Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser

Yang, Naomi Chu‐Chiao; Lee, Ming-Jen; Chao, Chi‐Chao; Chuang, Yao-Chung; Wan, Lin; Chang, Ming-Fong; Hsieh, Paul-Chen; Kan, Hung‐Wei; Lin, Yu‐Min; Yang, Wen-Chi; Chiu, Ming‐Jang; Liou, Horng-Huei; Hsieh, Sung‐Tsang

doi:10.1212/wnl.0b013e3181ec7fda

Cited by 78 publications

(85 citation statements)

References 39 publications

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“…Gait impairment and the need for walking assistance occurred earlier in non‐Portuguese patients than in our PortMet30 patients and in previously reported PortMet30 patients 9. This rapid course has previously been noted in a Japanese series of LateMet30 FAP11 and some other variants 15, 30. Apart from these studies, patient disability has rarely been documented, especially with respect to gait disorders and overall survival, ruling out any direct statistical comparison of times to onset.…”

Section: Discussionmentioning

confidence: 87%

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Mariani¹,

Lozeron

Théaudin

et al. 2015

Annals of Neurology

146

102

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ObjectiveTo compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.MethodsWe compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression.ResultsBy comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies.InterpretationIle107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large‐fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). Ann Neurol 2015;78:901–916

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Section: Discussionmentioning

confidence: 87%

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Mariani¹,

Lozeron

Théaudin

et al. 2015

Annals of Neurology

146

102

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“…Ttr has been implicated in amyloid-related degeneration: amyloid polyneuropathy, cardiac amyloidopathy, and amyloidosis in general (3,38,48). As the Wfs1 mutation is related to the degeneration of several organs (islets, brain, heart, etc.…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice

Kõks

Soomets

Plaas³

et al. 2011

Physiological Genomics

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The Wfs1 gene codes for a protein with unknown function, but deficiency in this protein results in a range of neuropsychiatric and neuroendocrine syndromes. In the present study we aimed to find the functional networks influenced by Wfs1 in the hypothalamus. We performed gene expression profiling (Mouse Gene 1.0 ST Arrays) in Wfs1-deficient mice; 305 genes were differentially expressed with nominal P value<0.01. FDR (false discovery rate)-adjusted P values were significant (0.007) only for two genes: C4b (t=9.66) and Wfs1 (t=-9.03). However, several genes related to G protein signaling were very close to the FDR-adjusted significance level, such as Rgs4 (regulator of G protein signaling 4) that was downregulated (-0.34, t=-5.4) in Wfs1-deficient mice. Changes in Rgs4 and C4b expression were confirmed by QRT-PCR. In humans, Rgs4 is in the locus for bipolar disease (BPD), and its expression is downregulated in BPD. C4b is a gene related to the neurodegenerative diseases. Functional analysis including the entire data set revealed significant alterations in the canonical pathway "G protein-coupled receptor signaling." The gene expression profile in the hypothalami of the Wfs1 mutant mice was significantly similar to the profiles of following biological functions: psychological disorders, bipolar disorder, mood disorder. In conclusion, hypothalamic gene expression profile resembles with some molecular pathways functionally related to the clinical syndromes in the Wolfram syndrome patients.

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“…Skin biopsy for nerve density quantification has been utilized in ATTR patients with advanced neuropathy, and has been found to correlate with disease severity. 49 However, the method has not been tested for early diagnosis of ATTR neuropathy and it requires neuropathological expertise not readily available at most centers. In addition, decreased blood flow in peripheral submit your manuscript | www.dovepress.com Dovepress Dovepress tissues of ATTR patients with ensuing impaired wound healing makes the method less attractive.…”

Section: Neuropathymentioning

confidence: 99%

New insights into the clinical evaluation of hereditary transthyretin amyloidosis patients: a single center's experience

Suhr¹,

Gustavsson²,

Heldestad³

et al. 2012

DNND

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Over the last decade, new medical treatment modalities have emerged based on increased insights into amyloid formation. With the increased possibilities for treatment of amyloidosis caused by transthyretin (TTR) amyloid deposits comes the need for diagnostic procedures for early diagnosis and better tools to follow disease progression. This is of particular importance in clinical trials evaluating the efficacy of new treatments. Until recently, the treatment of TTR amyloidosis (ATTR) was based solely on liver transplantation, a procedure that has halted disease progression in many patients. Liver transplantation has been especially effective in patients under the age of 50 years carrying the TTR V30M mutation, whereas the outcome of the procedure has been variable for others, particularly elderly male patients and those carrying a non-V30M mutation. This review concentrates on new insights derived from our center's experience with liver transplantation, how to implement this experience in evaluation of new treatment modalities for ATTR, and how to facilitate early diagnosis of neuropathy with easily available diagnostic tools. Attention has focused on manifestations of the disease that involve the heart and the peripheral nervous system; change in peripheral nerve function has been the primary endpoint in two controlled clinical trials, one finished and one ongoing. New insights into the amyloid formation process and the lessons learned from liver transplantation give the opportunity to design potentially effective treatment modalities for ATTR. It appears reasonable to suspect that a combination of different treatment modalities may be required to treat the disease, and that different treatment regimes will be designed according to the phenotype of the disease. For the patients and their relatives there is now a solid foundation for optimism, with prospects of several effective medical treatment possibilities within the coming decade.

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Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser

Abstract: Skin denervation was common in Ala97Ser, and degeneration of cutaneous nerve terminals was correlated with the severity of clinical phenotypes and the level of CSF protein.

Cited by 78 publications

References 39 publications

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice

New insights into the clinical evaluation of hereditary transthyretin amyloidosis patients: a single center's experience

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