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Journal ArticleDOI

Amyloid polyneuropathy caused by wild‐type transthyretin

01 Jul 2015-Muscle & Nerve (Muscle Nerve)-Vol. 52, Iss: 1, pp 146-149

TL;DR: Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene.
Abstract: Introduction Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene. Methods We describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis. Results The diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elderly patients with cardiomyopathy, but a few cases of polyneuropathy have been reported. Conclusions This entity is especially noteworthy in light of emerging treatment options for hereditary transthyretin amyloidosis, which are likely to also be beneficial in wild-type disease. Muscle Nerve 52: 146–149, 2015
Topics: Transthyretin (68%), Amyloidosis (66%), Polyneuropathy (57%), Nerve biopsy (54%), Amyloid (50%)

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Title
Amyloid polyneuropathy caused by wild-type transthyretin.
Permalink
https://escholarship.org/uc/item/4ms4s9b0
Journal
Muscle & nerve, 52(1)
ISSN
0148-639X
Authors
Lam, Lynda
Margeta, Marta
Layzer, Robert
Publication Date
2015-07-01
DOI
10.1002/mus.24563
Copyright Information
This work is made available under the terms of a Creative Commons Attribution License,
availalbe at https://creativecommons.org/licenses/by/4.0/
Peer reviewed
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University of California

Amyloid Polyneuropathy Caused By
Wild-Type Transthyretin
Authors:
Lynda Lam, MD
1
Marta Margeta, MD, PhD
2
Robert Layzer, MD
3
Affiliations:
1
Department of Neurology, Kaiser Permanente Medical Center, San Rafael, California, USA
2
Department of Pathology, University of California, San Francisco, California, USA
3
Department of Neurology, University of California, San Francisco, California, USA
Requests for Reprints:
Lynda Lam, MD (lynda.l.lam@kp.org)
Running Title: Amyloid Polyneuropathy
Key Words: amyloid polyneuropathy; wild type transthyretin amyloidosis; senile system
amyloidosis; nerve biopsy; sensorimotor polyneuropathy

AmyloidPolyneuropathy
2
Abstract
Introduction: Amyloidosis derived from transthyretin (TTR) molecules is typically caused by
mutations of the TTR gene.
Case or Methods: We describe an elderly patient with a severe length-dependent polyneuropathy
that unexpectedly proved to be caused by wild-type transthyretin amyloidosis.
Results: The diagnosis was made by muscle biopsy, since no amyloid deposits were found in the
biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elderly
patients with cardiomyopathy, but a few cases of polyneuropathy have been reported.
Discussion: This entity is especially noteworthy in light of emerging treatment options for
hereditary transthyretin amyloidosis, which are likely also to be beneficial in wild-type disease.

AmyloidPolyneuropathy
3
Senile systemic amyloidosis (SSA), or wild-type transthyretin (TTR) amyloidosis, is associated
most commonly with cardiomyopathy and carpal tunnel syndrome. Polyneuropathy has not been
thought to occur in this form of amyloidosis. However, the Transthyretin Amyloidosis Outcomes
Survey (THAOS), an international multicenter longitudinal study, recently reported sensory
neuropathies in one-third of patients with SSA
1
; a few other cases of SSA with polyneuropathy
have been reported.
2,3,4
Here, we describe the case of a patient with SSA who exhibited a
severe, painful sensorimotor polyneuropathy.
CASE REPORT
An 84-year-old woman with a history of coronary artery disease, congestive heart failure, atrial
fibrillation, and borderline diabetes was admitted to the hospital complaining of progressive
difficulty walking for 4 years. For several years she had deep burning pain and numbness in her
legs to the level of the mid-shins. She used a cane initially and required a walker 2 years later.
She was on no medications associated with a toxic neuropathy. Neurological examination 14
months prior to current presentation demonstrated full strength except for moderate weakness of
dorsiflexion and eversion of the left foot. There was impaired sensation to light touch and
pinprick from the mid-shins distally. Vibratory perception was decreased in the toes. Computed
tomography of the lumbar spine showed hypertrophic changes with marked stenosis, and she was
given a diagnosis of spinal stenosis; no treatment was given. Her leg numbness and weakness
continued to worsen; for 6 weeks she had difficulty arising from a chair or her bed, and for 1
month she was unable to walk. The upper extremities were not involved. Her mother (deceased)
was said to have developed a polyneuropathy in her 80s, while her sister had an unspecified
neuropathy; neither condition was disabling.

AmyloidPolyneuropathy
4
Neurological examination revealed severe weakness and atrophy of the distal lower extremities
with no movements in the feet, and mild weakness of the hips and thighs. The upper extremities
and neck muscles were normal. Reflexes were absent in the lower extremities. Proprioception
was absent in the toes, and vibratory perception was absent in the feet up to the ankles. Other
sensory modalities were not tested. She was unable to sit or stand without assistance.
Laboratory studies in the hospital revealed a HgbA1c of 6.5%. Serial blood glucose monitoring
(fasting glucose and HgbA1c) showed glucose intolerance for several years prior, with the
highest HgbA1c (6.7%) about 4 months prior to presentation. She had normal serum creatine
kinase, TSH, vitamin B12, ANA, and ANCA. Serum protein immunoelectrophoresis showed
biclonal IgG kappa paraproteins, and electrocardiogram showed atrial fibrillation.
Echocardiogram demonstrated a severely dilated left atrium and mild concentric left ventricular
hypertrophy. There was normal left ventricular size and ejection fraction (> 60%).
Nerve conduction studies of the lower extremities showed absent sural sensory nerve action
potentials, very low amplitude right fibular and bilateral tibial compound muscle action
potentials (CMAPs) and absent left fibular CMAP. Electromyography showed acute denervation
and chronic reinnervation below the knees and chronic reinnervation in the proximal lower
extremities.
A right gastrocnemious muscle biopsy showed abundant deposits of congophilic amorphous
material in the walls of perimysial and epimysial vessels, in the interstitium, and within
hypertrophied muscle fibers (Fig. 1, A-D); this amyloid material stained with anti-TTR antibody

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21 Aug 2012-Neurology
TL;DR: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment.
Abstract: Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this rando ...

534 citations


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John L. Berk1, Ole B. Suhr2, Laura Obici3, Yoshiki Sekijima4  +21 moreInstitutions (9)
25 Dec 2013-JAMA
TL;DR: Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life.
Abstract: RESULTS By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, −7.6 to −2.2) points in the placebo group and increased by 1.5 (95% CI, −0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, −4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.

452 citations


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TL;DR: The mean heart weight, frequency of atrial fibrillation, percentage of patients with heart failure, and frequency of myocardial infarction were increased in patients with cardiac amyloid, but these differences failed to reach statistical significance.
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  • ...namely atrial fibrillation, cardiac conduction abnormalities, and hypertrophic cardiomyopathy.(9) Carpal tunnel syndrome is observed commonly and can precede cardiac manifestations....

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