ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia.

Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP); this mutation leads to variable skipping of exon 20 and to a drastic reduction of ELP1 in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception; this loss leads to severe gait ataxia, spinal deformities, and respiratory insufficiency due to neuromuscular incoordination. There is currently no effective treatment for FD, and the disease is ultimately fatal. The development of a drug that targets the underlying molecular defect provides hope that the drastic peripheral neurodegeneration characteristic of FD can be halted. We demonstrate herein that the FD mouse TgFD9;IkbkapΔ20/flox recapitulates the proprioceptive impairment observed in individuals with FD, and we provide the in vivo evidence that postnatal correction, promoted by the small molecule kinetin, of the mutant ELP1 splicing can rescue neurological phenotypes in FD. Daily administration of kinetin starting at birth improves sensory-motor coordination and prevents the onset of spinal abnormalities by stopping the loss of proprioceptive neurons. These phenotypic improvements correlate with increased amounts of full-length ELP1 mRNA and protein in multiple tissues, including in the peripheral nervous system (PNS). Our results show that postnatal correction of the underlying ELP1 splicing defect can rescue devastating disease phenotypes and is therefore a viable therapeutic approach for persons with FD.

Relative validity and reliability of a diet risk score (DRS) for clinical practice.

INTRODUCTION: Adherence to cardioprotective dietary patterns can reduce risk for developing cardiometabolic disease. Rates of diet assessment and counselling by physicians are low. Use of a diet screener that rapidly identifies individuals at higher risk due to suboptimal dietary choices could increase diet assessment and brief counselling in clinical care. METHODS: We evaluated the relative validity and reliability of a 9-item diet risk score (DRS) based on the Healthy Eating Index (HEI)-2015, a comprehensive measure of diet quality calculated from a 160-item, validated food frequency questionnaire (FFQ). We hypothesised that DRS (0 (low risk) to 27 (high risk)) would inversely correlate with HEI-2015 score. Adults aged 35 to 75 years were recruited from a national research volunteer registry (ResearchMatch.org) and completed the DRS and FFQ in random order on one occasion. To measure reliability, participants repeated the DRS within 3 months. RESULTS: In total, 126 adults (87% female) completed the study. Mean HEI-2015 score was 63.3 (95% CI: 61.1 to 65.4); mean DRS was 11.8 (95% CI: 10.8 to 12.8). DRS and HEI-2015 scores were inversely correlated (r=-0.6, p<0.001; R2=0.36). The DRS ranked 37% (n=47) of subjects in the same quintile, 41% (n=52) within ±1 quintile of the HEI-2015 (weighted κ: 0.28). The DRS had high reliability (n=102, ICC: 0.83). DRS mean completion time was 2 min. CONCLUSIONS: The DRS is a brief diet assessment tool, validated against a FFQ, that can reliably identify patients with reported suboptimal intake. Future studies should evaluate the effectiveness of DRS-guided diet assessment in clinical care. Trial registration details ClinicalTrials.gov (NCT03805373).