Objectives Hereditary sensory neuropathy type 1 (HSN1) is a rare, slowly progressive neuropathy causing profound sensory deficits and often severe motor loss. L-serine supplementation is a possible candidate therapy but the lack of responsive outcome measures is a barrier for undertaking clinical trials in HSN1. We performed a 12-month natural history study to characterise the phenotype of HSN1 and to identify responsive outcome measures.
Methods Assessments included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), CMTNSv2-Rasch modified, nerve conduction studies, quantitative sensory testing, intraepidermal nerve fibre density (thigh), computerised myometry (lower limbs), plasma 1-deoxysphingolipid levels, calf-level intramuscular fat accumulation by MRI and patient-based questionnaires (Neuropathic Pain Symptom Inventory and 36-Short Form Health Survey version 2 [SF-36v2]).
Results 35 patients with HSN1 were recruited. There was marked heterogeneity in the phenotype mainly due to differences between the sexes: males generally more severely affected. The outcome measures that significantly changed over 1 year and correlated with CMTNSv2, SF-36v2-physical component and disease duration were MRI determined calf intramuscular fat accumulation (mean change in overall calf fat fraction 2.36%, 95% CI 1.16 to 3.55, p=0.0004), pressure pain threshold on the hand (mean change 40 kPa, 95% CI 0.7 to 80, p=0.046) and myometric measurements of ankle plantar flexion (median change −0.5 Nm, IQR −9.5 to 0, p=0.0007), ankle inversion (mean change −0.89 Nm, 95% CI −1.66 to −0.12, p=0.03) and eversion (mean change −1.61 Nm, 95% CI −2.72 to −0.51, p=0.006). Intramuscular calf fat fraction was the most responsive outcome measure.
Conclusion MRI determined calf muscle fat fraction shows validity and high responsiveness over 12 months and will be useful in HSN1 clinical trials.
- Guillain-Barré syndrome
- neurophysiol, clinical
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Contributors UK, JMM, CDJS, JST, TAY, DLHB, ML and MMR contributed to study concept and design. UK, MRBE, TH, SS, KO-A, GL, RL and JMP contributed to data acquisition and analysis. All authors contributed to drafting or revising the manuscript and figures.
Funding UK is grateful for fellowships from the National Institutes of Neurological Diseases and Stroke and Office of Rare Diseases (U54NS065712) and the Medical Research Council (519779). TH received support from the Swiss National Foundation SNF (Project 31003A_153390/1); Rare Disease Initiative Zurich ('radiz', Clinical Research Priority Program for Rare Diseases, University of Zurich). DLHB is a senior Wellcome clinical scientist (Ref 202747/Z/16/Z). MMR is grateful to the Medical Research Council (MRC), MRC Centre Grant (G0601943) and the National Institutes for Neurological Diseases and Stroke and Office of Rare Diseases (U54NS065712) for their support. This research was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (BRC51/NS/MR).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study was approved by the local ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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