Know Your Brain: Huntington's disease

Background

George Huntington was not a prolific researcher. In fact, he only published three scientific papers in his career. The first of these, however, published in 1872 when Huntington was just 22 years old, would lead to his name being found in most neuroscience textbooks today.

In that paper, titled On chorea, Huntington discussed a disorder called chorea that had been known since the Middle Ages. The word chorea comes from the Geek word choreia, which means to dance, and it was used to describe a disorder characterized by involuntary, spasmodic movements of the limbs that bore some resemblance to an odd dance. 

There are a number of different types of chorea, each linked to a different underlying cause. George Huntington wrote the best description to that point of a particular form of chorea that began in adulthood and was inherited, inexorably progressive, and always fatal. Within a few decades, the chorea Huntington described was widely-recognized as a unique disorder, which---in appreciation for Huntington's clear and accurate depiction of the disease---was called Huntington's chorea. The name was eventually changed to Huntington's disease (HD), as it became apparent that the condition involved more than just chorea. Not all patients with HD develop chorea and even those who do experience a number of other symptoms that are not related to movement.

In the 20th century, the hereditary nature of HD became even clearer as our understanding of common patterns of inheritance improved. In the 1980s, a gene was identified that seemed to be the cause of HD. With this discovery, HD joined a short list of diseases caused by the mutation of a single gene.

What is Huntington's disease?

The symptoms of HD can appear at any age, but typically emerge in middle age (the average age of onset is 40 years). At first, patients will often experience subtle changes in personality, cognition, and movement. For example, a patient might become irritable, have trouble remembering things, or be especially restless or fidgety. These symptoms, however, are usually not enough to lead to a diagnosis. 

The early symptoms then progress into symptoms that allow for a clear diagnosis of HD. These include: conspicuous movement problems like chorea, impaired coordination and balance, abnormal eye movements, and muscle rigidity. Also, cognitive symptoms can become debilitating, and can involve difficulty focusing, a tendency to become fixated on a thought, lack of impulse control, and lack of awareness. Psychiatric symptoms like depression, insomnia, and fatigue are common as well.

huntington's disease causes significant neurodegeneration in the basal ganglia (highlighted structures here in the middle of the brain).

HD is a neurodegenerative disorder, meaning it is characterized by the degeneration and death of neurons. Thus, symptoms are accompanied by pathological changes to the brain, including neuronal loss in specific brain regions. The caudate and putamen (both part of the basal ganglia) are the two areas where cell loss is the most prominent, and damage to them is thought to be the cause of some of the movement problems HD patients experience. Other areas of the brain, however, like the substantia nigra, cerebral cortex, hippocampus, cerebellum, hypothalamus, and thalamus are also affected. The disease is invariably fatal; the average time from diagnosis to death is around 20 years

What causes Huntington's disease?

HD is a rare disorder, occurring in the western world at a rate of about 4-10 cases per every 100,000 people. As mentioned above, the disease is inherited, and can be traced back to a mutation in a single gene called huntingtin (HTT). The HTT gene contains a DNA sequence that consists of three nucleotides (cytosine, adenosine, and guanine, or CAG) in repetition---a pattern known as a trinucleotide repeat. 

Some degree of trinucleotide repetition in the HTT gene is normal and will not result in HD. When the gene is mutated, however, excess CAG repeats (above 35) can occur. The higher the number of repeats, the greater the risk of developing HD. For example, 36-39 repeats leads to an increased risk of HD, but also the possibility that the onset of the disease will be so late in life that noticeable symptoms may not appear before death due to other causes. 40 or more repeats, however, is a fully penetrant mutation, meaning that all people with the mutation will develop disease. As the number of repeats increases, the age of onset is more likely to be younger, with 70 or more repeats causing the disease to appear during youth. The largest repeat length seen so far has been 250, but it is very uncommon to see repeat lengths greater than 80.

The mutation in the HTT gene that leads to HD is known as an autosomal dominant mutation. This means that the gene variation that encodes for the mutant protein is dominant, and will be expressed if it's inherited. If one parent has HD, their child has a 50% chance of inheriting the mutated gene, and thus of developing HD.

The function of the huntingtin protein (which is produced by the HTT gene) is not fully understood, but it is thought to play important roles in embryonic development. There are also indications it is an important regulator of signaling pathways in the cell. It's expressed throughout the body, but is especially prevalent in the central nervous system.

An excess number of CAG repeats in the HTT gene leads to the production of a mutated form of huntingtin protein. The characteristics of these mutated proteins cause them to be likely to be cleaved by cellular enzymes. The cleaved fragments then have a propensity to group together, forming clusters within neurons that are not easily removed by brain enzymes. It has been hypothesized that these protein clusters (which are similar in some ways to the protein aggregates seen in Alzheimer's, Parkinson's, and other neurodegenerative diseases) may play a role in the neuronal damage seen in HD.

Additionally, mutant huntingtin seems to also be able to recruit other, normal proteins, into these clusters. In this way, huntingtin protein is thought to spread its abnormal state to healthy proteins, which might cause normal cell functions to be disrupted. Finally, some have suggested that mutated huntingtin may also have direct toxic effects on neurons.

As with other neurodegenerative diseases, however, the exact way HD leads to neurological damage is not fully understood, and the effect the protein aggregates have on the brain is still not completely clear. Some researchers, for example, have even argued that huntingtin aggregates are part of the brain's defense mechanism as it tries to cope with other pathogenic changes that are occurring. In general, though, the evidence supports the hypothesis that huntingtin aggregates are toxic and play some role in the progression of disease.

As huntingtin protein deposits accumulate in the brain of an HD patient, areas of the brain also begin to display neurodegeneration. As mentioned above, the basal ganglia (e.g. caudate, putamen) are strongly affected, but other regions like the substantia nigra, cerebral cortex, hippocampus, cerebellum, hypothalamus, and thalamus experience degeneration as well.

There is no cure for HD. There are a number of medications, however, that can be taken to treat the symptoms of the disease. These vary depending on the symptoms being targeted, and range from drugs liked tetrabenazine to treat chorea to selective serotonin reuptake inhibitors for depression. While drugs like tetrabenazine are effective in treating symptoms of HD, some also have significant side effects. This often leaves patients without great options for treatment. The sparsity of treatment options combined with the inevitably fatal nature of the disease contributes to the suicide rate being about 5 to 10 times higher in HD patients.

Reference (in addition to linked text above):

Walker FO. Huntington's disease. Lancet. 2007 Jan 20;369(9557):218-28.

Know your brain: Lyme disease

Background

There are a number of documented cases throughout history of what was probably the same disorder we now call Lyme disease. But Lyme disease didn't earn its name and become appreciated as a syndrome of its own until the 1970s, when two exasperated mothers from a town in southern Connecticut contacted the Connecticut State Department of Health and the Yale School of Medicine in search of help with an outbreak of (what seemed to be) arthritis that was primarily affecting children.

The outbreak spanned three towns in a small region of Connecticut: Old Lyme, Lyme, and East Haddam. By that point, 51 residents (including 39 children) of this region, which had a total population of only 12,000, had been diagnosed with some form of arthritis. 

Researchers from Yale and the Department of Health came to Lyme to investigate. One clue that emerged from the investigation was that 25% of the patients had noticed a skin lesion that formed several weeks before the symptoms began. Researchers began to find other similarities: most patients lived in wooded areas of town, patients often lived near one another, and the cases generally appeared in summer and early fall months. 

Based on these clues and descriptions of the rash that can occur after a tick bite, researchers began to suspect ticks were spreading the disease, which had come to be known as Lyme arthritis. The name would soon be changed to Lyme disease to reflect the fact that this was much more than just a type of arthritis.

In the 1980s it was confirmed that Lyme disease was spread by ticks when the bacterium responsible was discovered. The bacterium was named Borrelia burgdorferi in honor of Willy Burgdorfer, the scientist who discovered it (Borrelia refers to the genus of bacteria B. burgdorferi belongs to). Sometimes Lyme disease is also called Lyme borreliosis to indicate the involvement of Borrelia bacteria.

What is Lyme disease?

B. burgdorferi is spread by several species of hard-bodied ticks. In the United States, the disease is primarily spread by the blacklegged tick, or deer tick, and the western blacklegged tick. Ticks are known as hematophages, meaning they need blood to survive and move through their life cycle. Ticks generally become infected with B. burgdorferi in the first stage of their life cycle (the larval stage) when they bite infected small mammals or birds. Subsequently, when they feed on the blood of a new host, B. burgdorferi will pass from the tick to the new host. 

After their first blood meal, the tick enters its nymph stage, which is a part of the insect life cycle where the insect is not quite an adult but resembles the adult form. Nymphal ticks feed on small mammals or birds, which helps to spread B. burgdorferi among these populations. 

Nymphal ticks can also feed on humans, however, and they are the most common source of Lyme disease because they are very small at that stage (about the size of a poppy seed). Thus, they are more likely to go unnoticed while they are attached to a host, which allows them to stay attached for the amount of time it takes Lyme to be transmitted (usually at least 36 hours). Since humans aren't thought to spread B. burgdorferi among themselves or to other animals, they are considered a dead-end host for the bacteria (meaning there is no other host for the bacteria to go to after them). Adult ticks can feed on humans too, but are most commonly found on large animals in the wild, like deer.

Symptoms

The initial sign of B. burgdorferi infection in most patients is a round or oval, gradually expanding skin lesion at the location of the tick bite. At the same time, patients may experience flu-like symptoms like fatigue, headache, and fever. Over the following days or weeks, patients may develop multiple skin lesions that are widespread and generally similar in appearance to the first, but smaller.

In around 5% of patients, cardiac symptoms will occur several weeks after the first signs of disease. These symptoms can range from mild ventricular dysfunction to a fatal form of pancarditis, a term that refers to inflammation of the heart.

Several months after the initial signs of infection, about 60% of untreated patients begin to experience symptoms of arthritis like joint swelling and pain.

Neuroborreliosis

About 15% of untreated patients will also experience neurological symptoms several weeks to a few months after the infection begins, and in about 5% of untreated patients these symptoms may become chronic. The neurological effects vary but often manifest initially as meningitis, cranial neuritis, and/or radiculoneuritis. Meningitis is an inflammation of the meninges and may involve headaches, vomiting, neck stiffness, and other symptoms. Cranial neuritis involves inflammation of the cranial nerves and may cause symptoms like facial palsy/weakness, abnormalities in facial sensation, visual disturbances, tinnitus, vertigo, hearing loss, or other symptoms depending on the cranial nerve most affected. Radiculoneuritis involves an inflammation of the nerve roots; symptoms often include pain, numbness, and/or tingling sensations. 

Chronic neurological symptoms are diverse as well. Chronic effects may include a brain disorder that is linked to cognitive problems like difficulties with memory, verbal fluency, and processing of information. Encephalomyelitis, which is an inflammation of the brain and spinal cord, may also occur and lead to symptoms like confusion, psychiatric problems, a variety of movement difficulties, and seizures. Other psychiatric symptoms may appear too, including irritability, anxiety, depression, mood swings, sleep disturbances, sensory hyperarousal (i.e. extreme sensitivity to sensory stimuli like light or sound), and, in rare cases, hallucinations.

What causes the symptoms of Lyme disease?

While the symptoms of Lyme disease can be severe if untreated, they are not thought to be caused by any toxins or detrimental substances produced by B. burgdorferi, as is the case with some other particularly harmful bacteria. Unfortunately, what does cause the symptoms is still not completely clear. It is thought, however, that most of the problems likely are due to side effects of the immune system response to the presence of the bacterium. The primary immune response thought to be at play is inflammation, a general reaction your immune system has to any potentially harmful or foreign substance.

Inflammation involves the accumulation of immune system cells at a site of infection or damage, and the goal of the response is to repair damage and remove potentially dangerous foreign invaders. Inflammation, however, can also lead to secondary symptoms; a well-known example of this is when you experience redness, pain, and swelling around the area of an injury. Secondary effects of this sort are thought to contribute to the symptoms of Lyme disease ranging from the initial skin rash to joint problems.

The inflammation that occurs after B. burgdorferi infection seems to be disproportionate to the threat of the bacterium. In other words, the inflammatory response is stronger than it needs to be. Often, it even continues after the immune system has eliminated B. burgdorferi from the body. The reasons for this exaggerated response are unclear.

In the nervous system, the inflammatory response to B. burgdorferi may lead to secondary damage to neurons and glial cells. Additionally, there is evidence B. burgdorferi may adhere directly to brain capillaries, neurons, and glial cells, in the process causing changes in the permeability of blood vessels as well as damage (e.g. demyelination, or the deterioration of the myelin sheath of neurons) to cells. There is also some indication B. burgdorferi may be able to invade neurons and glial cells to cause additional damage. These direct effects, of course, may compound the damage caused by inflammation. In truth, however, these mechanisms for B. burgdorferi's pathogenic effects are poorly understood at this point. 

Outcomes

The immune system is capable of removing B. burgdorferi such that the bacterial numbers eventually fall even without treatment, and symptoms in most patients are mitigated over time. In untreated patients, however, the bacterium has the capability of remaining in the system at low levels for years, which can cause chronic symptoms.

Treatment primarily consists of antibiotics, and if begun early enough, the treatment is often completely effective. A small percentage of patients, however, may experience lingering effects, even after treatment. These patients are sometimes said to be suffering from post-treatment Lyme disease syndrome, or PTLDS. There is some controversy about these chronic symptoms, however, and how much we can say they are attributable to the infection with B. burgdorferi versus immune system abnormalities occurring post-infection or other factors altogether.

Steere AC, Strle F, Wormser GP, Hu LT, Branda JA, Hovius JW, Li X, Mead PS. Lyme borreliosis. Nat Rev Dis Primers. 2016 Dec 15;2:16090. doi: 10.1038/nrdp.2016.90.