PAF is considered rare. The exact worldwide prevalence is unknown, although estimates of 1-5 per 100,000 people are mentioned. The typical age of onset is in mid-to-late adulthood, commonly affecting individuals in their 40s to 60s or older. It appears to occur more frequently in males than in females. Because symptoms overlap with other autonomic disorders, PAF is likely underdiagnosed.

PAF belongs to a class of diseases known as alpha-synucleinopathies, characterized by the abnormal, toxic accumulation of a protein called alpha-synuclein in the peripheral nerves and autonomic ganglia (clusters of nerve cells near the spinal cord and target organs). This abnormal protein buildup gradually damages these nerve cells, preventing them from releasing essential neurotransmitters like norepinephrine. Without adequate norepinephrine, blood vessels cannot receive the signal to constrict when a person stands up, for example. The exact underlying cause remains unknown, and no clearly established environmental or genetic risk factors have been identified. Rare familial cases have been reported, but most cases are sporadic.

Because the autonomic nervous system innervates multiple organ systems, symptoms are widespread. 

• Cardiovascular: One cardinal feature is orthostatic hypotension, a sharp drop in blood pressure when transitioning to a standing position, leading to dizziness, lightheadedness, visual blurring, neck pain, or syncope (fainting). Paradoxically, patients may also experience supine hypertension (dangerously high blood pressure when lying down).

• Genitourinary: Urinary urgency, frequency, incontinence, or urinary retention. Sexual dysfunction, including erectile dysfunction, is very common.

• Gastrointestinal: Severe constipation or, less frequently, fecal incontinence (loss of bowel movement control).

• Thermoregulatory: Decreased sweating (anhidrosis) leading to severe heat intolerance.

• Sleep: REM (rapid eye movement) sleep behavior disorder, characterized by physically acting out vivid dreams, is a frequent non-motor manifestation of the disease.

• Eye symptoms:  Blurred vision, reduced tear production, difficulty adapting to darkness.

PAF is a "diagnosis of exclusion," meaning physicians must first rule out other causes of autonomic dysfunction (such as diabetes, medication side effects, or structural neurological diseases).

• Clinical Evaluation: A defining criterion is a drop in systolic blood pressure of ≥20 mmHg or diastolic blood pressure of ≥10 mmHg within 3 minutes of standing, without an appropriate compensatory increase in heart rate. Generally, there is an absence of major motor or cognitive abnormalities.

• Laboratory and Autonomic Testing: Patients typically show abnormally low levels of circulating norepinephrine in their blood while resting flat, which fails to appropriately increase when they stand up;  tilt-table testing looking for blood pressure drop and heart rate changes leading to dizziness or fainting when moving from a flat to an upright position;  thermoregulatory sweat testing;  skin biopsy for phosphorylated alpha-synuclein (available at specialized centers). 

• Neurological Exam: To confirm classic PAF, the patient must lack signs of central nervous system involvement (no tremors, rigidity, or cognitive decline);  a DaTscan that visualizes dopamine uptake in the brain can help rule out Parkinson disease.

There is currently no specific treatment to stop progression in PAF; management of autonomic symptoms to improve daily function and to prevent traumatic falls is the mainstay of treatment.

• Non-pharmacologic measures:  Slowly transitioning from lying or sitting to standing, increasing water intake (providers may recommend around 3 liters a day), increasing salt intake or using electrolyte-replacement drinks, elevating the head of the bed four to six inches, and wearing waist- or thigh-high compression garments. Leg-crossing and muscle tensing maneuvers before standing can also help. Avoid excessive heat and standing. Constipation may be treated with a high fiber diet, hydration and laxatives.

• Pharmacologic treatment:  Midodrine and fludrocortisone are commonly used vasopressor/mineralocortioid agents for orthostatic hypotension. Other agents (e.g., droxidopa, pyridostigmine) are also used depending on severity.

Supine hypertension (elevated blood pressure when lying down) often requires balancing treatment carefully against orthostatic hypotension (drop in blood pressure when standing up) management.

The disorder progresses gradually, usually over decades. While severe orthostatic hypotension can be debilitating and cause dangerous injuries from fainting, PAF itself is not considered immediately life-threatening and life expectancy may be near normal for many patients..

However, long-term tracking has revealed that PAF is often a precursor state. Up to 30% of patients with PAF will eventually "phenoconvert"—meaning their disease will spread to the central nervous system and evolve into a more severe synucleinopathy, such as Multiple System Atrophy (MSA), Parkinson's disease, or Dementia with Lewy Bodies (DLB). Regular neurological monitoring is essential to catch early signs of motor or cognitive changes.

1. Coon EA, Singer W, Low PA. 2019. “Pure Autonomic Failure.” Mayo Clin Proc. 94(10):2087-2098. doi: 10.1016/j.mayocp.2019.03.009. Epub 2019 Sep 9. PMID: 31515103; PMCID: PMC6826339.

2. Cleveland Clinic:  Pure autonomic failure.

3. Genetic and Rare Disease Information Center (GARD):  Pure autonomic failure.

4. National Organization for Rare Disorders (NORD):  Pure autonomic failure.