Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations

Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications

A Comparison of the Liver Fat Score and CT Liver-to-Spleen Ratio as Predictors of Fatty Liver Disease by HIV Serostatus.

Non-alcoholic fatty liver disease (NAFLD) is common among HIV-infected (HIV+) adults. The Liver Fat Score (LFS) is a non-invasive, rapid, inexpensive diagnostic tool that uses routine clinical data and is validated against biopsy in HIV-uninfected (HIV-) persons. CT liver-to-spleen (L/S) attenuation ratio is another validated method to diagnose NAFLD. We compared NAFLD prevalence using the LFS versus L/S ratio among Multicenter AIDS Cohort Study participants to assess the LFS's performance in HIV+vs. HIV-men. In a cross-sectional analysis of men reporting<3 alcoholic drinks daily (308 HIV+, 218 HIV-), Spearman correlations determined relationships between LFS and L/S ratio by HIV serostatus. Multivariable regression determined factors associated with discordance in LFS- and L/S ratio-defined NAFLD prevalence. NAFLD prevalence by LFS and L/S ratio were 28%/15% for HIV+men and 20%/19% for HIV-men, respectively. Correlations between LFS and L/S ratio were weaker among HIV+than HIV-men, but improved with increasing BMI and exclusion of HCV-infected men. LFS and L/S ratio discordance occurred more frequently and across BMI strata among HIV+men, but predominantly at BMI<30 kg/m2 among HIV-men. In multivariate analysis, only lower total testosterone levels were significantly associated with discordance. NAFLD prevalence was similar by LFS and L/S ratio identification among HIV-men, but dissimilar and with frequent discordance between the two tests among HIV+men. As discordance may be multifactorial, biopsy data are needed to determine the best non-invasive diagnostic test for NAFLD in HIV+persons

Loss-of-function mutations in YY1AP1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease

Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells