Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies

Abstract

Purpose of reviewPure autonomic failure (PAF) is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons. Patients present with insidious features of autonomic failure that have a chronic course.In this review, we highlight the features of PAF, the differentiating features from other autonomic neuropathies, the diagnostic tests, and the predictors for conversion to a central synucleinopathy.Recent findingsNatural history studies have defined the predictors for and rate of conversion to a central alpha-synucleinopathy. Skin immunohistochemistry techniques and demonstration of length-dependent neuronal loss of both somatic and autonomic small fiber nerves, and intraneural phosphorylated synuclein deposition provide diagnostic biomarkers. In the future, diagnosis maybe supported by measuring cerebrospinal fluid alpha-synuclein oligomers using techniques, such as protein misfolding cyclic amplification assay and real-time quaking-induced conversion.SummaryPAF is a sporadic peripheral autonomic neurodegenerative disease that belongs to the group of disorders known as alpha-synucleinopathies. Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies. Novel diagnostic procedures like skin immunohistochemistry for alpha-synuclein, and protein amplification techniques are being investigated to provide an earlier and more specific diagnosis. A substantial number of PAF patients’ phenoconvert to a central alpha-synucleinopathy.

Small fiber neuropathy as a complication of SARS-CoV-2 vaccinations

“…Genetic SFN is because of mutations in a number of genes, such as GLA (Fabry disease), TTR (transthyretin-related amyloidosis), or SNCA (alpha-synucleinopathy) and many others. Secondary causes of SFN prevail and include, for example, diabetes, renal failure, thyroid dysfunction, hypovitaminoses, acute infections (SARS-CoV-2,[ 8 ] borreliosis[ 9 ]), vaccinations (rabies, varicella, human papillomavirus, lyme, SARS-CoV-2),[ 8 10 ] auto-immune disease,[ 11 12 ] pure autonomic failure because of alpha-synuclein deposition,[ 13 ] sarcoidosis,[ 14 ] Sjögren syndrome,[ 15 ] Parkinson’s disease,[ 16 ] and many others. [ 17 ] SFN may go along with or without affection of large motor or sensory fibers.…”

Small fiber neuropathy

“…42 The most frequent causes of predominantly autonomic SFN include alcoholism, diabetes, hypothyroidism, amyloidosis, and autoimmune autonomic disorders. 38 In a study of 186 patients with type 2 diabetes, 25% had selective SFN and 17% had mixed fiber neuropathy on corneal confocal microscopy (CCM). 43 In a study of 84 patients with SFN, the etiology remained undetermined in one third of them.…”

“…21 Neoplasms associated with SFN include keloids, 37 lymphoma, carcinoid, 18 and others. Rare secondary causes of SFN include selective autonomic failure due to alpha-synuclein deposition, 38 Parkinson's disease due to peripheral sympathetic denervation, 39,40 The most frequent causes of secondary SFN are diabetes and autoimmune disease. 42 The most frequent causes of predominantly autonomic SFN include alcoholism, diabetes, hypothyroidism, amyloidosis, and autoimmune autonomic disorders.…”

“…Neoplasms associated with SFN include keloids, 37 lymphoma, carcinoid, 18 and others. Rare secondary causes of SFN include selective autonomic failure due to alpha‐synuclein deposition, 38 Parkinson's disease due to peripheral sympathetic denervation, 39,40 and erythromelalgia, which is due to mutations in SCN9A 41 …”