Current Review of Leptomeningeal Amyloidosis Associated With Transthyretin Mutations

Abstract

Introduction: Leptomeningeal amyloidosis (LA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges. Of >120 TTR mutations identified, few have been associated with LA. Case Report: A 27-year-old male presented with a 2-year history of progressive symptoms including cognitive decline and right-sided weakness and numbness. Cerebrospinal fluid (CSF) analyses demonstrated high protein level. Gadolinium-enhanced magnetic resonance imaging (MRI) revealed extensive leptomeningeal enhancement over the surface of the brain and spinal cord. Pathologic analyses revealed a TTR mutation c.113A>G (p.D38G). Review Summary: Fifteen mutations and genotype-phenotype correlation of 72 LA patients have been summarized to provide an overview of LA associated with transthyretin mutations. The mean age of clinical onset was 44.9 years and the neurological symptoms primarily included cognitive impairment, headache, ataxia seizures and hearing, visual loss. CSF analysis showed elevated high CSF protein level and MRI revealed extensive leptomeningeal enhancement. Conclusion: Clinicians should be aware of this rare form of familial transthyretin amyloidosis as well as its typical MRI enhancement and high CSF protein. The important role of biopsy, genetic testing and the potential early diagnosis value of contrast MRI were suggested. Early recognition of these characteristics is important to provide misdiagnosis and shorten the time before correct diagnosis. These findings expand the phenotypic spectrum of TTR gene and have implications for the diagnosis, treatment, and systematic study of LA.

Leptomeningeal Disease Secondary to Thr60Ala Transthyretin Amyloidosis: Case Report and Review of the Literature

“…13 A recent review of 72 patients with leptomeningeal disease includes a total of 15 known causative TTR mutations with mean age of onset 44.9 years. 14 The most common mutations associated with leptomeningeal amyloidosis are C.113A>G (16.7%), c265T>C (16.7%), and c.148G>A (15.2%). 14 CNS symptoms include stroke, subarachnoid hemorrhage, dementia, ataxia, seizures, depression, and fluctuating levels of consciousness.…”

“…14 The most common mutations associated with leptomeningeal amyloidosis are C.113A>G (16.7%), c265T>C (16.7%), and c.148G>A (15.2%). 14 CNS symptoms include stroke, subarachnoid hemorrhage, dementia, ataxia, seizures, depression, and fluctuating levels of consciousness. 13,15 The wide variety of clinical manifestations of amyloid leptomeningeal disease has been postulated to lead to delayed diagnosis and worse outcomes.…”

Leptomeningeal amyloidosis: features of the clinical picture (clinical observation)

“…В качестве причины заболевания рассматривается мутация в гене белка транстиретина (18q12.1), осуществляющего транспорт ретинола и тироксина. Основным источником синтеза транстиретина в организме является печень, а также сосудистые сплетения боковых желудочков головного мозга и пигментный слой сетчатки глаза [7]. Механизм передачи наследственного амилоидоза -аутосомно-доминантный, однако описаны и спорадические случаи.…”

“…Существует ряд мутаций, при наличии которых выявляется определенная фенотипическая картина. Например, для неврологического варианта характерны мутации Val50Met, Leu78His, Ile104Ser, Tyr134His; для кардиологического -Val122Ile, Leu131Met, Pro44Ser, Glu112Lys; для лептоменингеального -Leu32Pro, Asp38Gly, Ala45Thr, Val50Gly [3,7,9].…”

“…В настоящее время в мировой литературе представлено около 72 случаев с данным фенотипом заболевания, среди которых наиболее часто встречаются следующие мутации: Asp38Gly, Tyr89His и Val50Met, характерные для европейской (60%), американской (33,3%) и японской (26,7%) популяций. Примечательно, что только при мутациях Val50Gly и Gly53Arg описаны признаки поражения ЦНС без развития кардиомиопатии, периферической соматической и автономной невропатии [7,10].…”