foreign Huntington disease or HD is a rare neurodegenerative disease that involves a repeated sequence of DNA that causes an abnormal protein to form leading to abnormal movements and cognitive problems Huntington disease is an autosomal dominant genetic disorder which means that one affected copy of the gene is enough to cause disease affected people are typically present in each generation because an affected person male or female has a 50 percent chance of passing on the affected Gene to a child which causes that child to have the disease in most people a gene called Huntington or HTT on chromosome 4 contains a triplet repeat where nucleotide C A and G are repeated 10 to 35 times in a row in people with Huntington disease this repeat goes on for 36 or more times in a row CAG codes for the amino acid glutamine so people with hunting to disease will have 36 or more glutamines in a row in the Huntington protein so in addition to being a triplet repeat disorder HD is more specifically a polyglutamine disease the specific way in which extra glutamines cause HD symptoms isn't fully worked out but some Clues are that the mutated protein aggregates within the neuronal cells of the caudate and putamen of the basal ganglia causing neuronal cell death cell death might be related to excitotoxicity which is excessive signaling of these neurons which leads to high intracellular calcium the expanded CAG repeats not only affect the Huntington protein they also affect DNA replication itself when copying the HTT Gene DNA polymerase can basically lose track of which CAG it's on and accidentally add extra cags since as a zygote develops into a fetus and eventually into a full adult by the time sperm and eggs are created several dozen cell divisions each with a round of DNA replication have taken place and so there have been a lot of opportunities for repeat expansion and the more repeats that are added the more unstable it gets this expansion of the originally inherited Gene means that a child of a parent with HD can inherit even more CAG repeats than the parent did the higher the number of repeats in the protein the earlier the age when a person starts having symptoms and this phenomenon is called anticipation which means that the Huntington disease families often show earlier symptom onset with each generation even repeats of 27 to 35 cags can expand occasionally and these are called premutation alleles since they don't cause the disease but they're set up for developing a mutation of 36 or more cags like we've mentioned this process of adding more repeats is called repeat expansion and it happens way more in the production of sperm than of eggs so both anticipation and new disease alleles generally happens when the father's the affected parent when a person has 40 plus repeats they show a hundred percent penetrance and they will have the disease for reasons that remain unknown people with 36 to 39 repeats can show reduced penetrance some may have symptoms While others may not because of this penetrance the test for HD which counts the number of CAG repeats is really good at determining whether Huntington disease will develop in an at-risk individual now the symptoms of Huntington disease involve Progressive central nervous system disturbances including movement cognitive and mood symptoms the average age of onset is around 40 years old although remember that the age of onset depends on the number of CAG repeats over time if enough of the neurons die in the caudate and putamen which together form the dorsal striatum then it can cause actual loss of brain tissue volume in that area an expansion of the lateral ventricles these areas play an important role in movement particularly inhibiting it and that's why neuronal death in the basal ganglia causes movement problems like choria which are purposeless dance-like jerky movements and athetosis which are slower writhing snake-like movements mainly affecting the hands these involuntary movements can't be consciously suppressed and stop only with sleep other Motor problems include abnormal eye movements and poor coordination loss of tissue in these regions can also lead to psychological problems as well like dementia personality changes and depression the diagnosis of Huntington disease is based on the person's history and physical assessment followed by genetic testing to confirm the diagnosis additionally brain Imaging tests like a CT scan or MRI can be used to assess the atrophy of the basal ganglia even though this might be oversimplifying things a bit the brain regions affected by Huntington disease have decreased Gaba and acetylcholine and increased dopamine levels this increased dopamine helps explain why neuroleptics which are dopamine receptor antagonists and tetrabenazine which depletes dopamine are used to treat choria and people with Huntington disease unfortunately these in other pharmacologic treatments don't affect overall survival and death usually happens within 10 to 20 years of diagnosis Often by aspiration pneumonia on account of discordinated swallowing or suicide there are actually several dozen other triplet repeat disorders in addition to Huntington disease some of which also have cags the repeated nucleotides but in a different Gene others of which though have different repeats like myotonic dystrophy which is a ctg repeat Axia a GAA repeat and fragile X syndrome a cgg repeat all right so as a quick recap Huntington disease is an autosomal dominant disease caused by having 36 or more tri-nucleotide repeats of CAG in the Huntington Gene which causes neuronal cell death in the basal ganglia causing movement symptoms like choria and athetosis as well as mental symptoms like depression and dementia helping current and future clinicians Focus learn retain and Thrive learn more