Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene.
Mutations in HSPB1 are one of the commonest causes of distal Hereditary Motor Neuropathy (dHMN). Transgenic mouse models of the disease have identified HDAC6 inhibitors as promising treatments for the condition paving the way for human trials. A detailed phenotype and natural history study of HSPB1 neuropathy is therefore required in order to inform the duration and outcome measures of any future trials. Clinical and neurophysiological data and lower limb muscle MRI were collected both prospectively and retrospectively from patients with mutations in HSPB1. The natural history was assessed by recording the weighted Charcot-Marie-Tooth Examination Score (CMTES) at annual intervals in a subset of patients. 20 patients from 14 families were recruited into the study. The average age of onset was in the 4th decade. Patients presented with a length dependent neuropathy but with early ankle plantar flexion weakness. Neurophysiology confirmed a motor neuropathy but also showed sensory nerve involvement in most patients. Cross sectional muscle MRI revealed soleus and medial gastrocnemius fat infiltration as an early signature of mutant HSPB1 disease. In this study neither semi quantitative muscle MRI, the CMTES nor neurophysiology were able to detect disease progression in HSPB1 neuropathy over 1 or 2 years. Further studies are therefore required to identify a suitable biomarker before clinical trials in HSPB1 neuropathy can be undertaken.
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. Electronic address: a.rossor@ucl.ac.uk.
Alexander M
AM
Rossor
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Jasper M
JM
Morrow
Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK.
James M
JM
Polke
Department of Neurology, Adelaide & Meath Hospitals Incorporating the National Children's Hospital, Tallaght, Dublin, Ireland; Academic Unit of Neurology, Trinity College Dublin, Ireland.
Sinead M
SM
Murphy
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Henry
H
Houlden
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Matilde
M
Laura
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Hadi
H
Manji
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK; Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, UK.
Julian
J
Blake
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Mary M
MM
Reilly
D000328:Adult; D017668:Age of Onset; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D015417:Hereditary Sensory and Motor Neuropathy / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D035002:Lower Extremity / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D018482:Muscle, Skeletal / Q000294:innervation*; D010375:Pedigree; D010641:Phenotype; D010865:Pilot Projects
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones
Charcot–Marie–Tooth disease; Distal hereditary motor neuropathy; HSPB1; Neuromuscular disease; Peripheral neuropathy