Trinucleotide Repeat Disorders

Trinucleotide repeat disorders (also known as trinucleotide repeat expansion disorders, triplet repeat expansion disorders or codon reiteration disorders) are a set of genetic disorders caused by trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene. The mutation is a subset of unstable microsatellite repeats that occur throughout all genomic sequences. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene.

Trinucleotide repeat disorders are classified as a type of Non-Mendelian inheritance

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Since the early 90’s, a new class of molecular disease has been characterized based upon the presence of unstable and abnormal expansions of DNA-triplets (trinucleotides). The first triplet disease to be identified was fragile X syndrome that has since been mapped to the long arm of the X chromosome. At this point, there are from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome in these patients, as compared with 60 to 230 repeats in carriers and 5 to 54 repeats in normal persons. The chromosomal instability resulting from this trinucleotide expansion presents clinically as mental retardation, distinctive facial features, and macroorchidism in males. The second, related DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded GCC repeat. Identifying trinucleotide repeats as the basis of disease has brought clarity to our understanding of a complex set of inherited neurologic diseases.

As more repeat expansion diseases have been discovered, several categories have been established to group them based upon similar characteristics. Category 1 includes Huntington’s disease (HD) and the spinocerebellar ataxias that are caused by a CAG repeat expansion in a protein-coding portion of specific genes. Category 2 expansions tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude, but also found in the exons of genes. Category 3 includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich’s ataxia. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located outside of the protein-coding regions of the genes.

Currently, ten neurologic disorders are known to be caused by an increased number of CAG repeats that encode an expanded series of glutamine residues in otherwise unrelated proteins. During protein synthesis, the expanded CAG repeats are translated into a series of uninterrupted glutamine residues forming what is known as a polyglutamine tract. These disorders are characterized by autosomal dominant mode of inheritance (with the exception of spino-bulbar muscular atrophy which shows X-linked inheritance), midlife onset, a progressive course, and a correlation of the number of CAG repeats with the severity of disease and the age at onset. Family studies have also suggested that these diseases are associated with anticipation, the tendency for progressively earlier or more severe expression of the disease in successive generations. Although the causative genes are widely expressed in all of the known polyglutamine diseases, each disease displays an extremely selective pattern of neurodegeneration.

Symptoms

A common symptom of Polyq diseases is characterized by a progressive degeneration of nerve cells usually affecting people later in life. Although these diseases share the same repeated codon (CAG) and some symptoms, the repeats for the different polyglutamine diseases occur on different chromosomes.

Trinucleotide repeat disorders generally show genetic anticipation, where their severity increases with each successive generation that inherits them.

Trinucleotide repeat disorders are the result of extensive duplication of a single codon. In fact, the cause is trinucleotide expansion up to a repeat number above a certain threshold level.

Why three nucleotides?

An interesting question is why three nucleotides are expanded, rather than two or four or some other number. Dinucleotide repeats are a common feature of the genome in general, as are larger repeats (e.g. VNTRs - Variable Number Tandem Repeats). One possibility is that repeats that are not a multiple of three would not be viable. Trinucleotide repeat expansions tend to be near coding regions of the genome, and therefore repeats that are not multiples of three could cause frameshift mutations that would be deadly

The non-Polyq diseases do not share any specific symptoms and are unlike the Polyq diseases. Trinucleotide repeat expansion

Trinucleotide repeat expansion, also known as triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. Robert I. Richards and Grant R. Sutherland called these phenomena, in the framework of dynamical genetics, dynamic mutations.

Triplet expansion is caused by slippage during DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base paring between the parent strand and daughter strand being synthesized. If the loop out structure is formed from sequence on the daughter strand this will result in an increase in the number of repeats. However if the loop out structure is formed on the parent strand a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally the larger the expansion the more likely they are to cause disease or increase the severity of disease. This property results in the characteristic of anticipation seen in trinucleotide repeat disorders. Anticipation describes the tendency of age of onset to decrease and severity of symptoms to increase through successive generations of an affected family due to the expansion of these repeats.

In 2007, a team of scientists led by Ehud Shapiro at the Weizmann Institute of Science in Rehovot, Israel, proposed a new disease model to explain the progression of Huntington's Disease and similar trinucleotide repeat disorders. The team's computer simulations accurately predict age of onset and the way the disease will progress in an individual, based on the number of repeats of a genetic mutation.

Deep brain stimulation & Parkinson's Disease

Deep brain stimulation (DBS) is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain. DBS in select brain regions has provided remarkable therapeutic benefits for otherwise treatment-resistant movement and affective disorders such as chronic pain, Parkinson’s disease, tremor and dystonia [1]. Yet, despite the long history of DBS [2], its underlying principles and mechanisms are still not clear. DBS directly changes brain activity in a controlled manner, its effects are reversible (unlike those of lesioning techniques) and is one of only a few neurosurgical methods that allows blinded studies.

The Food and Drug Administration (FDA) approved DBS as a treatment for essential tremor in 1997, for Parkinson's disease in 2002, and dystonia in 2003 . DBS is also routinely used to treat chronic pain and has been used to treat various affective disorders including clinical depression. While DBS has proven helpful for some patients , there is potential for serious complications and side effects.

The deep brain stimulation system consists of three components: the implanted pulse generator (IPG), the lead, and the extension. The IPG is a battery powered neurostimulator encased in a titanium housing, which sends electrical pulses to the brain to interfere with neural activity at the target site. The lead is a coiled wire insulated in polyurethane with four platinum iridium electrodes and is placed in one of three areas of the brain. The lead is connected to the IPG by the extension, an insulated wire that runs from the head, down the side of the neck, behind the ear to the IPG, which is placed subcutaneously below the clavicle or in some cases, the abdomen. The IPG can be calibrated by a neurologist, nurse or trained technician to optimize symptom suppression and control side effects.

DBS leads are placed in the brain according to the type of symptoms to be addressed. For essential tremor and Parkinsonian tremors, the lead is placed in the thalamus. For dystonia and symptoms associated with Parkinson's disease (rigidity, bradykinesia/akinesia and tremor), the lead may be placed in either the globus pallidus or subthalamic nucleus.

All three components are surgically implanted inside the body. The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa.

Procedure

The procedure begins with preoperative identification of the neurosurgical target with computed tomography (CT), magnetic resonance imaging (MRI) or in earlier times ventriculography.[9]

During surgery, the patient is given local anesthesia and remains awake. A craniotomy is performed and a DBS lead is placed either unilaterally or bilaterally, depending on the patient's symptoms. Microelectrode recording may be used to more precisely locate the desired target within the brain. The IPG and extension are then implanted and connected to each lead.

Depending on the procedures of the medical facility, all components of the DBS system may not be implanted during a single surgery. After surgery is completed, the IPG is calibrated to maximize its effectiveness. Programming can take up to a year to achieve optimal settings.

Due to battery depletion, the IPG must be replaced—usually after three to five years, depending on the settings used. The entire unit is replaced to maintain an uncontaminated field within the body. Nevertheless, this is a minor surgical procedure involving only the shallow subclavicular pocket where the IPG resides. Remaining battery life may be reliably determined with a telemetric programmer so that arrangements can be made to replace the unit prior to battery failure.

Parkinson's disease

Parkinson's disease is a disorder that affects nerve cells, or neurons, in a part of the brain that controls muscle movement. In Parkinson's, neurons that make a chemical called dopamine die or do not work properly. Dopamine normally sends signals that help coordinate your movements. No one knows what damages these cells. Symptoms of Parkinson's disease may include

• Trembling of hands, arms, legs, jaw and face
• Stiffness of the arms, legs and trunk
• Slowness of movement
• Poor balance and coordination

As symptoms get worse, people with the disease may have trouble walking, talking or doing simple tasks. They may also have problems such as depression, sleep problems or trouble chewing, swallowing or speaking.

Parkinson's usually begins around age 60, but it can start earlier. It is more common in men than in women. There is no cure for Parkinson's disease. A variety of medicines sometimes help symptoms dramatically.

Immature Male Sex Cells

Immature sex cells, or spermatogonia, in the testes divide by mitosis and become primary spermatocytes. Each one then divides by meiosis, a cell division peculiar to the reproductive organs, to form two secondary spermatocytes, each containing half the full number of chromosomes. A second meiotic division splits each spermatocyte into two spermatids, which then mature into sperm.

The Neuroscience of Nothing lecture

Richard O. Brown, Staff Neuroscientist at The Exploratorium, talks about the interaction between mind and matter and visual perception. He talks about and illustrates with fascinating visuals three concepts: 1. There is nothing out there and we perceive nothing which he feels comes closest to blackness. 2. There is something out there and we can't perceive it, which comes closest to invisibility. 3. There is nothing out there and we're still experiencing or perceiving something.