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Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies

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Abstract

Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement—i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB—but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA.

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Acknowledgements

This research was supported (in part) by the Intramural Research Program of the NIH, NINDS and by NIH U54-NS065736 from the NIH Rare Disease Clinical Research Network (RDCRN).

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  1. Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, 9000 Rockville Pike MSC-1620, Bethesda, MD, 20892, USA

    David S. Goldstein & Risa Isonaka

  2. Department of Neurology, University of Utah, Salt Lake City, UT, 84108, USA

    Guillaume Lamotte

  3. Division of Autonomic Disorders, Department of Neurology, NYU Langone Health, NYU Dysautonomia Center, New York University Grossman School of Medicine, 530 First Avenue, Suite 9Q, New York, NY, 10016, USA

    Horacio Kaufmann

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Goldstein, D.S., Isonaka, R., Lamotte, G. et al. Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies. Clin Auton Res 31, 677–684 (2021). https://doi.org/10.1007/s10286-021-00829-y

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