In PAH, the balance is shifted away from synthesis of prostacyclin towards synthesis of thromboxane. Other pathways
The three pathways described above are all targeted by currently available medical therapies for PAH. However, several other pathways have been identified that are also altered in PAH and are being investigated as potential targets for future therapies. For example, the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) is pathologically activated in PAH, causing a metabolic shift from oxidative phosphorylation to glycolysis and leading to increased cell proliferation and impaired apoptosis. Expression of vasoactive intestinal peptide, a potent vasodilator with anti-inflammatory and immune-modulatory roles, is reduced in PAH, while expression of its receptor is increased. Plasma levels of serotonin, which promotes vasoconstriction, hypertrophy and proliferation, are increased in patients with PAH, although the role played by serotonin in the pathogenesis of PAH remains uncertain. The expression or activity of several growth factors (including platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor) is increased and contributes to vascular remodeling in PAH. Other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include OPG and TRAIL. Focusing only on the pulmonary vasculature provides an incomplete picture of PAH; the ability of the right ventricle to adapt to the increased workload varies between patients and is an important determinant of survival. The molecular pathology of PAH in the right ventricle is therefore also being investigated, and recent research has shifted to consider the cardiopulmonary unit as a single system rather than two separate systems.
Treatment for people with L1 syndrome is supportive and aims to improve quality of life and minimize functional impairment. Signs and symptoms
L1 syndrome presents as a spectrum ranging from mild to severe features. There is a genotype -phenotype correlation across the L1 spectrum, meaning that the specific genetic variant causing an L1-spectrum disorder in a patient determines the severity of the L1 syndrome in that patient. Patients with truncating (loss-of-function) variants in L1CAM, which prevent the full synthesis of L1 (protein) experience more severe features than patients with missense variants in L1CAM, which may result in an abnormal protein but do not prevent its synthesis. Illustrating this difference in L1 syndrome severity, up to 50% of infants born with L1 syndrome caused by a truncating mutation will die before the age of 3 years despite provision of best available medical treatment. In comparison, roughly 10% of infants born with L1 syndrome caused by a missense mutation will die before the age of 3 years.Despite its presentation on a continuous spectrum, L1 syndrome is loosely divided into four discrete phenotypes. Societal Implications Based on Symptoms
People diagnosed with L1 syndrome often experience issues with respect to societal roles and interactions due to the severe physical and mental disabilities associated with the disorder.