Massive leptomeningeal amyloidosis associated with a Val30Met transthyretin gene

Herrick, Maie Kaarsoo; DeBruyne, K.; Horoupian, Dikran S.; Skare, James; Vanefsky, Marc A.; Ong, T.K.

doi:10.1212/wnl.47.4.988

Cited by 77 publications

(58 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…More worrisome is that amyloid deposition on subarachnoid vessels and leptomeninges was found in a patient with V30M FAP (Ushiyama et al, 1991). Although CNS involvement in V30M FAP is not generally considered to be clinically significant, three reports question this generally held perception (Herrick et al, 1996;Horta et al, 1964;Sakashita et al, 2001). Therefore, CNS amyloidosis could be a future problem for the Ͼ 500 patients who have received V30M transplantation (Familial Amyloidotic Polyneuropathy World Transplant Register, www.fapwtr.org/).…”

Section: Discussionmentioning

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

115

146

View full text Add to dashboard Cite

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).

show abstract

Section: Discussionmentioning

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

115

146

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

“…31,32 This is often a familial disorder associated with vitreous amyloid deposits and seen in oculoleptomeningeal amyloidosis or FAP. Pathologically, vascular, leptomeningeal, subpial, subependymal, and choroid plexus deposition of amyloid with sparing of intracerebral blood vessels is seen.…”

Section: Meningeal Depositsmentioning

confidence: 99%

Imaging of Focal Amyloid Depositions in the Head, Neck, and Spine: Amyloidoma

Parmar¹,

Rath²,

Castillo³

et al. 2010

AJNR Am J Neuroradiol

View full text Add to dashboard Cite

SUMMARY:Amyloidomas are benign tumorlike lesions consisting of localized deposits of amyloid and are the rarest form in the group of amyloidosis-related lesions. Diagnosis requires special stains; therefore, a high degree of suspicion for this disease is required. In this review, we describe the imaging features of amyloidomas involving the intracranial compartment, head and neck, and spine. We also discuss the differential diagnosis and briefly review the pertinent literature.ABBREVIATIONS: FAP ϭ familial amyloidotic polyneuropathy; T1WI ϭ T1-weighted images; T2WI ϭ T2-weighted images

show abstract

Massive leptomeningeal amyloidosis associated with a Val30Met transthyretin gene

Cited by 77 publications

References 8 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

A new Thr49Pro transthyretin gene mutation associated with leptomeningeal amyloidosis

Imaging of Focal Amyloid Depositions in the Head, Neck, and Spine: Amyloidoma

Contact Info

Product

Resources

About