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

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OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

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