Let’s talk “diagnose and adios” today. I am going to tell you about one of the biggies, one of the really bad neurologic diseases, up there in the top 10, maybe even the top 5, of “neurologic diseases that you don’t want to get”. But in a weird way, it is near and dear to my heart (no, I don’t have it, nor am I likely to develop it), and I’ll get to why in a bit. I am talking about Huntington’s disease (or Huntington’s chorea, as it was once called). Huntington’s disease is a classic progressive, degenerative neurologic disease that neurologists really can’t treat. Clinical signs and symptoms include chorea, cognitive impairments and psychiatric problems.
It is a hereditary disease that is transmitted from one parent in an autosomal dominant pattern. For those of you who took high school biology, but don’t remember it, autosomal inheritance occurs when the gene carrying the mutation is located on an “autosome” (non-sex chromosome). If something is inherited in an dominant pattern that means that only one gene is necessary for the disease to occur. And because only one gene is necessary for development of the disease, children of an affected parent have a 50/50 chance of having the disease. I am going to leave this genetics discussion simple and not get into variable expression or reduced penetrance. Suffice it to say that if one of your parents has Huntington’s disease (HD), you have a 50% chance of getting it. But it is a little more complicated than that, actually.
It is the genetics of Huntington’s disease that is so fascinating. The Huntingtin gene, located on the short arm of chromosome 4, was identified in 1993 and was the first non-sex-linked dominant disease gene to be documented. It is one of the trinucleotide repeat disorders. These are genetic disorders in which one DNA triplet (trinucleotide) in the gene sequence is repeated multiple times. It is this repetition, at least in the case of HD, that causes the clinical symptoms. The three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...) in a protein-coding portion of the gene (the protein is, not surprisingly, called huntingtin). CAG is the genetic code for the amino acid glutamine, so a series of CAGs results in a chain of glutamine known as a polyglutamine or polyQ tract.
Normal people do have CAG repeats in that region of chromosome 4; normal is considered less than 29 glutamine repeats. If a person has 29 – 34 CAG repeats, the resulting huntingtin protein will function normally, but the next generation is at risk. The gray zone is 35-39 CAG repeats, which will cause the disease in some patients but not others (the reduced penetrance I mentioned earlier). If the patient has 40 or more repeats, they will develop HD. Trinucelotide repeat disorders are frequently associated with genetic anticipation, in which successive generations have increasing numbers of CAG repeats and earlier/more severe disease expression.
There is genetic testing available that calculates the number of trinucleotide repeats. Most people at risk of developing HD do not actually take the test prior to developing symptoms, primarily because there is no treatment. Prior to ordering the test, significant counseling is recommended. In utero genetic screening is also available.
The altered or mutant huntingtin increases the decay rate of medium spiny neurons, which affects specific regions of the brain depending on the amounts of these neurons. The areas of the brain most affected, as seen in histopathological examinations are the caudate nucleus and putamen. These comprise the striatum. Other areas that are affected include the substantia nigra, parts of the cerebral cortex, hippocampus, angular gyrus, purkinje cells in the cerebellum, parts of the hypothalamus and thalamus. It is the striatal degeneration that causes the most prominent symptoms of HD.
Huntington's brain ------------- Normal brain
The symptoms of HD most commonly appear between the ages of 35 and 44, typically after the patient has had children. Presentation may occur before age 20, which is called the akinetic-rigid or Westphal variant. The most common symptom seen in HD patients is chorea. These are jerky, random, and uncontrollable movements that are almost dance-like (hence the name chorea – from choreos – dance in Greek). Other motor symptoms are rigidity and dystonia (sustained muscle contractions causing twisting movements or abnormal posture), which typically become more prominent than the chorea as the disease progresses. Motor impersistence (difficulty maintaining a specific motor task) is another common sign of HD. One way to assess this is to have the patient stick his tongue out. He will not be able to hold it out for more than a few seconds. It will go back in, then out, etc… Motor control is severely affected as the disease progresses, causing instability, inability to walk, difficulty chewing swallowing and talking.
Cognitive dysfunction is also present, commonly prior to development of the motor symptoms. Progressive cognitive decline will almost inevitably occur in these patients, with memory difficulties (initially short-term, then long-term as well). The cognitive decline eventually leads to dementia in most patients. It is a subcortical dementia, with prominent personality changes and attentional difficulties, rather than a cortical dementia, as seen in Alzheimer’s disease. Psychiatric problems are also not infrequently seen in these patients – depression, anxiety, aggression, even psychosis. The psychiatric manifestations can severely affect the patient’s ability to function and may be a trigger for institutionalization.
There is no cure and no effective treatment for the disease. Tetrabenazine was approved for the treatment of chorea in HD patients, the only drug approved for this particular use. Other drugs used in the reduction of HD chorea are neuroleptics (antipsychotic drugs) and benzodiazepines (Valium and its cousins). For the most part, medications are used to reduce the symptoms and are only semi-effective. Anti-parkinsonian drugs can sometimes be used for rigidity. Anti-depressants may help mood disorders. Speech therapy to help with the dysphagia is crucial for the patients to maintain their weight. Prognosis for these patients basically sucks. Life expectancy ranges from 10-30 years from diagnosis, and the disease is inexorably progressive. Patients die of associated complications (pneumonia, aspiration, injury, choking). Suicide is not uncommon (~7%).
Tomorrow, I will tell you why this disease is important to me…