN‐early and OPC‐early subtypes; p = 0.0049), more frequent rapid progression (57% vs 24% and 41% in SN‐early and OPC‐early subtypes; p = 0.0048), and more frequent early falls (70% vs 36% and 50% in SN‐early and OPC‐early subtypes; p = 0.0039). Immunohistochemical validation confirmed extensive α‐synuclein pathology in both SN and OPC systems in the SN‐OPC‐synchronous subtype. Interpretation The SN‐OPC‐synchronous subtype provides insights into α‐synuclein propagation mechanisms, suggesting multiple initial seeding sites rather than unidirectional spread. This computational approach uncovered disease heterogeneity undetectable by conventional methods, potentially benefiting clinical trials through patient stratification. ANN NEUROL 2026;99:989–1000

Purpose: The prevalence and phenotype of capillaroscopic abnormalities in patients with autonomic nervous system dysfunction have not yet been investigated. Multiorgan involvement in dysautonomia entails abnormal vasoreactivity. We aim to correlate the diagnosis of autonomic dysfunction with certain clinical manifestations, which may provide prognostic or diagnostic information using a noninvasive technique, i.e., nailfold video capillaroscopy (NVC). Methods: Patients with autonomic nervous system dysfunction were recruited from rheumatology and neurology clinics with voluntary NVC procedures from 31 January 2024 to 10 January 2024, and a comparison with normal controls was performed. Additional recorded information include demographics and diagnoses of autonomic dysfunction types by autonomic testing, including, but not limited to, the following: reflex screen, sweat test, Valsalva maneuver, nerve fiber density, electromyography (EMG), serology, and history of autoimmune diseases. NVC was performed on a total of 27 patients. This study was approved by the Mayo Clinic Institutional Review Board. Results: The autonomic dysfunction group consisted of small-fiber neuropathy (37%), orthostatic hypotension (48%), autonomic neuropathy (30%), limited autonomic neuropathy (7%), postural orthostatic tachycardia syndrome (POTS) (7%), and connective tissue disease (7%), among other types. Patients with autonomic dysfunction had statistically significant increases in microhemorrhages, dilated capillaries, and ramifications when compared to controls. Conclusions: Autonomic dysfunction was associated with statistically significant microvascular abnormalities compared to normal controls with a distinct NVC pattern. There was a statistically significant correlation between age and BMI with microvascular abnormalities. Here, we demonstrate the diagnostic potential of NVC in autonomic dysfunction and advocate for further study of capillary structures in autonomic dysfunction.

Abstract Purpose The prevalence and phenotype of capillaroscopic abnormalities in patients with autonomic nervous system dysfunction has not been investigated. Multiorgan involvement in dysautonomia entails abnormal vasoreactivity. We aim to corelate the diagnosis of autonomic dysfunction with certain clinical manifestations that may provide prognostic or diagnostic information using a noninvasive technique: nailfold video capillaroscopy (NVC). Methods Patients with autonomic nervous system dysfunction were recruited from rheumatology and neurology clinic with voluntary NVC procedure from 1/31/24 to 10/1/24 and a comparison with normal controls was done. Additional information recorded includes demographics, diagnosis of type of autonomic dysfunction with autonomic testing including but not limited to reflex screen, sweat test, Valsalva maneuver, nerve fiber density, electromyography (EMG), serology, history of autoimmune disease. NVC was performed on a total of 27 patients. The study was approved by the Mayo Clinic Institutional Review Board. Results Autonomic dysfunction group consisted of small fiber neuropathy (37%), orthostatic hypotension (48%), autonomic neuropathy (30%), limited autonomic neuropathy (7%), POTS (7%) and connective tissue disease (7%) amongst other types. Patient with autonomic dysfunction had statistically significant increased microhemorrhages, dilated capillaries and ramifications compared to controls. There was statistically significant correlation of age with capillary ramifications and BMI with capillary density and dilated capillaries. Conclusion Autonomic dysfunction was associated with statistically significant microvascular abnormalities compared to normal controls with a distinct NVC pattern. There was statistically significant correlation of age and BMI with microvascular abnormalities. We demonstrate diagnostic potential of NVC in autonomic dysfunction and advocate for further study of capillary structure in autonomic dysfunction.

Abstract Purpose This study examined occupational histories in neuropathologically confirmed cases of multiple system atrophy to identify environmental associations of potential relevance to disease causation. Methods 270 neuropathologically confirmed cases of multiple system atrophy obtained from the Mayo Clinic brain bank for neurodegenerative disorders in Jacksonville, Florida, were included in this case-control study. Demographic and disease information was collected from medical records. Information regarding occupational history was collected retrospectively from medical records and published obituaries. Proportions of employment by occupational sector were compared to United States census data. Results The most common prior occupations in patients were healthcare (15.2%), education (15.2%), administration (14.8%), clerical (10.7%), petroleum industry (8.9%), business ownership (8.5%), and metal industry (7.8%). When comparing patients to United States census data, significant differences were identified for electrical (5.6% vs. 0.4%, P < 0.001), education (15.2% vs. 2.3%, P < 0.001), real estate (4.4% vs. 0.7%, P < 0.001), metal industry (7.8% vs. 3.0%, P < 0.001), information technology (4.1% vs. 1.8%, P = 0.011), clerical (10.7% vs. 5.5%, P = 0.001), and petroleum industry (8.9% vs. 5.6%, P = 0.024). Conclusions Electrical engineers and electricians, educators, real estate agents, workers in the metal industry, information technologists, clerical staff, and workers in the petroleum industry were significantly overrepresented in our series of multiple system atrophy patients as compared to population data. We hypothesize that these occupational associations may signify environmental exposures increasing disease risk in genetically susceptible individuals. We cannot exclude a potential selection bias in patients willing to donate their brains to an academic center in order to contribute to scientific knowledge.

This Diagnostic Test Interpretation uses a patient case to illustrate tilt table testing, useful for evaluating patients with syncope of unknown cause or postural orthostatic tachycardia syndrome (POTS).