Physiology and Neuroanatomy of Huntington's Disease

Genetics and Physiology of Huntington's Disease

Whether or not a person has Huntington's depends entirely on genetics. Huntington's Disease (HD) is an autosomal dominant disease. Autosomal means that the disease is not found on one of the sex determining chromosomes. It is on one of the other 22. Dominant means that if one of your parents has the disease, you have a 50% chance of inheriting it. Using the paradigm from the Genetics at a Glance section, the parent with HD will have the alleles (Hh), (H) being the dominant allele for Huntington's, and the spouse without HD will have the alleles (hh). You will inherit one of these four combinations: two combinations resulting in HD because they contain the dominant HD allele, (Hh), and two combinations resulting in no HD, (hh).

In a person who doesn't have HD, the gene IT15 on chromosome 4p16.3 (identified in 1993), codes for a protein called huntingtin. Basically this means that the trouble begins at a gene on chromosome 4. In a normal person, the gene IT15 will contain between 11 and 34 repeats of the nitrogenous base triplet CAG. The CAG triplet encodes the amino acid glutamine. Therefore, the number of CAG triplets in gene IT15 equals the number of glutamine amino acids in the huntingtin protein. In people with HD, there are between 37 and 121 repeats of the CAG triplet. When this happens, it is called a stutter. This series of CAG repeats is called the polyglutamine region because it codes for several glutamine molecules. A person who has between 37 and 41 CAG triplet repeats may develop some of the symptoms of HD, but not necessarily the full-blown disease. The entire huntingtin protein is made up of over 3000 amino acids. This may be why just a few extra repeats causes only partial symptoms. People who have over 41 repeats almost always develop the disease; and the more repeats they have, the earlier the onset, and the worse the symptoms are.

The phenomenon of increasing disease severity and decreasing age of onset is known as anticipation. Anticipation increases as the number of glutamine triplets increases. It is not known exactly how the length of the polyglutamine region increases, but it seems the longer the region is to begin with the more likely it is to expand. A majority of people with juvenile onset inherited the disease paternally, or from the father. This may be because sperm has to undergo more cell divisions, on average, than an ovum, and thus there is more chance for an expansion mutation. There may also be some sort of maternal protecting factor as well, because there are smaller increases in length in maternal transmission.

Huntington's Disease symptoms arise due to damage to the basal ganglia and the cortex of the brain. The basal ganglia is a small system in the middle of the brain that has a lot of control over movement. The basal ganglia consists of many parts, but the caudate, putamen, globus pallidus, substantia nigra, and the subthalamus are the major players in this system. The globus pallidus is divided into two parts, interna (GPi) and externa (GPe). The substantia nigra is also divided into two parts, pars compacta (SNc) and pars reticulata (SNr). The striatum is the name given to the caudate nucleus and the putamen together, and is the place where HD has its most severe effects.

Eventually, HD knocks out many neurons throughout the basal ganglia, but it apparently starts with the inhibitory GABA neurons projecting to the Gpe from the putamen. GABA, gamma-aminobutyric acid, is the primary inhibitory neurotransmitter in the brain. When these neurons are functioning normally, they cause decreased inhibition of motion through a long pathway in the basal ganglia. Knocking out the GABA neurons in the putamen will result in excess motor signals from the GPi through two different pathways. Here are the pathways in a nutshell. They are confusing, so it is helpful to follow along on the diagram.

In one pathway, the putamen's inhibitory GABA neurons which project to the GPe are destroyed. This allows the inhibitory GABA neurons from the GPe to the subthalamus to fire. The subthalamus' excitatory glutamate neurons to the GPi are thus inhibited. The GPi has inhibitory GABA neurons projecting to the thalamus and the brainstem which would normally inhibit motion. In this case, the neuron activating these inhibitory neurons is, itself, inhibited, so the thalamus and brainstem are disinhibited, causing random, frequent motion.

In the other pathway, the putamens' projection to the SNpc is destroyed. This causes increased firing of dopamine neurons, which synapse back on the putamen. This activates inhibitory neurons from the putamen to the GPi. Thus, the same inhibitory neurons as in the first pathway, going from the GPi to the thalamus and brainstem, are disinhibited. Again the result is excess motion.

Striatal atrophy results in hydrocephalus ex vacuo, literally meaning water-head. Hydrocephalus is the enlargement of cerebral ventricles and thinning of cerebral substance. As the brain atrophies, space is created in the brain, and it needs to be filled with something. That something is extra cerebrospinal fluid, the liquid normally found in the ventricles.

The striatum is not the only part of the brain to atrophy. Both parts of the globus pallidus, the subthalamus, and the cerebral cortex decay as well. In extreme cases, there is loss of 25-30% of brain matter. The basal ganglia is small and can't account for this much loss. About 20-25% of the loss is cortical. Findings have also shown that cortical degradation does not occur due to the changes occurring in the striatum. There is no correlation between extent to which the striatum and cortex degenerate. The atrophy of the cortex is believed to account for the dementia seen in later stages of the disease.

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