Oculoleptomeningeal Amyloidosis Associated With a New Transthyretin Variant Ser64

Uemichi, Tomoyuki; Uitti, Ryan J.; Koeppen, Arnulf H.; Donat, Jane F.; Benson, Merrill D.

doi:10.1001/archneur.56.9.1152

Cited by 65 publications

(49 citation statements)

References 25 publications

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“…Eight of Ͼ 80 TTR disease-associated variants are reported to have CNS involvement at an early stage of pathology (Brett et al, 1999;Ellie et al, 2001;Garzuly et al, 1996;Ikeda et al, 2002;Mascalchi et al, 1999;Petersen et al, 1997;Uemichi et al, 1997Uemichi et al, , 1999 (Table 1). These TTR variants share common features, including a fifth decade age of disease onset, low serum variant TTR levels, and, in the two cases examined thus far, extreme mutation induced protein destabilization.…”

Section: Discussionmentioning

confidence: 99%

“…TTR amyloid deposition on the leptomeninges and subarachnoid vessels seems to cause CNS symptoms such as recurrent subarachnoid hemorrhage, hearing loss, ataxia, dementia, seizures, myelopathy, brain hemorrhage, and brain infarction. A few TTR variants are associated with CNS amyloidosis (Brett et al, 1999;Ellie et al, 2001;Garzuly et al, 1996;Ikeda et al, 2002;Mascalchi et al, 1999;Petersen et al, 1997;Uemichi et al, 1997;Uemichi et al, 1999); however, the requirements for a CNS selective disease as opposed to a systemic amyloid disease are unclear, and this study represents our first attempt to gain some insight.…”

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confidence: 99%

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Energetic Characteristics of the New Transthyretin Variant A25T May Explain Its Atypical Central Nervous System Pathology

Sekijima

Hammarström

Matsumura

et al. 2003

Laboratory Investigation

113

146

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SUMMARY:Transthyretin (TTR) is a tetrameric protein that must misfold to form amyloid fibrils. Misfolding includes rate-limiting tetramer dissociation, followed by fast tertiary structural changes that enable aggregation. Amyloidogenesis of wild-type (WT) TTR causes a late-onset cardiac disease called senile systemic amyloidosis. The aggregation of one of Ͼ 80 TTR variants leads to familial amyloidosis encompassing a collection of disorders characterized by peripheral neuropathy and/or cardiomyopathy. Prominent central nervous system (CNS) impairment is rare in TTR amyloidosis. Herein, we identify a new A25T TTR variant in a Japanese patient who presented with CNS amyloidosis at age 42 and peripheral neuropathy at age 44. The A25T variant is the most destabilized and fastest dissociating TTR tetramer published to date, yet, surprising, disease onset is in the fifth decade. Quantification of A25T TTR in the serum of this heterozygote reveals low levels relative to WT, suggesting that protein concentration influences disease phenotype. Another recently characterized TTR CNS variant (D18G TTR) exhibits strictly analogous characteristics, suggesting that instability coupled with low serum concentrations is the signature of CNS pathology and protects against early-onset systemic amyloidosis. The low A25T serum concentration may be explained either by impaired secretion from the liver or by increased clearance, both scenarios consistent with A25T's low kinetic and thermodynamic stability. Liver transplantation is the only known treatment for familial amyloid polyneuropathy. This is a form of gene therapy that removes the variant protein from serum preventing systemic amyloidosis. Unfortunately, the choroid plexus would have to be resected to remove A25T from the CSF-the source of the CNS TTR amyloid. Herein we demonstrate that small-molecule tetramer stabilizers represent an attractive therapeutic strategy to inhibit A25T misfolding and CNS amyloidosis. Specifically, 2-[(3,5-dichlorophenyl)amino]benzoic acid is an excellent inhibitor of A25T TTR amyloidosis in vitro. (Lab Invest 2003, 83:409 -417).

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Energetic Characteristics of the New Transthyretin Variant A25T May Explain Its Atypical Central Nervous System Pathology

Sekijima

Hammarström

Matsumura

et al. 2003

Laboratory Investigation

113

146

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“…However, Tyr is uncharged polar while Phe is nonpolar. How this may affect the clinical phenotype is unclear, but different amino acid substitutions at the same TTR position are known to express distinct clinical features [24]. …”

Section: Discussionmentioning

confidence: 99%

Extended Phenotype in the Transthyretin Tyr77 Familial Amyloid Polyneuropathy

Lossos¹,

Soffer²,

Steiner-Birmanns³

et al. 2005

Eur Neurol

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The transthyretin Tyr77 variant of familial amyloid polyneuropathy (FAP) has been identified in a few North American and European patients, but the full spectrum of its clinical manifestations is still not known. We report a 3-generation family of Jewish-Yemenite origin with Tyr77 FAP presenting with atypical features. The affected individuals had sensorimotor and autonomic neuropathy and cardiomyopathy accompanied by prominent dysphagia, hearing loss and asymptomatic carpal tunnel syndrome. Brain MRI in the proband showed multifocal white matter lesions. These features extend the reported Tyr77 phenotype and support the modifying effect of additional factors on the disease expression.

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“…There may be some overlap with the FAP phenotype involving both central and peripheral nervous system [6]. Ten different TTR gene mutations (Leu12Pro, Asp18Gly, Ala25Thr, Val30Met, Val30Gly, Ala36Pro, Gly53Glu, Phe64Ser, Tyr69His, Tyr114Cys) associated with leptomeningeal amyloidosis have been reported [4][5][6][7][8][9][10][11][12][13]. Here we report a case of leptomeningeal amyloidosis with a novel point mutation at codon 49 of the TTR gene, leading to proline-for-threonine substitution.…”

Section: Introductionmentioning

confidence: 89%

A new Thr49Pro transthyretin gene mutation associated with leptomeningeal amyloidosis

Nakagawa

Sheikh

Snuderl

et al. 2008

Journal of the Neurological Sciences

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Oculoleptomeningeal Amyloidosis Associated With a New Transthyretin Variant Ser64

Abstract: In this kindred, oculoleptomeningeal amyloidosis is related to a mutation in transthyretin (Phe64Ser).

Cited by 65 publications

References 25 publications

Energetic Characteristics of the New Transthyretin Variant A25T May Explain Its Atypical Central Nervous System Pathology

Energetic Characteristics of the New Transthyretin Variant A25T May Explain Its Atypical Central Nervous System Pathology

Extended Phenotype in the Transthyretin Tyr77 Familial Amyloid Polyneuropathy

A new Thr49Pro transthyretin gene mutation associated with leptomeningeal amyloidosis

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