Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population

Hellman, Urban; Alarcon, Flora; Lundgren, Hans-Erik; Suhr, Ole B.; Bonaïti‐Pellié, Catherine; Planté‐Bordeneuve, Violaine

doi:10.1080/13506120802193720

Cited by 150 publications

(120 citation statements)

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“…23 For a patient with FAP, the age at which symptoms develop depends on the genetic mutation, the patient's origin, and the penetrance of the disease. [24][25][26] Other factors directly related to transplantation have also been implicated in the early development of amyloidotic changes in domino liver recipients. First, the presence of amyloid fibers in the graft may trigger the disease.…”

Section: Discussionmentioning

confidence: 99%

Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation

et al. 2010

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Recent reports of the transmission of systemic transthyretin (TTR) amyloidosis after domino liver transplantation (DLT) using grafts from patients with familial amyloid polyneuropathy (FAP) have raised concerns about the procedure. The aim of this study was to evaluate the transmission incidence of systemic TTR amyloidosis after DLT with a complete clinical, neurological, and pathological assessment. At our institution, DLT has been performed 31 times with livers from patients with FAP. Seventeen of the 19 patients still alive in 2008 agreed to enter the study. This cross‐sectional study of this cohort of patients included clinical assessments, rectal biopsy, and electroneuromyography (as well as sural nerve biopsy when it was indicated). The mean follow‐up at the time of the study was 62.6 ± 2.9 months. Clinically, 3 patients complained of weak dysesthesia. When a focused study was performed, 8 patients reported some kind of neurological and/or gastrointestinal disturbance. Six of the rectal biopsy samples showed amyloid deposits (TTR‐positive). Electromyography (EMG) showed signs of mild sensorimotor neuropathy in 3 cases and moderate to severe sensorimotor neuropathy in 1 case. Only 2 of the 4 patients with EMG signs of polyneuropathy showed amyloid deposits in their rectal biopsy samples. Sural nerve biopsy revealed amyloid deposits (TTR‐positive) in all 4 patients with EMG signs of polyneuropathy. Two patients with normal EMG findings had TTR‐positive amyloid deposits in their sural nerve biopsy samples. In conclusion, de novo systemic amyloidosis after DLT may be more frequent and appear earlier than was initially thought. In our opinion, however, the graft shortage still justifies DLT in selected patients, despite the risk of de novo systemic amyloidosis. Sural nerve biopsy with EMG and clinical correlation is mandatory for confirming the disease. Indeed, other causes of neuropathy should be excluded. Liver Transpl 16:1386–1392, 2010. © 2010 AASLD.

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Section: Discussionmentioning

confidence: 99%

Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation

et al. 2010

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“…In Japan, Met30 families with early onset neuropathy were initially identified in 2 limited areas (Arao district and Ogawa village) with a penetrance of 80% 10. Late onset (>50 years) TTR‐FAP Val30Met (LateMet30) is widely distributed throughout Japan11 as well as in northern Sweden, where penetrance is lower 12. FAP patients of French descent are divided into 2 groups depending on their pathogenic TTR mutation.…”

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confidence: 99%

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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“…19 At present, there is no explanation for the important difference in penetrance estimation between countries. [10][11][12] One might speculate that a mitochondrial polymorphism could account for at least part of this difference if the at-risk alleles had different frequencies among countries. The results of our study on the Portuguese and the Swedish families favor this hypothesis as the estimated frequency of the at-risk allele was much higher in the Portuguese (0.69) than in the Swedish (0.32) populations.…”

Section: Discussionmentioning

confidence: 99%

“…9 In a previous work, we showed that important differences in disease expression, and in particular in penetrance estimation, exist among countries. [10][11][12] The cumulative risks by age 70 years were estimated to be 91% in Portuguese carriers, 64% in French carriers, and 36% in Swedish carriers.…”

Section: Introductionmentioning

confidence: 99%

TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?

et al. 2010

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The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n¼33) and Swedish families (n¼86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

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Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population

Cited by 150 publications

References 21 publications

Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation

Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation

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

TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?

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