Disease-specific wearable sensor algorithms for profiling activity, gait, and balance in individuals with Charcot-Marie-Tooth disease type 1A.

BACKGROUND/AIMS: Charcot-Marie-Tooth Disease type 1A (CMT1A), the most common inherited peripheral neuropathy, is characterized by progressive sensory loss and weakness, which results in impaired mobility. Increased understanding of the genetics and pathophysiology of CMT1A has led to development of potential therapeutic agents, necessitating clinical trial readiness. Wearable sensors may provide useful outcome measures for future trials. METHODS: Individuals with CMT1A and unaffected controls were recruited for this 12-month study. Participants wore sensors for in-clinic assessments and at-home, from which activity, gait, and balance metrics were derived. Mann-Whitney U tests were used to analyze group differences for activity, gait, and balance parameters. Test-retest reliability of gait and balance parameters and correlations of these parameters with clinical outcome assessments (COAs) were examined. RESULTS: Thirty individuals, 15 CMT1A, and 15 controls, participated. Gait and balance metrics demonstrated moderate to excellent reliability. CMT1A participants had longer step durations (p < .001), shorter step lengths (p = .03), slower gait speeds (p < .001), and greater postural sway (p < .001) than healthy controls. Moderate correlations were found between CMT-Functional Outcome Measure and step length (r = -0.59; p = .02), and gait speed (r = 0.64; p = .01); 11 out of 15 CMT1A participants demonstrated significant increases in stride duration between the first and last quarter of the 6-min walk test, suggesting fatigue. INTERPRETATION: In this initial study, gait and balance metrics derived from wearable sensors were reliable and associated with COAs in individuals with CMT1A. Larger longitudinal studies are needed to confirm our findings and evaluate sensitivity and utility of these disease-specific algorithms for clinical trial use.

Is skin biopsy a predictor of transition to symptomatic HIV neuropathy? A longitudinal study.

OBJECTIVE: To investigate whether serially assessed epidermal nerve fiber (ENF) density and quantitative sensory thresholds (QSTs) are associated with the clinical transition from HIV infection with no neuropathy or asymptomatic neuropathy to symptomatic distal sensory neuropathy (SDSP). BACKGROUND: Identifying predictors of transition to SDSP would enable identification of subjects at enhanced risk for development of HIV-SDSP and facilitate intervention studies with the ultimate goal of disease prevention. Asymptomatic signs of sensory dysfunction in the feet have been shown to be weakly predictive of SDSP; however, bedside evaluation of small sensory fibers is limited. Abnormality of these fibers may play an important role in the genesis of SDSP. METHODS: Fifty-eight HIV-infected subjects underwent serial clinical, virologic, immunologic, skin biopsy, and QST assessments. Cox proportional hazards modeling was used to examine the associations of serial ENF density and QST assessments with the risk of development of SDSP among the subset of 26 subjects who had asymptomatic or no neuropathy at study entry. RESULTS: Median follow-up was 2.9 years (range 6 months to 4.5 years) during which 19 of 26 subjects transitioned to SDSP. Using a model where ENF density and QST measures from the study visit before potential transition were examined, a lower leg ENF density, a higher cooling threshold, and a higher heat pain threshold for minimal pain (HP 0.5) were associated with a greater risk of SDSP in univariate analyses. In multiple regression analyses, leg ENF density but not QST measures were significantly associated with SDSP. A leg ENF density of 10 fibers/mm or less conferred a 14-fold greater risk of SDSP than a leg ENF density greater than 10 fibers/mm. CONCLUSIONS: Measures of small sensory fibers (leg epidermal nerve fiber density, cooling and heat pain thresholds) seem to be associated with transition to symptomatic HIV-associated distal sensory neuropathy 6 to 12 months later.

Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation.

An in frame, lys236 deletion in the intracytoplasmic domain of myelin protein zero (MPZ) has recently been designated as a mutation possibly associated with Charcot-Marie-Tooth disease (CMT) but requiring further documentation. In this report we present a detailed clinical, electrophysiological, and genotype correlation in three generations of a family with the MPZ lys236del mutation and provide further evidence that this mutation is associated with CMT. The MPZ lys236del mutation is associated with an autosomal dominant, adult onset CMT phenotype, with variable penetrance ranging from an asymptomatic state to foot deformities, pedal numbness, and muscle cramps. Nerve conduction studies disclose intermediate range, somewhat non-uniform slowing of motor nerve conduction, which is accentuated in forelimb rather than distal nerve segments. Based on the contrasting finding of entirely normal conduction velocities (CV) in a genetically affected 15 year old in this family, it remains to be established whether CV slowing with this mutation is progressive in life, a pattern that would contrast with CMT1a (PMP22 gene duplication).