The identification of a transthyretin variant p.D38G in a Chinese family with early-onset leptomeningeal amyloidosis

Familial amyloid polyneuropathies (FAPs) are life-threatening, autosomal dominant diseases resulting, in most instances, from transthyretin gene (TTR) variants. A small number of TTR variants lead to leptomeningeal amyloidosis (LA), which is a rare FAP subtype with late-onset central nervous system (CNS) impairment symptoms. Previous studies suggest that LA’s CNS selectivity was due to complete endoplasmic reticulum-associated degradation of highly destabilized mutants in peripheral tissues. LA’s later age at onset (AAO) was due to lower choroid plexus secretory efficacy. This study reports on a family with LA, including six symptomatic and three presymptomatic members. The LA diagnosis was confirmed by leptomeningeal enhancement on contrast MRI, elevated cerebrospinal fluid protein levels, and positive Congo red staining. The predominant symptoms included headaches, dizziness, vomiting, hallucinations, and cognitive impairments which associated with obstructive hydrocephalus. The TTR p.D38G variant with the lowest secretory efficacy was identified as the genetic cause by whole exome sequencing. The family had a statistically significantly earlier mean AAO of 31.3 ± 7.4 (p = 0.001). These uncommon phenotypes indicate unknown factors influencing the progress of CNS impairment via TTR mutants. Medical imaging examinations suggest the potential early diagnosis value of contrast MRI and the importance of ependyma involvement in LA. LA genetic and clinical data were reviewed and summarized. These findings expand the FAPs’ phenotypic spectrum and are valuable in FAP diagnosis, treatment, and further research.