title: Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates.
abstract: OBJECTIVE
  Autonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation. This study aimed to investigate the pathology and clinical significance of sudomotor denervation.
  
  
  METHODS
  Skin biopsies were performed on the distal leg of FAP patients with a follow-up duration of 3.8 ± 1.6 years. Sudomotor innervation was stained with 2 markers: protein gene product 9.5 (PGP 9.5), a general neuronal marker, and vasoactive intestinal peptide (VIP), a sudomotor nerve functional marker, followed by quantitation according to sweat gland innervation index (SGII) for PGP 9.5 (SGIIPGP 9.5) and VIP (SGIIVIP).
  
  
  RESULTS
  There were 28 patients (25 men) with Ala97Ser transthyretin and late onset (59.9 ± 6.0 years) disabling neuropathy. Autonomic symptoms were present in 22 patients (78.6%) at the time of skin biopsy. The SGIIPGP 9.5 and SGIIVIP of FAP patients were significantly lower than those of age- and gender-matched controls. The reduction of SGIIVIP was more severe than that of SGIIPGP 9.5 (p = 0.002). Patients with orthostatic hypotension or absent sympathetic skin response at palms were associated with lower SGIIPGP 9.5 (p = 0.019 and 0.002, respectively). SGIIPGP 9.5 was negatively correlated with the disability grade at the time of skin biopsy (p = 0.004), and was positively correlated with the interval from the time of skin biopsy to the time of wheelchair usage (p = 0.029).
  
  
  CONCLUSIONS
  This study documented the pathological evidence of sudomotor denervation in FAP. SGIIPGP 9.5 was functionally correlated with autonomic symptoms, autonomic tests, ambulation status, and progression of disability.
authors.affiliation: Department of Neurology, National Taiwan University Hospital.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chao
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Cho-Min
authors.initials: CM
authors.lastname: Huang
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Hao-Hua
authors.initials: HH
authors.lastname: Chiang
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Kai-Ren
authors.initials: KR
authors.lastname: Luo
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Kan
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Naomi Chu-Chiao
authors.initials: NC
authors.lastname: Yang
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Hao
authors.initials: H
authors.lastname: Chiang
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Whei-Min
authors.initials: WM
authors.lastname: Lin
authors.affiliation: Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Lai
authors.affiliation: Department of Neurology, National Taiwan University Hospital.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, National Taiwan University Hospital.|Department of Forensic Medicine.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Neurology, National Taiwan University Hospital.|Department of Anatomy and Cell Biology, National Taiwan University College of Medicine.|Graduate Institute of Brain and Mind Sciences.|Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Sung-Tsang
authors.initials: ST
authors.lastname: Hsieh
mesh_terms: D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001342:Autonomic Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D004817:Epidermis / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007866:Leg; D008297:Male; D008875:Middle Aged; D011228:Prealbumin / Q000235:genetics; D012867:Skin / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D013545:Sweat Glands / Q000294:innervation* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D011228:Prealbumin; C482860:UCHL1 protein, human; D014660:Vasoactive Intestinal Peptide; D043222:Ubiquitin Thiolesterase