TRANSTHYRETIN FAMILIAL AMYLOID POLYNEUROPATHY

(TTR-FAP) A PROTEIN MISFOLDING DISEASE

Sekijima Y, Kelly JW, Ikeda S. Curr Pharm Des. 2008;14:3219-3230. Sekijima 2008, p 3219

Image Courtesy J. Kelly, TSRI. TAF281239 © 2011 Pfizer Inc. All rights reserved. Printed in USA/March 2011

THE PATHOGENESIS OF TTR-FAP IS DUE TO THE DESTABILIZATION OF TTR

Araki S, Ando Y. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(7):694-706.Araki, p 699

HETEROTETRAMER FOLDED PROTEINS

Image Courtesy of J. Kelly, TSRI.

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TTR DESTABILIZATION LEADS TO MISFOLDED PROTEINS THAT FORM

AMYLOID FIBRILS

Hou X, Aguilar M-I, Small DH. FEBS Journal. 2007;274:1637-1650. Hou,

p 1639

FREE TETRAMER

FOLDEDPROTEIN

FUNCTIONAL TTR STRUCTURES

MISFOLDEDPROTEIN

PROTEINMISFOLDING

AMYLOIDFIBRILS

TTR STRUCTURES ASSOCIATED WITH

PATHOLOGY

AGGREGATION

Image Courtesy of J. Kelly, TSRI.

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Congo red–stained section of posterior tibial nerve from a patient with TTR amyloidosis shows

hallmark green color under polarized lightBenson MD, Kincaid JC. Muscle Nerve. 2007;36:411-423.

PERIPHERALNERVE BUNDLE

AMYLOID

AMYLOID DEPOSITS IN PERIPHERAL AND AUTONOMIC NERVES

1. Benson MD, Kincaid JC. Muscle Nerve. 2007;36:411-423. 2. Planté-Bordeneuve V, Ferreira T, Lalu T, et al. Neurology. 2007;69:693-698. 3. Sekijima Y, Yoshida K, Tokuda T, Ikeda S. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2009. 4. Ando Y, Nakamura M, Araki S. Arch Neurol. 2005;62:1057-1062. 5. Coutinho P, da Silva AM, Lima JL, Barbosa AR. In: Glenner GG, e Costa PP, de Freitas AF, eds. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica; 1980:88-98.

NEURODEGENERATION SYMPTOMATOLOGY

Planté-Bordeneuve, p 696

Ando, p 1059

Benson, p 416

Progression to upper limbs5

Muscle weakness, difficulties walking

and performing fine movements3

Degeneration progresses to larger myelinated fibers4

Axonal degeneration of small myelinated and unmyelinated

nerve fibers2

Sensory loss or pain in lower limbs2

AMYLOID DEPOSITION IS ASSOCIATED WITH DISTAL TO PROXIMAL NEURODEGENERATION1-5

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Araki S, Ando Y. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(7):694-706.

Unintentional weight loss

Alternating constipation and diarrhea

Erectile dysfunction

Orthostatic hypotension

AUTONOMIC NEUROPATHY ACCOMPANIES PERIPHERAL NEURODEGENERATION

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1. Coutinho P, da Silva AM, Lima JL, Barbosa AR. In: Glenner GG, e Costa PP, de Freitas AF, eds. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica; 1980:88-98. 2. Planté-Bordeneuve V, Ferreira A, Lalu T, et al. Neurology. 2007;69:693-698. 3. Sekijima Y, Yoshida K, Tokuda T, Ikeda S. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2009.

TTR-FAP:NEED FOR EARLY DIAGNOSIS

The mean time to diagnosis after initial onset of symptoms can be up to 4 years,‡ while the life expectancy of untreated patients with TTR-FAP is, on average, 10 years2

• Considerations for the management of TTR-FAP include:

- Medical screening for cardiac arrhythmias for identified patients3

- Genetic testing and counseling for family members of identified patients3

‡Mean time to diagnosis based on data collected in France, a nonendemic TTR-FAP region.

†ADL = activities of daily living.Adapted from Coutinho et al.1

*Disease severity as observed in a retrospective study of TTR-FAP patients in Portugal, an endemic TTR-FAP region.

Disease Severity at 4 Years1*

SeverityModerate/severeMild/moderateLower/upperModerateSignificantCrutches orcanes

Sign/SymptomsSensoryMotorLimb involvementAutonomicADL†

Ambulation

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Image Courtesy of M. Benson, Indiana University School of Medicine. Congo red–stained section of posterior tibial nerve from a patient with TTR amyloidosis.2

Once suspected, the diagnosis of TTR-FAP can be confirmed by1:

• A biopsy (eg, nerve or subcutaneous fat aspirate) stained with Congo red to determine amyloid deposits1

- A Congo red stain that turns apple green when viewed under polarized light is indicative of amyloid deposits1

• Protein evaluation and genetic testing1

AN APPROACH TO DIAGNOSING TTR-FAP

1. Sekijima Y, Yoshida K, Tokuda T, Ikeda S. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2009. 2. Benson MD, Kincaid JC. Muscle Nerve. 2007;36:411-423.

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