An Unexpected Association of a Novel MYOF Variant with Generalized Myopathy and HAE-nl-C1-INH

Abstract

Myoferlin (encoded by MYOF) is a highly expressed protein in myoblasts and endothelial cells; mutations in MYOF are linked to malignancies, skeletal and cardiac myopathy, and hereditary angioedema with normal C1-inhibitor (HAE-nl-C1-INH).

We present a 31- year-old female with recurrent severe abdominal angioedema attacks since late childhood. Mucocutaneous angioedema attacks began in early adolescence, triggered by stress and mechanical stimuli, and hormonal changes, often proceded bya fatigue or chest discomfort. Assessment of C1INH level and function had not shown any deficiency C1-INH protein level and function. Because C1-INH protein level and function were normal, whole exome sequencing (WES) was performed, identifying a novel heterozygous missense mutation in MYOF. Family screening revealed the same mutation in her mother and brother.

Her angioedema symptoms were partially controlled using daily tranexamic acid and weekly anti-androgenic agents, while fresh frozen plasma or Berinert reserved for severe attacks.

Over the past two years, she developed slowly progressive weakness in her facial, proximal, and distal extremity muscles, causing fatigue, bilateral ptosis, and difficulty climbing stairs or rising from a chair. Neurological examination, EMG-NCV studies, and elevated serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels confirmed reduced muscle strength and generalized myopathy. Additionally, she experienced palpitations and unprovoked sinus tachycardia, likely reflecting cardymyopathy secondary to myoferlin deficiency.