This also leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo the normal processing. Other RNA metabolism genes associated with ALS include ANG, SETX, and MATR3.C9orf72 is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS. The three mechanisms of disease associated with these C9orf72 repeats are deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein. Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in C9orf72-ALS using human induced pluripotent stem cell (iPSC) technologies coupled with CRISPR/Cas9 gene-editing, and human post-mortem spinal cord tissue examination.Excitotoxicity, or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by the excitatory neurotransmitter glutamate, is a mechanism thought to be common to all forms of ALS. Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the AMPA receptor) that is more permeable to calcium.
Rheumatic fever (RF) is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a streptococcal throat infection. Signs and symptoms include fever, multiple painful joints, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves, known as rheumatic heart disease (RHD), usually occurs after repeated attacks but can sometimes occur after one. The damaged valves may result in heart failure, atrial fibrillation and infection of the valves.Rheumatic fever may occur following an infection of the throat by the bacterium Streptococcus pyogenes. If the infection is left untreated, rheumatic fever occurs in up to three percent of people. The underlying mechanism is believed to involve the production of antibodies against a persons own tissues. Due to their genetics, some people are more likely to get the disease when exposed to the bacteria than others. Other risk factors include malnutrition and poverty. Diagnosis of RF is often based on the presence of signs and symptoms in combination with evidence of a recent streptococcal infection.Treating people who have strep throat with antibiotics, such as penicillin, decreases the risk of developing rheumatic fever. In order to avoid antibiotic misuse this often involves testing people with sore throats for the infection; however, testing might not be available in the developing world. Other preventive measures include improved sanitation.