New insights into small fiber neuropathy

Small fiber neuropathy (SFN) manifests clinically with a variable combination of limb paresthesias, neuropathic pain, and autonomic dysfunction. Its prevalence is difficult to ascertain with precision, but the disorder is frequently encountered in neurology practice and is likely to be under-recognized by even experienced clinicians. A confident clinical diagnosis is not easy, as many patients have few or no objective abnormalities on the routine neurological examination. Electromyography and nerve conduction study, commonly used to investigate neuropathies, only assess the function of large-diameter somatic fibers and are usually uninformative. A definitive diagnosis of SFN depends on specialized tests that include skin biopsy to evaluate the intraepidermal nerve fibers, quantitative measurement of autonomic functions, and quantitative sensory testing with thermal stimuli. Presently, the use of these tools is largely limited to tertiary care centers, although general availability to community clinicians has gradually improved over the past decade. Improved diagnosis of SFN comes at an opportune time, as new insights into its underlying etiologies have accumulated in recent years. It has long been recognized that this neuropathy may result from a wide range of systemic conditions, of which diabetes mellitus and impaired glucose tolerance are by far the most important. Other potential causes, such as amyloidosis, Fabry disease, alcoholism, human immunodeficiency virus infection, connective tissue diseases, and exposure to a few neurotoxins, account for a small additional fraction, with no etiology being found in a sizable remaining group of patients. This idiopathic SFN constitutes around 22 to 93% of all patients, depending on the study population and the case definition. One recent study and the study published in this issue of Annals of Neurology indicate that we are finally making inroads into the sizable block of idiopathic SFN. The 2 studies approached the problem differently. The first study investigated serum antibody to peripherin, a neuronal intermediate filament protein that is present in enteric ganglia and sympathetic nerve trunk. Twenty-six patients had peripherin antibody, of which the majority had clinical dysautonomia or sensory neuropathy. In a separate analysis of archived serum from 12 patients with SFN, 4 had peripherin antibody. The study outlined in this issue offers another potential breakthrough in our understanding of SFN. In a Dutch Caucasian cohort with strictly defined idiopathic SFN, there was a surprisingly high prevalence (8 of 28 patients) of mutations in the Nav1.7 channel gene SCN9A. The 8 patients with Nav1.7 mutations as a group appear to be younger than the average patient with SFN. Seven of the 8 had symptom onset at or before the age of 37 years. Half of the 8 had 19 or more years of symptoms at the time of evaluation. Interestingly, a definitive family history was lacking, although 4 patients had family members reporting suggestive symptoms. The investigators went on to show elegantly that the Nav1.7 mutations lead to a gain of function in the sodium channels. These functional changes resemble those seen in 2 other painful disorders known to be associated with Nav1.7, inherited erythromelalgia and paroxysmal extreme pain disorder. The findings in the present study will need to be confirmed and expanded in other clinic populations with SFN. Moreover, more work will be needed to further understand the inheritance, penetrance, phenotypic manifestations, and pathophysiology of Nav1.7 mutations. Nevertheless, there is little doubt that Nav1.7 plays a vital role in human neuropathic pain disorders. This recognition will undoubtedly aid future attempts to devise better pharmacological treatment of neuropathic pain. The surprisingly high prevalence of mutation in the Dutch cohort reminds us of an observation 30 years ago, well before the present era of DNA analysis, that a hereditary cause may be suspected in about 40% of patients with undiagnosed neuropathy after intensive evaluations of family members. If the prevalence of Nav1.7 mutation in other SFN populations is similar to that in the Dutch cohort, Nav1.7 mutation is poised to become 1 of the more common hereditary neuropathies. It seems safe to assume that many of today’s idiopathic neuropathies will eventually be shown to have a genetic basis. Improved technologies such as exome or whole genome sequencing will allow gene discovery and molecular diagnosis rapidly and in a relatively inexpensive manner. The swift pace of technological advancement will open an entirely new level of understanding of these disorders in the coming decades.