Symptoms of MSMDS: a medical puzzle

Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) affects fewer than 100 people worldwide, and its symptoms vary widely from one patient to another. Because it involves multiple organs and systems, early signs are often misdiagnosed or only partially recognized.



From congenital mydriasis to cardiovascular, neurological, or digestive complications, many symptoms resemble more common conditions, delaying diagnosis and increasing risk.

Highlight: This page does not replace medical advice. Always consult your healthcare team.

The hallmark signs of MSMDS

MSMDS symptoms differ between patients, but the most characteristic include:


  • Congenital mydriasis (fixed and dilated pupils): often the first visible sign, frequently accompanied by tortuous retinal vessels
  • Congenital heart defects (Coarctation of the aorta, Patent Ductus Arteriosus –PDA- or Aortopulmonary Window –APW-)
  • Brain white matter abnormalities
Dilated pupils as early sign of Multisystemic Smooth Muscle Dysfunction Syndrome
Aortic coarctation as early sign of MSMDS
PDA repair needed as early sign of MSMDS
Aortopulmonary window as early sign of MSMDS
White matter abnormalities are usually present as early symptom of MSMDS

 When two of these three signs are present, genetic testing for ACTA2 mutations should be strongly considered.

These hallmark signs often appear early in life, sometimes even at birth, and are critical for early recognition.


Most frequent symptoms

MSMDS symptoms vary between individuals, but the most characteristic include:

Moyamoya-like is a term that is often used to describe MSMDS brain vasculature

Neurological & Cerebrovascular

  • Moyamoya-like cerebrovascular arteriopathy: dilated, tortuous vessels, especially in the internal carotid arteries
  • Abnormal brain white matter, present from birth in most cases 
  • Transient ischemic attacks (TIAs)
  • Pediatric stroke, a common trigger for MSMDS diagnosis
  • Altered autoregulation cerebral



Seizures may occur due to ischemic brain injury or abnormal blood flow regulation

Moyamoya-like is a term that is often used to describe MSMDS brain vasculature

Ocular

  • Congenital mydriasis: typically the first visible sign, noticeable from day 1 after birth
  • Retinal vascular tortuosity
  • Pupils appear large, fixed, and unresponsive to light



Often associated with scalloped iris margin and tortuous retinal vessels

Moyamoya-like is a term that is often used to describe MSMDS brain vasculature

Cardiovascular

  • Patent Ductus Arteriosus (PDA) or Aortopulmonary Window (APW) requiring early surgical repair
  • Aortic aneurysms, present in an estimated 85–92% of children and young adults with MSMDS
  • Other defects: coarctation of the aorta, septal defects


These conditions may require early surgical intervention and lifelong monitoring.

Interstitial lung disease in a patient with MSMDS

Respiratory

  • Pulmonary arterial hypertension (PAH)
  • Chronic or restrictive lung disease, often with presence of atelectasis
  • Laryngomalacia
  • Recurrent respiratory distress and upper respiratory infections
  • Reduced oxygen levels or increased breathing effort
  • In some patients, asthma, emphysema, pneumothorax, or rarer forms of interstitial lung disease


Pulmonary complications can range from mild respiratory symptoms to severe disease requiring close follow-up.

Interstitial lung disease in a patient with MSMDS

Respiratory

  • Progressive dysfunction of blood vessels throughout the body
  • Increased risk of:
  • Aortic dissection or rupture
  • Blood clots
  • Poor circulation and temperature regulation


Patients often report difficulty regulating body temperature and may not experience normal “chills”.

Interstitial lung disease in a patient with MSMDS

Gastrointestinal

  • Intestinal malrotation or volvulus
  • Gut dysmotility (hypoperistalsis) 
  • Chronic constipation or reflux


Symptoms range from mild feeding difficulties to life-threatening bowel obstruction.

Interstitial lung disease in a patient with MSMDS

Urinary

  • Atonic (hypotonic) bladder
  • Urinary retention and recurrent infections
  • Prenatal megacystis, often detected on fetal ultrasound, especially in girls


Prune‑Belly Syndrome (PBS): genetic testing is recommended when PBS appears without mechanical obstruction and coexists with PDA

Interstitial lung disease in a patient with MSMDS

Autonomic Nervous system

  • Difficulty regulating blood pressure
  • Impaired temperature control
  • Reduced ability to respond to physiological stress

Why MSMDS is often missed

MSMDS affects smooth muscle cells throughout the body. Because these cells are present in blood vessels, lungs, digestive system, and bladder, the disease can impact multiple organs simultaneously, although its symptoms are frequently treated as separate conditions:


  • An eye condition
  • A congenital heart defect
  • A neurological disorder
  • A digestive issue


Individually, these symptoms may seem unrelated, but this fragmentation can delay diagnosis for years. Recognizing them together is essential for suspecting MSMDS and initiating genetic testing.


Connecting the dots

MSMDS is a complex puzzle, but not an impossible one.

Each symptom alone may be confusing, but together, they form the map that leads to a timely and accurate diagnosis.

MSMDS: a diagnostic odyssey

Bibliography:

1. Anna Lynch, Lyvia Zhang, Diana Tambala, Ryan Gise, Nimesh Patel, and Patricia Musolino.Congenital Mydriasis and Retinal Arteriolar Tortuosity: Biomarkers of Disease for MSMDS ACTA2 Arg179 Pathogenic Variants (S40.005) Neurology®, 2024 

https://www.neurology.org/doi/abs/10.1212/WNL.0000000000206311 


2. Tonia M. Sabo, Mathew A. Stokes, Nishika Karbhari, Daniel L. Veltkamp, ​​Cory M. Pfeifer,

ACTA2 leukovasculopathy: A rare pediatric white matter disorder,

Radiology Case Reports,2020 https://www.sciencedirect.com/science/article/pii/S193004332030203X


3. Catherine Wing Yan Tam, MB, BCh, BAO, MSc, FRCR • King Kenneth Cheung, MBBS, BSc, PhD, FRCR. Case 319: Multisystemic Smooth Muscle DysfunctionSyndrome. Radiology 2023 309:2

https://pubs.rsna.org/doi/epdf/10.1148/radiol.222049 


4. Logeswaran, T. et al.Two patients with the heterozygous R189H mutation in ACTA2 and Complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome. Am. J. Med. Genet. A 173, 959–965 (2017). https://pubmed.ncbi.nlm.nih.gov/28328125/ 



5. Tonia M. Sabo, Mathew A. Stokes, Nishika Karbhari, Daniel L. Veltkamp, ​​Cory M. Pfeifer,

ACTA2 leukovasculopathy: A rare pediatric white matter disorder, Radiology Case Reports,

Volume 15, Issue 8, 2020. https://www.sciencedirect.com/science/article/pii/S193004332030203X 


6. Micke K. C., Stence N. V., Meyers M. L., Chatfield K. C., Vemulakonda V. M. (2023).Megacystis associated with an underlying ACTA2 variant and diagnosis of multisystemic smooth muscle dysfunction syndrome: a case report. Urology, 2022 https://pubmed.ncbi.nlm.nih.gov/36495950/ 


7. J Richer 1, D M Milewicz, R Gow, J de Nanassy, G Maharajh, E Miller, L Oppenheimer, G Weiler, M O'Connor, R179H mutation in ACTA2 expanding the phenotype to include prune-belly sequence and skin manifestations Am J Med Genet A. 2012

https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.35206 


8. Li Q, Cui L, Su J and Shen Y (2025) Case report: Multisystemic smooth muscle dysfunction syndrome: a rare genetic cause of infantile interstitial lung disease Front. Pharmacol. 15:1510969. doi: 10.3389/fphar.2024.1510969 

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1510969/full