Clinical and genetic analysis of a family with transthyretin amyloid polyneuropathy caused by a TTR Lys55Asn mutation

Abstract Background transthyretin-mediated familial amyloid polyneuropathy (ATTR-PN), caused by TTR gene mutations, leads to systemic amyloid deposition and multisystem dysfunction. The c.165G > C (p.Lys55Asn) mutation is a rare variant with limited clinical data. This study investigates a family with this mutation, focusing on genotype-phenotype correlations and clinical challenges. Methods We conducted a detailed clinical analysis of a family with ATTR-PN, using whole exome sequencing to identify the transthyretin (TTR) mutation. Clinical data from 17 affected individuals were collected, including symptom onset, disease progression, and outcomes. Electromyography and gastric emptying studies were performed to assess peripheral nerve and gastrointestinal function. Results The c.165G > C mutation was confirmed in all affected family members, presenting with early-onset gastrointestinal dysfunction and sensorimotor polyneuropathy. The mean age at onset was 39.76 ± 2.77 years, with rapid progression to death (mean age 46.13 ± 2.97 years) due to cachexia from gastrointestinal complications. Genetic anticipation was observed, with earlier onset in successive generations. Conclusion The p.Lys55Asn mutation in the TTR gene leads to a severe, rapidly progressive ATTR-PN phenotype, characterized by prominent gastrointestinal dysfunction. This study enhances understanding of the clinical spectrum associated with this rare mutation, emphasizing the need for early diagnosis and targeted management strategies.