Small fibre neuropathy

Patients typically present with distal neuropathic pain, paraesthesia, dysesthesia, impaired temperature sensation, allodynia, and hyperalgesia, often following a length-dependent distribution. Autonomic manifestations such as orthostatic intolerance, sweating abnormalities, gastrointestinal dysmotility, and urinary dysfunction are common. Clinical examinations may reveal impaired pinprick and thermal sensation, while muscle strength, tendon reflexes, and nerve conduction studies are usually preserved. The clinical phenotype is highly heterogeneous, ranging from mild sensory symptoms to severe pain syndromes with substantial autonomic involvement. The diagnosis of SFN is often challenging because routine nerve conduction studies are usually unremarkable, necessitating specialised techniques for the evaluation of small nerve fibres. No universally accepted diagnostic gold standard currently exists.

The epidemiology of SFN remains incompletely defined. In a recent nationwide Dutch study using multiple-system estimation, the prevalence of SFN was estimated at 69.7 cases per 100,000 (approximately 1/1,429) adults and the incidence at 3.55 cases per 100,000 person-years. The observed increase in incidence, particularly among women, was attributed to improved disease recognition and diagnostic awareness, indicating that SFN may represent a larger public health burden than previously recognised.

Genetic forms of SFN comprise disorders in which small-fibre dysfunction constitutes the principal clinical feature, as well as inherited systemic diseases in which small fibres are secondarily affected. The disease may arise secondary to a variety of immune-mediated and metabolic disorders; however, no underlying cause can be identified in up to half of all cases, which are therefore considered idiopathic. The genetic forms group into voltage-gated sodium-channel sensory channelopathies and inherited metabolic and storage disorders. Variants in the sodium channels (SCN9A, SCN10A, SCN11A) are the most commonly reported genetic cause. Among hereditary causes of SFN, and are of particular clinical importance because both conditions may present SFN manifestations and have disease-modifying treatment options available.

Inheritance varies by gene. Variants in the voltage-gated sodium-channel genes SCN9A, SCN10A and SCN11A are typically heterozygous, segregating in an autosomal dominant manner where familial. (GLA) is X-linked, and (TTR) is autosomal dominant. Autosomal recessive forms occur within the broader spectrum of hereditary sensory and metabolic neuropathies.

Owing to the absence of a universally accepted gold-standard test, the diagnosis of SFN currently relies on two established diagnostic criteria sets. Diagnostic criteria for SFN were proposed and validated based on the combination of clinical signs, quantitative sensory testing (QST), and intraepidermal nerve fibre density (IENFD). These criteria have become widely used in both clinical practice and research and support a combined clinical, functional, and structural approach to SFN diagnosis. Where a genetic cause is suspected, molecular genetic testing of this panel clarifies the underlying entity.

Main differential diagnosis:

• Acquired SFN: autoimmune or metabolic causes, frequently diabetes-associated; no monogenic cause

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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