title: A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK.
abstract: BACKGROUND
  Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland. The neuropathy phenotype is less well described than the cardiac manifestations in this group.
  
  
  METHODS
  We present the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset.
  
  
  RESULTS
  Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38-75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (-1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used.
  
  
  CONCLUSIONS
  The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history.
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Carr
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK Department of Neurology, University Hospital "Marqués de Valdecilla", Santander, Spain.
authors.forename: A L
authors.initials: AL
authors.lastname: Pelayo-Negro
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors.forename: M Rb
authors.initials: MR
authors.lastname: Evans
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Laurà
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: J
authors.initials: J
authors.lastname: Blake
authors.affiliation: Autonomic unit, National Hospital of Neurology and Neurosurgery, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Stancanelli
authors.affiliation: Autonomic unit, National Hospital of Neurology and Neurosurgery, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Iodice
authors.affiliation: National Amyloidosis Centre, University College London Medical School, Royal Free Campus, London, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Wechalekar
authors.affiliation: National Amyloidosis Centre, University College London Medical School, Royal Free Campus, London, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Whelan
authors.affiliation: National Amyloidosis Centre, University College London Medical School, Royal Free Campus, London, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Gillmore
authors.affiliation: National Amyloidosis Centre, University College London Medical School, Royal Free Campus, London, UK.
authors.forename: P N
authors.initials: PN
authors.lastname: Hawkins
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors.forename: M M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D000225:Adenine; D000328:Adult; D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009431:Neural Conduction / Q000502:physiology; D009460:Neurologic Examination; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D011228:Prealbumin / Q000235:genetics; D012189:Retrospective Studies; D014443:Tyrosine / Q000235:genetics
chemical_list: D011228:Prealbumin; D014443:Tyrosine; D000225:Adenine