Phenoconversion Risk in Pure Autonomic Failure

Key Takeaways

• About 30% of pooled pure autonomic failure cases later developed a central alpha-synucleinopathy during longitudinal follow-up.
• Multiple system atrophy was the most common reported destination and clustered earlier, while dementia with Lewy bodies and Parkinson disease were also observed and Lewy body disorders followed steadier trajectories.
• Hyposmia was the only feature described as distinguishing phenoconversion to PD or DLB from MSA, while rapid eye movement sleep behavior disorder and subtle motor signs predicted phenoconversion more broadly.

In a JAMA Neurology systematic review and meta-analysis, 270 of 900 patients with pure autonomic failure developed a central alpha-synucleinopathy over a mean 6.4 years. The analysis tracked phenoconversion from pure autonomic failure to central alpha-synucleinopathy diagnoses over time. Pooled longitudinal cohorts showed how often that transition emerged during extended clinical follow-up and whether destination diagnoses followed different timelines. Phenoconversion emerged as a measurable long-term outcome rather than an isolated late event.

The investigation pooled 9 longitudinal cohort studies that included 900 individuals with confirmed pure autonomic failure. Mean age at onset was 63.1 years, and 63.8% of participants were male across the pooled sample. Investigators searched PubMed and Embase from inception through June 2025, and 2 independent reviewers screened studies and extracted data under PRISMA guidance. Incidence estimates were pooled with generic inverse-variance random-effects models, and prediction intervals and meta-regression were used to examine study-level moderators. The result was a longitudinal view of conversion frequency, diagnostic trajectory, and baseline features linked with later phenoconversion across studies.

In pooled follow-up, the incidence of pure autonomic failure phenoconversion to any central alpha-synucleinopathy was 5.09 per 100 person-years, with a 95% CI of 3.79 to 6.85. Across the pooled cohorts, 12% developed multiple system atrophy, 11% developed dementia with Lewy bodies, and 7% developed Parkinson disease. Destination-specific pooled rates were 1.96 per 100 person-years for MSA, 1.56 for DLB, and 1.35 for PD. The rate of MSA phenoconversion was highest in the first years of follow-up, distinguishing it from the other destinations. Lewy body disorders showed more constant rates over time and a less front-loaded trajectory during follow-up.

Hyposmia was the only feature described as having diagnostic value for distinguishing phenoconversion to PD or DLB from MSA, with a pooled risk ratio of 1.88 and 95% CI 1.26 to 2.97. Rapid eye movement sleep behavior disorder and subtle motor signs were consistent predictors of phenoconversion to any central alpha-synucleinopathy. Meta-regression suggested that follow-up duration partly explained between-study heterogeneity. Incidence rates were also similar to those reported in rapid eye movement sleep behavior disorder cohorts. Investigators interpreted the overall trajectory as suggesting that pure autonomic failure may represent a prodromal presentation of PD, DLB, or MSA in some patients.