Faculty Bibliography

OBJECTIVE: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. METHODS: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). RESULTS: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. CONCLUSIONS: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.

GNE myopathy is a rare autosomal recessive myopathy without an approved treatment. Symptoms of distal leg weakness typically present in early adulthood and progressive weakness results in greater dependence and disability over time. The GNEM-FAS is a disease-specific measure of functional activity and independence in ambulatory patients. Mobility (MOB), Upper Extremity (UE) and Self-Care (SC) domains are assessed. A Total Score (TS) is calculated and higher scores represent greater independence. The GNEM-FAS was administered by clinical interview to 47 ambulatory subjects enrolled in a randomized, placebo-controlled, 48 week, Phase 2 study of extended release sialic acid (SA-ER). Subjects were randomized to receive placebo, 3g or 6g of SA-ER/ day and after 24 weeks, the placebo group crossed to 3g or 6g/day for the remaining 24 weeks. Strength and functional performance measures administered in the study included hand-held dynamometry to evaluate UE and lower extremity (LE) strength and a 6-minute walk test (6MWT). The GNEM-FAS was administered at 12 week intervals. At baseline, the mean TS was 69 out of 100 (range 22-94) with MOB scores indicating more limitations than in UE or SC function. Higher MOB scores were associated with greater LE strength (r = 0.85) and longer 6MWT distances (r = 0.83). A moderate association was seen between UE strength and the UE (r = 0.66) and MOB (r = 0.62) domains. At week 48, the differences between subjects treated with 6g and 3g doses are reported. Analysis of the GNEM-FAS TS demonstrated a 3.71 point difference favoring the high dose group (p = 0.08). Further analysis revealed a statistically significant difference in the MOB score (2.14; p = 0.02) although this effect was not evident in measures of LE strength or function. A positive trend in the UE domain score (1.60; p = 0.11) was also observed and supported by a statistically significant difference in UE strength (p = 0.003). No differences in SC domain scores were observed. The statistically significant differences observed in both the MOB domain and UE strength may reflect an increased reliance on UE use as the disease and weakness progresses. The GNEM-FAS shows promise in evaluating patient-reported change in functioning and for use in future studies of patients with GNE myopathy. Additional work is underway to further validate this version of the GNEM-FAS and expand it for use with more impaired patients