ACTA2 mutations, affecting positions different from Arg179, are generally associated with predominantly vascular disease, often with a later or more variable presentation.
These variants most commonly affect the aorta and major blood vessels and are part of the spectrum of heritable thoracic aortic disease.
In contrast to MSMDS, these variants typically do not involve widespread multisystem smooth muscle dysfunction and are less likely to present with congenital features such as fixed dilated pupils. The most common presentations are:
Although these variants often present later in life, disease severity can vary significantly, even within the same family. Importantly, aortic complications such as dissection may occur at relatively small aortic diameters, which has implications for monitoring and clinical management.
Cerebrovascular involvement can also occur in some individuals, including Moyamoya-like arteriopathy. For example, certain variants such as Arg198Cys have been associated with combined aortic disease and cerebral vascular abnormalities, illustrating the variability within ACTA2-related conditions.
Clinical History and Management Recommendations of the Smooth Muscle Dysfunction Syndrome Due to ACTA2 Arginine 179 Alterations
European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants
2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
2024 ESC Guidelines for the management of peripheral arterial and aortic diseases
Hafen BB, Shook M, Burns B. Anatomy, Smooth Muscle. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from:
*This content is not intended as a substitute for professional medical advice, diagnosis, or treatment. Should you require medical advice, please contact a qualified medical professional who is familiar with Multisystemic Smooth Muscle Dysfunction Syndrome.
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