Amyloid polyneuropathy caused by wild‐type transthyretin

TLDR: 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

Figures

Fig. 1. Muscle biopsy findings. (A and B) Hematoxylin and eosin stain demonstrated widespread accumulation of amorphous pink material in blood vessel walls and large muscle fibers; the majority of muscle fibers had small angulated appearance. Arrows, vessel wall deposits;

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UCSF
UC San Francisco Previously Published Works
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

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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

AmyloidPolyneuropathy
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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.

AmyloidPolyneuropathy
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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.

AmyloidPolyneuropathy
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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

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "Amyloid polyneuropathy caused by wild-type transthyretin" ?

The authors describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis. 

Q2. What is the predominant disease in SSA?

Cardiac disease predominates in SSA, namely atrial fibrillation, cardiac conduction abnormalities, and hypertrophic cardiomyopathy. 

Q3. What is the preferred initial diagnostic test for senile amyloidosis?

When systemic amyloidosis is suspected, fat pad biopsy may be the preferred initial diagnostic test, with a sensitivity of up to 80%, and relative ease and safety of the procedure. 

Q4. What is the cause of the senile systemic amyloidosis?

Small-diameter sensory fibers tend to be affected first, and neuropathic pain is often prominent, but eventually all sensory and motor fibers as well as the peripheral autonomic nervous system are affected. 

Q5. What is the common type of amyloidosis?

In particular, oral treatment with tafamadis and diflunisal, agents that stabilize the TTR tetramer and thus prevent the monomer from forming amyloid, was shown to be effective in stage III clinical trials. 

Q6. What was the result of the blood test?

despite having a gammopathy on serum testing, light chain staining on immunohistochemistry was negative, ruling out primary systemic amyloidosis. 

Q7. What was the diagnosis of the patient?

Although the patient had a family history of polyneuropathy, genetic testing revealed that she had a nonfamilial form of amyloidosis. 

Q8. What is the diagnosis of senile systemic amyloidosis?

This syndrome, known as senile systemic amyloidosis (SSA), is seen primarily in elderly men, although it can begin at a younger age; it is estimated to occur in up to 25% of individuals older than 80. 

Q9. What is the acronym for Amyloid Polyneuropathy?

Amyloid Polyneuropathy  9Abbreviations transthyretin (TTR), senile systemic amyloidosis (SSA), Transthyretin Amyloidosis Outcomes Survey (THAOS), compound muscle action potential (CMAP)Amyloid Polyneuropathy  10 

Q10. What is the common type of amyloidosis in SSA?

19Although liver transplantation is ordinarily not a therapeutic option in SSA because of the advanced age of most patients, new treatments are being introduced. 

Q11. What is the common diagnosis of SSA?

In this case, the patient had the classic presentation of a painful, severe, and rapidly progressive polyneuropathy without a plausible alternative explanation and with evidence of system amyloid involvement, making amyloid polyneuropathy the most compatible diagnosis. 

Q12. What is the percentage of wild-type TTR in late-onset cases?

the amyloid fibrils in hereditary TTR amyloidosis contain both mutant and wild-type TTR, and the percentage of wildtype TTR is higher (50%) in late-onset cases than in early-onset cases (30%).