Faculty Bibliography

Our genome encodes for all proteins in the body and controls our biological functions. Mutations in DNA sequences that encode for proteins highly expressed in nerve tissue can result in specific lesions within the autonomic pathways. Mutations that result in a deficiency in a protein important for the survival of autonomic neurons at key developmental stages are usually expressed at birth or in early childhood. Hereditary sensory and autonomic neuropathies (HSAN) are a group of inherited diseases with insensitivity to pain. There are currently 6 major HSAN subtypes and at least 12 known gene-causing mutations. The severity of autonomic involvement is most profound in types 3 and 4, which are both autosomal recessive, but their autonomic phenotypes are distinctly different. Genetic mutations that result in the overexpression of proteins expressed in autonomic neurons typically present later in life and follow a more degenerative course. Familial amyloid polyneuropathies are a group of disorders caused by deposits of amyloid fibrils, most commonly due to mutations within the transthyretin (TTR) gene. This results in a length-dependent sensorimotor and autonomic neuropathy affecting unmyelinated and small myelinated fibers. The most common auto-nomic features are orthostatic hypotension, erectile dysfunction and gastrointestinal dysmotility, and can sometimes be a presenting sign. Genetic factors may also play a role in susceptibility to neurode-generative diseases. A recent genome wide association study found several genes that may emerge as genetic players in synucleinopathies including multiple system atrophy. For now, clinical trials are underway to explore whether modifying gene expression can influence the survival of autonomic neurons in HSAN3 and transthyretin-related hereditary amyloidosis. In the future, it may be possible to modify our future risk of developing an autonomic disorder with genetic therapy

OBJECTIVE:We report the results of a pilot, enrichment-design, placebo-controlled crossover trial of pregabalin for the treatment of prediabetic small-fiber neuropathic pain. METHODS:Individuals with impaired fasting glucose or impaired glucose tolerance and neuropathic pain were evaluated according to UTAH Early Neuropathy Scale (UENS), Quantitative Sensory Testing, and intraepidermal nerve fiber density (IENFD). Symptoms were graded according to the Numeric Rating Scale (NRS). Individuals who responded to the administration of placebo were not eligible. Pregabalin was initiated at a dose of 75 mg qid and tapered up to 300 mg bid. Only individuals with a reduction of pain scores ≥30% were eligible to continue with the double-blind phase, which consisted of a randomized crossover period of 1 month of pregabalin and 1 month of placebo, with 7 days of washout between periods. RESULTS:Forty-five participants were enrolled in the study. There was 36% reduction in the NRS from baseline after 1 month of single-blind pregabalin (NRS=5.1±2.6). Twenty-six participants were eligible for the double-blind phase. There was further reduction of pain in the double-blind pregabalin and the placebo groups, but the pregabalin group had a statistically significant reduction of pain (NRS=3.2±2.2 vs. 4.0±2; P<0.05). Participants who did not respond showed a lower IENFD than those who responded, suggesting more severe nerve damage. CONCLUSIONS:This pilot study showed improvement of prediabetic neuropathic pain. Participants with higher pain scores at baseline had higher UENS scores and a lower IENFD. Limitations of the study include the small number of participants and the carry-over effect.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016.

BACKGROUND:Quantitative Sensory Testing (QST) is more often used because of the increasing recognition of small fiber neuropathy. METHODS:We studied QST in a systematic way in an age-stratified cohort of 83 neurological-free Hispanic Latinamerican patients. Predefined standardized stimuli were applied using the method of limits. RESULTS:WDT range from 2.2 to 3.3°C in hands, and from 4.0°C up to 6.6°C in feet. Cold detection threshold range from 2.2 to 3.6°C in hands, and from 2.6°C to 4.5°C in feet. Heat-induced pain (HP) was induced at lower temperatures than previously reported, with a range from 41.8°C to 44.5°C in hands and from 43.2 to 45.7°C in feet. Similar to HP, cold pain was also induced at much higher temperatures, between 21.4-17.3°C in hands and 21.5-16.5°C in feet. Vibratory stimuli ranged from 0.8 to 1.7 μ/sec in hands and from 1.4 to 3.5 μ/sec in feet. CONCLUSION:Temperature and vibration thresholds were similar to those previously reported in other populations except for pain thresholds that were lower in this population than in the Caucasian population.