Cardiovascular Syncope and Autonomic Disorders (199)
Heart Rate Variability and Autonomic Control (162)
Parkinson's Disease Mechanisms and Treatments (119)
Botulinum Toxin and Related Neurological Disorders (93)
Pain Mechanisms and Treatments (81)
Klein CJ, Wu Y, Kilfoyle DH, Sandroni P, Davis MD , et al.
Journal of neurology, neurosurgery, and psychiatry •
Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia. We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes. In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations. Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.
To assess the frequency and type of vascular changes and neurologic abnormalities in patients with erythromelalgia. Prospective study of patients with no spontaneous symptoms at the time of their visit and with provoked symptoms. Tertiary referral center. Sixty-seven patients presenting with erythromelalgia at Mayo Clinic, Rochester, Minn, from 1999 through 2001. Testing nerve and vascular function in patients without symptoms present; testing vascular function after provoking symptoms with exercise or by increasing ambient temperature. In patients in whom symptoms could be elicited, vascular function with and without symptoms was assessed by measurement of local skin temperature, laser Doppler flow, and transcutaneous oximetry. Neurologic assessment included electromyography, nerve conduction studies, and autonomic reflex screening (using the quantitative sudomotor axon reflex test, adrenergic function testing, heart rate response to deep breathing, and the Valsalva ratio). Autonomic reflex screening was performed on 57 (85%) of the 67 patients. Of these 57 patients, 46 (81%) had abnormal quantitative sudomotor axon reflex test results; 14 (25%) had abnormal adrenergic function; and 15 (26%) had abnormal cardiovagal function. Put in another way, results were abnormal for 49 (86%) of the 57 patients who had autonomic reflex screening. Severe sudomotor abnormalities (ie, absent or markedly reduced sweat production) were present in 46 (94%) of these 49 patients; 14 (29%) had abnormal adrenergic function, and 15 (31%) had a cardiovagal abnormality. Electromyography and nerve conduction studies were performed in 24 (36%) of the 67 patients. Of these 24 patients, 14 (58%) had abnormal electromyographic results and 10 (42%) had abnormal nerve conduction study results. Vascular function studies, with and without symptoms present, were performed in 13 of the 67 patients. During symptoms, the mean temperature of the toe skin increased by 7.8 degrees C, and blood flow increased 10.2-fold. Paradoxically, mean transcutaneous oximetry measurements did not change. This prospective study extends and confirms our previous observation that, in addition to other forms of neuropathy, most patients with erythromelalgia have small-fiber neuropathy.