Resistance to conventional drug therapy and good response to lomitapide allowed the identification of a novel bi-allelic semi-dominant monogenic HoFH: a case report.

Introduction: Familial hypercholesterolaemia (FH) is a genetic disorder associated with high cholesterol levels and an increased risk of premature cardiovascular events. Rare forms, such as semi-dominant bi-allelic mutations, pose diagnostic and therapeutic challenges. Misdiagnosis of FH is a significant concern, as highlighted by both this case and a review of the literature.

Case report: We report the case of a 54-year-old woman with an acute myocardial infarction at the age of 43 years. She had a positive family history of early cardiovascular events and was diagnosed with familial hypercholesterolaemia at the age of 33 years. She tried statins with no benefit. In 2017, evolocumab was introduced but was insufficient to control cholesterol values (low-density lipoprotein cholesterol 324 mg/dL). She started lomitapide, and next-generation sequencing screening was performed in consideration of the different pharmacological effects and clinical trends compared to other family members. A bi-allelic semi-dominant mutation (c.241C > T in exon 3 of the LDLR gene) was found in addition to the previously identified mutation. She is now in good clinical condition and laboratory response with lomitapide, evolocumab, statin, and ezetimibe. A literature review was conducted to explore the clinical and diagnostic challenges of FH, with a focus on the risk of misdiagnosis.

Conclusion: This case underscores the importance of genetic testing in diagnosing rare forms of FH, such as semi-dominant bi-allelic mutations, which may lead to misdiagnosis. Lomitapide proved effective in controlling cholesterol levels, highlighting its value in managing complex FH cases. The literature review further emphasizes the critical need for improved diagnostic approaches to minimize the risk of misdiagnosis.