Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinsons disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patients medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.Relatively common side effects include involuntary muscle movements (dyskinesia), constipation, hallucinations, dizziness and, much like its parent molecule caffeine, nausea and sleeplessness.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Mechanism of action
Istradefylline is a selective antagonist at the adenosine A2A receptor (A2AR), but the precise mechanism by which it exerts its therapeutic effect in Parkinsons disease is unknown. However, it is known that dimers of these receptors form heterotetramers with the dimers of dopamine D2 receptors (D2R) within striatum. Adenosine acts as an endogenous A2AR agonist, but also as a negative allosteric modulator (NAM) within these tetramers towards D2Rs, thus inhibiting the D2R mediated effects of dopamine, an endogenous D2R agonist. Istradefylline is believed to bind an A2AR within an A2AR-D2R-tetramer and function as a NAM towards the other A2AR (instead of D2R), thus inhibiting the effects of adenosine and enhancing the movement (locomotion) promoting effects exerted by dopamine via D2R.
Genetics
A number of mutations have been identified in individuals with Joubert syndrome (JBTS) which allowed for classification of the disorder into subtypes.This disorder can be caused by mutations in more than 30 genes within genetic makeup. The primary cilia play an important role in the structure and function of cells. When primary cilia are mutated and defected, it can cause various genetic disorders among individuals. This mutation of primary cilia can disrupt significant signaling pathways during the development of the fetus.Mutations in these various genes are known for causing around 60-90% of Joubert Syndrome cases. The remaining cases, the cause is unknown if isnt linked to a mutation of known genes. Diagnosis
The disorder is characterized by absence or underdevelopment of the cerebellar vermis and a malformed brain stem (molar tooth sign), both of which can be visualized on a transverse view of head MRI scan. Together with this sign, the diagnosis is based on the physical symptoms and genetic testing for mutations. If the gene mutations have been identified in a family member, prenatal or carrier diagnosis can be pursued.Joubert Syndrome is known to affect 1 in 80,000-100,000 newborns. Due to the variety of genes this disorder is affected by, it is likely to be under-diagnosed. It is commonly found in Ashkenazi Jewish, French-Canadians, and Hutterite ethnic populations. Most cases of Joubert syndrome are autosomal recessive - in these cases, both parents are either carriers or affected. Rarely, Joubert syndrome is inherited in an X-linked recessive pattern.