Is a Novel Transthyretin Gene Mutation Associated With Cerebral Amyloid Angiopathy?

To report a case of a novel variant of the TTR gene associated with Cerebral Amyloid Angiopathy (CAA), thereby expanding the spectrum of TTR-related amyloidosis.

A 56-year-old man presented with a history of right fronto-parietal intracerebral haemorrhage and recurrent transient episodes of right arm paraesthesia. Based on clinical and radiological presentation, a probable CAA diagnosis was established according to Boston Criteria 2.0. The patient underwent an extensive evaluation, including genetic testing, cerebrospinal fluid (CSF) analysis and amyloid PET imaging.

CSF analysis and amyloid PET imaging corroborated CAA diagnosis. Genetic testing identified an undescribed heterozygous c.124G > A (p.Gly42Ser) TTR variant, absent from population databases, within a region known for pathogenic mutations. Family genetic testing revealed the same mutation in the patient's father, who had a history of cerebral haemorrhage.

To our knowledge, this case represents one of the first documented examples of a TTR gene variant exclusively associated with CAA, in the absence of systemic amyloidosis. These findings suggest the existence of TTR variants that may result in a brain-restricted amyloid pathology. Genetic screening for TTR mutations should be considered in familial cases of CAA to refine diagnostic accuracy and guide clinical management strategies.