家族性淀粉样多发性神经病.doc

familial amyloid polyneuropathy
1. J Peripher Nerv Syst. 2015 Dec 13. doi: 10.1111/jns.12153. [Epub ahead of print]

"Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy.

Conceição I(1), González-Duarte A(2), Obici L(3), Schmidt HH(4), Simoneau D(5),
Ong ML(6), Amass L6).

Author information:
(1)CHLN - Hospital de Santa Maria, and Clinical and Translational Physiology
Unit, Physiology Institute, Faculty of Medicine-IMM, Lisbon, Portugal.
(2)Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México
City, México. (3)Amyloidosis Research and Treatment Center, Fondazione IRCCS
Policlinico San Matteo, Pavia, Italy. (4)Klinik für Transplantationsmedizin,
Universitätsklinikum Münster, Münster, Germany. (5)Pfizer IO, Paris, France.
(6)Pfizer Inc, New York, NY, USA.

BACKGROUND: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare,
progressive, life-threatening, hereditary disorder caused by mutations in the
transthyretin gene and characterized by extracellular deposition of
transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart,
and other organs. TTR-FAP is frequently diagnosed late because the disease is
difficult to recognize due to phenotypic heterogeneity.
METHODS: Based on published literature and expert opinion, symptom clusters
suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier
diagnosis is provided. Results and conclusions TTR-FAP should be suspected if
progressive peripheral sensory-motor neuropathy is observed in combination with
one or more of the following: family history of a neuropathy, autonomic
dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight
loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP
is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy,
large- and small-fiber assessment by nerve conduction studies and autonomic
system evaluations, and cardiac testing should be performed.

This article is protected by copyright. All rights reserved.

PMID: 26663427 [PubMed - as supplied by publisher]

2. Transplantation. 2015 Dec 11. [Epub ahead of print]

Survival After Transplantation in Patients With Mutations Other Than Val30Met:
Extracts From the FAP World Transplant Registry.

Suhr OB(1), Larsson M, Ericzon BG, Wilczek HE; FAPWTRʼs investigators.

Author information:
(1)1 Department of Public Health and Clinical Medicine, Umeå University Hospital,
Umeå, Sweden. 2 Division of Transplantation Surgery, Karolinska Institutet,
CLINTEC, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

BACKGROUND: Liver transplantation (LTx) has been performed for hereditary
transthyretin amyloidosis (ATTR) since 1990. Outcomes for a relatively large
series of LTx ATTR patients with the Val30Met (mutation are available, but for
non-Val30Met patients, only a few reports with a small number of patients exist.
Here, we present outcomes for non-Val30Met ATTR patients after LTx, as reported
to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR).
METHODS: Data regarding outcome were extracted for all non-Val30Met patients
reported to the registry. Survival rates were analyzed by the Kaplan-Meier method
and log-rank test.
RESULTS: The total number of patients with a non-Val30Met mutation in the
registry was 264 (174 men and 90 women), representing 57 mutations. The 10-year
survival varied markedly for the 9 most common mutations, ranging from 21% for
Ser50Arg to 85% for Val71Ala. Poor survival was noted for all mutations with
leptomeningeal complications except for those with the Tyr114Cys mutation.
CONCLUSIONS: Large differences in survival were observed relative to different
mutations and between mutations with similar phenotypes. Excellent survival was
noted for mutations, such as Leu111Met, Val71Ala, and Leu58His. Patients with
mutations other than Val30Met are not a homogeneous group, and the term
non-Val30Met should be used with caution or avoided. Moreover, for several
mutations, data are too limited to allow evaluation of the efficacy of LTx, and
continuous international collaboration is important for obtaining treatment
guidance.This is an open-access article distributed under the terms of the
Creative Commons Attribution-Non Commercial-No Derivatives 3.0 License, where it
is permissible to download and share the work provided it is properly cited. The
work cannot be changed in any way or used commercially.

PMID: 26656838 [PubMed - as supplied by publisher]

3. Ann Med. 2015 Dec;47(8):625-38. doi: 10.3109/07853890.2015.1068949. Epub 2015 Nov
27.

Evolving landscape in the management of transthyretin amyloidosis.

Hawkins PN(1), Ando Y(2), Dispenzeri A(3), Gonzalez-Duarte A(4), Adams D(5), Suhr
OB(6).

Author information:
(1)a National Amyloidosis Centre, Royal Free Hospital, University College London
, London , UK. (2)b Department of Neurology , Graduate School of Medical Sciences
Kumamoto University , Kumamoto , Japan. (3)c Mayo Clinic, Division of Hematology
, Rochester, Minnesota, USA. (4)d Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán , Mexico City , Mexico. (5)e National Reference Centre
for FAP, APHP, CHU Bicêtre, Université Paris-Sud, INSERM U788 , Paris , France.
(6)f Department of Public Health and Clinical Medicine , Umeå University , Umeå ,
Sweden.

Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic,
multigenotypic disease resulting from deposition of insoluble ATTR amyloid
fibrils in various organs and tissues. Although considered rare, the prevalence
of this serious disease is likely underestimated because symptoms can be
non-specific and diagnosis largely relies on amyloid detection in tissue
biopsies. Treatment is guided by which tissues/organs are involved, although
therapeutic options are limited for patients with late-stage disease. Indeed,
enthusiasm for liver transplantation for familial ATTR amyloidosis with
polyneuropathy was dampened by poor outcomes among patients with significant
neurological deficits or cardiac involvement. Hence, there remains an unmet
medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow
disease progression in some patients with ATTR amyloidosis with polyneuropathy,
and the postulated synergistic effect of doxycycline and tauroursodeoxycholic
acid on dissolution of amyloid is under investigation. Another therapeutic
approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR
concentration can be significantly reduced with ISIS-TTRRx, an investigational
antisense oligonucleotide-based drug, or with patisiran and revusiran, which are
investigational RNA interference-based therapeutics that target the liver. The
evolving treatment landscape for ATTR amyloidosis brings hope for further
improvements in clinical outcomes for patients with this debilitating disease.

PMID: 26611723 [PubMed - in process]

4. J Am Coll Cardiol. 2015 Dec 1;66(21):2451-66. doi: 10.1016/j.jacc.2015.09.075.

Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis.

Gertz MA(1), Benson MD(2), Dyck PJ(3), Grogan M(4), Coelho T(5), Cruz M(6), Berk
JL(7), Plante-Bordeneuve V(8), Schmidt HH(9), Merlini G(10).

Author information:
(1)Division of Hematology, Mayo Clinic, Rochester, Minnesota. Electronic address:
[e-mail]. (2)Indiana University School of Medicine, Indianapolis,
Indiana. (3)Division of Peripheral Nerve, Mayo Clinic, Rochester, Minnesota.
(4)Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.
(5)Hospital de Santo Antonio, Porto, Portugal. (6)Federal University of Rio de
Janeiro of Brazil, University Hospital, Rio de Janeiro, Brazil. (7)Amyloidosis
Center, Boston University School of Medicine, Boston, Massachusetts.
(8)University Hospital, Henri Mondor, Créteil, France. (9)Universitätsklinikum
Münster, Münster, Germany. (10)Department of Molecular Medicine, University of
Pavia, Pavia, Lombardy, Italy.

Transthyretin amyloidosis is a fatal disorder that is characterized primarily by
progressive neuropathy and cardiomyopathy. It occurs in both a mutant form (with
autosomal dominant inheritance) and a wild-type form (with predominant cardiac
involvement). This article guides clinicians as to when the disease should be
suspected, describes the appropriate diagnostic evaluation for those with known
or suspected amyloidosis, and reviews the interventions currently available for
affected patients.

Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier
Inc. All rights reserved.

PMID: 26610878 [PubMed - in process]

5. Neurol Ther. 2015 Dec;4(2):61-79. doi: 10.1007/s40120-015-0031-3. Epub 2015 Aug
15.

A Review of Tafamidis for the Treatment of Transthyretin-Related Amyloidosis.

Waddington Cruz M(1), Benson MD(2).

Author information:
(1)Amyloidosis Research and Treatment Center (CEPARM), University Hospital
(HUCFF), Federal University of Rio de Janeiro, Rio De Janeiro, Brazil.
mwaddingtoncruz@. (2)Department of Pathology and Laboratory Medicine,
Indiana University School of Medicine, Indianapolis, IN, USA.

Transthyretin (TTR)-related amyloidosis (ATTR) is a devastating disease which
affects a combination of organs including the heart and the peripheral nerves,
and which has a fatal outcome if not treated within a average of 10 years.
Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively
binds to TTR with negative cooperativity and kinetically stabilizes wild-type
native TTR and mutant TTR; tafamidis therefore has the potential to halt the
amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding,
and aggregation. The first tafamidis trial, Fx-005, evaluated the effect of
18 months of tafamidis treatment (20 mg once daily) on disease progression, as
well as assessing its safety in TTR-FAP Val30Met patients. The secondary
objective of this trial was to study the pharmacodynamic stabilization of mutated
TTR. Tafamidis proved effective in reducing the progress of neuropathy, and in
maintaining the nutritional status and quality of life of stage 1 (able to walk
without support) Val3OMet TTR-FAP patients. Furthermore, TTR stabilization was
achieved in more than 90% of patients. An extension study, Fx-006, was conducted
to determine the long-term safety and tolerability of tafamidis and to assess the
efficacy of the drug on slowing disease progression. No significant safety or
tolerability issues were noticed. Taken together, the results from both trials
indicated that the beneficial effects of tafamidis were sustained over a 30-month
period and that starting treatment early is desirable. Results are expected from
an extended open-label study but data that have already been presented show that
long-term use of tafamidis in Val30Met patients is associated with reduced
progression in polyneuropathy. Tafamidis was initially approved for commercial
use in Europe in 2011 and has since been approved for use in Japan, Mexico, and
Argentina where it is used as a first-line treatment option for patients with
early-stage TTR-FAP. Patients should be carefully followed at referral centers to
ascertain the individual response to treatment. In cases of discontinuation,
liver transplantation and enrollment in clinical trials of novel drugs aimed
mostly toward suppression of TTR production are options.

PMCID: PMC4685869
PMID: 26662359 [PubMed]

6. Parkinsonism Relat Disord. 2015 Dec;21(12):1465-8. doi:
10.1016/j.parkreldis.2015.10.012. Epub 2015 Oct 21.

A peripheral pathway to restless legs syndrome? Clues from familial amyloid
polyneuropathy.

Teodoro T(1), Viana P(2), Abreu D(3), Conceição I(4), Peralta R(5), Ferreira
JJ(6).

Author information:
(1)Department of Neurology, Hospital de Santa Maria, Lisboa, Portugal; Clinical
Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine,
University of Lisbon, Lisboa, Portugal; St Georges University London, London,
United Kingdom. Electronic address: tiagoteodoro@. (2)Department of
Neurology, Hospital de Santa Maria, Lisboa, Portugal. (3)Clinical Pharmacology
Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon,
Lisboa, Portugal. (4)Department of Neurology, Hospital de Santa Maria, Lisboa,
Portugal; Translational and Clinical Physiology Unit, Instituto de Medicina
Molecular, Faculty of Medicine, University of Lisbon, Lisboa, Portugal.
(5)Department of Neurology, Hospital de Santa Maria, Lisboa, Portugal; EEG/Sleep
Laboratory, Hospital de Santa Maria, Lisboa, Portugal. (6)Department of
Neurology, Hospital de Santa Maria, Lisboa, Portugal; Clinical Pharmacology Unit,
Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon,
Lisboa, Portugal.

BACKGROUND: The relationship between restless legs syndrome (RLS) and peripheral
neuropathy remains unclear. In order to clarify this relationship, we
investigated if RLS is increased in familial amyloid polyneuropathy related to
transthyretin (TTR-FAP) and investigated factors associated with RLS in this
population.
METHODS: RLS frequency was compared between TTR-FAP patients and controls.
Secondly, TTR-FAP patients with and without RLS were compared regarding
demographic and clinical characteristics.
RESULTS: RLS frequency was significantly increased in TTR-FAP, with 18/98 (18.4%)
cases contrasting with 5/104 (4.8%) controls (p-value 0.002). This difference
remained significant after adjusting for confounders. In TTR-FAP patients, female
sex (p-value 0.037), obesity (p-value 0.036) and weight excess (p-value 0.048)
were associated with RLS, contrary to other classical RLS risk factors.
CONCLUSIONS: RLS frequency is increased in TTR-FAP, thus supporting an
association between RLS and neuropathy. This may represent a peripheral pathway
in RLS pathogenesis. Furthermore, our results suggest that female sex and
obesity/weight excess may be risk factors for RLS development among TTR-FAP
patients.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 26508424 [PubMed - in process]

7. Rev Neurosci. 2015 Dec 1;26(6):691-8. doi: 10.1515/revneuro-2015-0003.

Receptor for advanced glycation end-products in neurodegenerative diseases.

Juranek J, Ray R, Banach M, Rai V.

This review, for the first time, aims to summarize the current knowledge in the
emerging field of RAGE (receptor for advanced glycation end-products) studies in
neurodegeneration and neurodegenerative diseases. RAGE, a member of the
multiligand cell surface immunoglobulin family, has been implicated in numerous
pathological conditions - from diabetes and cardiovascular diseases to tumors and