Introduction: Multisystemic smooth muscle dysfunction syndrome (MSMDS) caused by recurrent variants in the arginine 179 codon of the ACTA2 gene causes a severe vasculopathy with neurological and cardiovascular manifestations. We are conducting a 3-year natural history study to gather preliminary clinical and imaging data in anticipation of therapeutic intervention. Here we present preliminary cardiovascular function and physical activity readouts to delineate early functional deficits. Methods: Fifteen children (14 R179H, 1 R179C variants; 4 males, 11 females; 2-16 years old) were enrolled in the prospective arm of the study at Massachusetts General Hospital. Baseline and 1-year assessments were inclusive of transthoracic echocardiography (ECHO), 24-hour ambulatory blood-pressure monitoring (ABPM), 6-minute walk test (6MWT), biannual wearable 5-day actigraphy monitoring and patient reported outcome measures (PROMs). Pediatric and adult databases were used for normative comparisons. Descriptive statistics, z-scores, and linear regression were employed for analysis. Results: All participants had a history of patent ductus arteriosus repair, while 3 additionally had ascending aortic repair. The median aortic root z-score was 1.70 (range −0.86 to 3.11). ABPM demonstrated a mean 24-hour BP of 99/47 mmHg, with mean awake and asleep values of 104/51 mmHg and 92/42 mmHg respectively. Ten participants (67%) exhibited asleep mean arterial pressure (MAP) below the 25th percentile. Pediatric trends show increasing diastolic BP, while our participants exhibited a slight decline (slope: –0.07). One participant with severe steno-occlusive cerebrovascular disease has hypertension. Actigraphy showed an age-associated rise in daily energy expenditure (R 2 = 0.4406, p= 0.0096), with activity profiles characterized by low intensity bouts and limited moderate to vigorous physical activity across ages. Physical activity PROMs had a wide distribution of performance. All participants walked less than predicted distances on 6MWT or adapted 2-minute test. Conclusions: Children with ACTA2-related MSMDS exhibit persistent low systemic blood pressure, a lack of expected age-related rise in diastolic BP, and annual declines in physical activity, consistent with underlying vascular dysautonomia and early loss of exercise capacity. Clinical wearables for longitudinal cardiovascular follow-up will be vital to define disease progression rates and therapeutic targets.
Ondeck et al. (Thu,) studied this question.