Three patients of transthyretin amyloidosis in a Japanese family with amyloidogenic transthyretin Thr49Ser (p.Thr69Ser) variant.

Transthyretin (TTR)-related hereditary amyloidosis (ATTRv) is a rare autosomal dominant disorder that is caused by pathogenic missense mutation of the TTR gene. As of today, more than 150 TTR gene variants have been reported to occur as causal mutations. Herein, we present three familial patients of ATTRv caused by the Thr49Ser (p.Thr69Ser) variant, including their phenotypes and penetrance. The first patient was a 68-year-old woman with a history of carpal tunnel syndrome, who was referred to our department with heart failure symptoms. Echocardiography, Technetium (Tc)-pyrophosphate scintigraphy, and myocardial biopsy confirmed her diagnosis as TTR-related amyloidosis. Genetic testing for the TTR gene was performed, which confirmed the presence of a Thr49Ser (p.Thr69Ser) variant. The second patient, a 45-year-old woman, who was the niece of the first patient, presented with dyspnea on exertion. Her clinical manifestations included cardiac symptoms in addition to polyneuropathy. Similarly, myocardial biopsy showed TTR amyloid deposition within cardiac tissues, and TTR gene sequencing detected the presence of a Thr49Ser (p.Thr69Ser) variant. The final patient was a 42-year-old man, who was the nephew of the first patient, presented with numbness in his hands. Abdominal wall fat pad biopsy showed TTR amyloid deposition, and TTR gene sequencing was performed considering the familial history to confirm the presence of Thr49Ser (p.Thr69Ser) variant. No cardiac symptoms or dysfunctions have been observed yet, but imaging has detected TTR amyloid deposition in the heart. The present three patients with Thr49Ser (p.Thr69Ser) variant showed variation in phenotypes including cardiac and neurological manifestations at a fairly young age. In addition, the familial relationship in this report suggested that this variant is highly penetrant. Early genetic diagnosis due to collecting the genetic information from family medical history may be beneficial to improve patient prognosis via early therapeutic intervention.