Abstract

Objectives: To report the clinical features of two Japanese brothers with familial leptomeningeal amyloidosis, showing a causative gene abnormality of a transthyretin (TTR) variant Asp18Gly, previously reported only in a Hungarian family.

Methods: The authors reported on a 42 year old man (patient 1) and his 45 year old brother (patient 2), both suffering from subarachnoid haemorrhage (SAH) without and with hydrocephalus, respectively. DNA sequences of the TTR gene were determined in both patients and the patients’ clinical features described. A surgical biopsy of the leptomeninges was performed on patient 1.

Results: DNA sequence analyses demonstrated the glycine-for-aspartate substitution at position 18 of the TTR variant. Both patients revealed pyramidal tract signs and cerebellar ataxia. Audiometric studies showed bilateral, mild sensorineural hearing loss in the patients whose cerebrospinal fluid (CSF) protein levels increased. T1 weighted MRI after contrast administration showed diffuse leptomeningeal enhancement along the Sylvian fissures and over the surface of the brainstem, cerebellum, and spinal cord. Gradient echo T2* weighted MRI showed superficial siderosis mainly in the cerebellum. A biopsy of the leptomeninges was obtained from the spinal cord of patient 1. While performing the biopsy, the authors observed the varicose, elongating, and fragile veins on the dorsal surface of the spinal cord. Immunohistochemical study revealed marked deposits of TTR derived amyloid on his leptomeninges.

Conclusions: This is the second report of familial leptomeningeal amyloidosis with an Asp18Gly TTR gene mutation, clinically causing only CNS symptoms. Repeated SAH from fragile veins on the dorsal surface of the spinal cord seemed to induce superficial siderosis of the CNS. So far, there have been two reliable hallmarks leading to the diagnosis of leptomeningeal amyloidosis: diffuse leptomeningeal enhancement on contrast MRI and greatly increased CSF protein content. This study has contributed a third hallmark: the presence of superficial siderosis is useful in diagnosing leptomeningeal amyloidosis.