A new transthyretin mutation associated with leptomeningeal amyloidosis

Leptomeningeal amyloidosis associated with transthyretin mutations is an uncommon but fatal form of amyloidosis. Here we present a new mutation associated with hydrocephalus and dementia. A 48-year-old woman presented with symptoms of transient ischemic attacks. Clinical evaluation revealed moderate hydrocephalus and cerebral amyloid angiopathy. The patient's mother developed hydrocephalus by age 56, was treated with a ventricular shunt, but the disease progressed with dementia. Autopsy at age 73 revealed marked thickening of leptomeninges and severe amyloid angiopathy. The amyloid deposits stained positive for transthyretin. DNA sequencing of transthyretin exons 2, 3, and 4 of the patient demonstrated a G to A transition at the first nucleotide of codon 53 resulting in a Gly53Arg mutation in the transthyretin protein. Biochemical characterization of the amyloid protein isolated from leptomeninges of the patient's mother indicated the vast predominance of variant Arg53 over normal Gly53 transthyretin in the amyloid deposit.