Rett Syndrome Model

Rett syndrome (RTT) is a rare random brain & nervous system disorder that only affects girls due to it being an X-linked mutation and although it is genetic, it is not hereditary; it rarely affects boys, when it does the symptoms are more severe and the “babies rarely live past birth” (Bhandari, 2017). The babies usually go through a normal pregnancy and start to show symptoms after the first six months; they become more prominent at “12 and 18 months, and they can be sudden or progress slowly.” (Bhandari, 2017). Symptoms include “slowed growth, trouble with breathing, no language skills, problems with hand movements, muscles, and coordination” (Bhandari, 2017). There is no cure, but the best available treatments include “standard medical care

NMDA Receptor is one of the crucial glutamate receptors present in the nerve cell. It gets activated when glutamate or Glycine binds to it. NMDA receptor is known for its role in synaptic plasticity and membrane function (learning and memory). Its activity is highly dependent on calcium influx. It is a tri heteromeric receptor with three different subunits NR1, NR2 and NR3. Each subunit has several other subunits, each of them having a unique function: NR1 has 8, NR2 has 4 (NR2A, NR2B, NR2C, NR2D), NR3 has 2 (NR3A, NR3B). Out of all the subunits, NR2A and NR2B have been extensively studied. NR2A, also known as GluN2A is believed to be involved in cell death pathways whereas NR2B, also known as GluN2B is believed to be involved in cell survival cascades (Bayer et al., 2006). Interestingly, GluN2B and GluN2A have differing roles, and both can affect either long-term potentiation (LTP) or long-term differentiation (LTD)

This gene contains a CGG trinucleotide repeats in the 5-UTR ranging from 5 to 54 repeats for the normal population. The 55-200 repeats is defined as premutation because this range is not enough to cause mental retardation (5). This range were initially thought to have no effect but it is now known to have the ability to develop a variety of neurological symptoms such as memory loss, executive function deficit, anxiety and depression, anxiety, and other problems with numerical processing (4). Also, female premutation carriers have a possibility to develop primary ovarian insufficiency while elderly preumation carriers have a possibility to develop a progressive neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome (6). Both of these premutation disorders displays an incomplete penetrance. A full mutation is when the trinucleotide repeats expands up to more than 200. This expansion leads to hypermethylation, which then leads to transcriptional silencing of the gene and inhibiting it from producing its protein – FMRP – which plays a role in brain development. Figure 1 portrays a simple summarization of the comparison among the ranges of CGG trinucleotide repeats (in the 5-UTR) of the FMR1

Stevens-Johnson syndrome (erythema multiforme) is an acute inflammatory polymorphic disease affecting skin and mucous membranes. All ages may be affected, and the incidence is equal in both sexes. This is a severe disease with a 5%–15% mortality rate. Ocular involvement, which occurs in as many as half of patients, varies from a mild mucopurulent conjunctivitis to severe perforating corneal ulcers. Blindness occasionally occurs in patients with severe late-phase corneal complications, such as ulceration, vascularization, and perforation.

“From my Friend” is a great story about a young girl and her life from grade school all the way to college. This young girl happens to have a syndrome known as Rett syndrome. I chose this piece over, “An A is an A,” because I found the syndrome more interesting to learn about. While doing some research on Rett syndrome I discovered a lot of things that I never knew at all about the syndrome. Rett syndrome is a rare, but severe brain disorder that affects girls. It is usually discovered in the first two years of life. There is no cure, but early detection and treatment can help the victims and families with coping with this syndrome. The symptoms that come along with Rett syndrome are loss of muscle tone, loss of any purposeful use of hands,

Overstimulation or prolonged activation of excitatory amino acid receptors is called excitotoxicity (64, 65). Overactivation of these excitatory receptors causes opening of post-synaptic ion channels which consequently increases intracellular Ca2+ and this affects Ca2+ regulatory mechanisms. Excitotoxicity seems to be a major contributor to many neurodegenerative disorders such as PD, AD and HD (65, 66). Although the pivotal role of excitotoxicity in neurodegenerative disorders has been proved, the exact mechanisms through which it promotes neurodegeneration still is unclear and more studies are needed (67). The N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionate (AMPA) subtypes are the main determinants,

The prolonged excitatory activation of ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors as well as metabotropic glutamate receptor lead to neuronal cell death (Caccamo et al., 2004, Park et al., 2004). It is commonly accepted that ionotropic glutamate receptors are responsible for the harmful effect of excitotoxicity. The continued binding of excess glutamate to NMDA receptor induces the uncontrolled influx of calcium ions (Ca2+). This massive overload of intracellular Ca2+ leads to activation of calpain and mitochondrial oxidative phosphorylation which ultimately causes apoptosis (Caccamo et al., 2004, Choi, 1992, Lawson and Lowrie, 1998). The AMPA receptor is involved in regulating the influx of sodium ions (Na+). The continued activation of AMPA receptors, due to the unwarranted glutamate level, induces influx of Na+ which consequently leads to osmotic imbalance and swelling of the neurons (Caccamo et al., 2004). The excess swelling of neurons can leads to necrosis (Park et al., 2004). Consider as a therapeutic target, extracellular glutamate concentrations increase to neurotoxic levels within the first three hours after the injury (Liu et al., 1999, Liu and Bilkey, 1999, McAdoo et al., 1999), leaving a small time window for immediate treatment to prevent

Rett syndrome is classified as a serious and lifelong, rare, non-inherited genetic, postnatal, neurological disorder that occurs almost entirely in girls and leads to severe impairments. It affects nearly every aspect of the child’s life including their ability to speak, walk, eat, and even breathe easily. The trademark of Rett syndrome is the constant repetitive hand movements, such as hand washing, hand wringing, hand tapping, hand clapping and hand mouthing.

The journal articles main focus was to “discus the history, incidence, pathophysiology, diagnostic criteria, disease staging, clinical presentation and physical exam findings, and role of the primary care provider (PCP) as they pertain to care for a child with Rett syndrome (RS). (Briggs, A. 2014) The article begins with Briggs brief introduction to Dr. Andrea Rett, who “observed two females in the waiting room exhibiting similar types of behavior and researched whether or not this pathology has been described” (as cited in Rett,1986). Her discovery would later be named after her. Briggs states that RS is found in 1 of every 8,000-10,000 females and a very small percentage of males (as cited in Saunders, Mainassian, Chow, Zhao & Vincent, 2008).

Rett's disorder (also known as Rett's syndrome) is sometimes mistaken for autism when diagnosed in very young children (and is linked to autism, Asperger's disorder, ADHD, and schizophrenia), but it is much less prevalent and has a distinctive onset and course. The condition occurs primarily in girls who, after early normal development, experience slower-than-expected head growth during the first months of life and a loss of purposeful hand motions between ages five and 30 months. Affected children are usually profoundly mentally retarded and exhibit stereotypical repetitive behaviors such as hand wringing or hand washing. Interest in socialization diminishes during the first few years of the disorder but may resume later in life, despite severe

Due to great progress in genetic testing during the last decade, there is an increasing awareness of congenital heart diseases that give a higher risk of sudden cardiac death (SCD). A good example of such heart disease is the congenital Long QT Syndrome (LQTS). This disorder is a leading cause of SCD in the non-adult population.1 Ion channels responsible for the ventricular repolarization are mutated, causing a prolongation of the QT-interval on ECG.2 This aberrant repolarization of the heart gives a risk of the occurrence of ventricular arrhythmias, called torsades de pointes. These arrhythmias are mainly precipitated by emotional or physical stress2 and cause symptoms such as syncope or cardiac arrest.

During learning, many physiological changes can be found to correlate with behaviors. However neural correlates that are not part of the dominant circuit may play a modulatory role in affecting learning rate, or it can have no effect on behavior as they may simply be passive relays from other structures. Critical structures and their projections are major contributors as the absence of any one of them will abolish behavior. Dysregulations that abolish behavioral performance must be either part of or at least influencing critical structures on the circuit. Focusing on circuits that contain only the necessary components is critical to narrow the search for malfunctioning elements that lead to downstream changes and cause behavioral impairment. Results from these aims would refine the current circuit underlying SFRLD. In turn, this information would be vital for electrophysiologically monitor information flow from major contributors throughout the pathway and set the stage for identifying cellular level abnormalities from critical structures. In order to restore the behavioral impairment in safety acquisition and reward regulation, treatment for PTSD-AD will need to rescue dysregulations in the critical structures or pathways.

Rett’s syndrome is a neurodevelopmental disorder characterized by the gradual loss of purposeful hand movements and development of characteristic, stereotypical hand movements (hand– wringing or hand – washing movements); loss of previously acquired speech; psychomotor retardation; ataxia; truncal apraxia; deceleration of head circumference; and autistic symptoms. These characterizations start to appear in a normally developed child after 6 months to 48 months of age170.

Noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP), evoke schizophrenia-like psychosis and cognitive deficits in healthy humans [10, 11] and similar cognitive deficits and hyperlocomotion related to positive symptoms in rodents [12, 13, 14, 15]. Studies on the behavioural deficits induced by PCP have focused on its possible mechanism in disrupting glutamatergic NMDA neurotransmission leading to neuronal degeneration [16]. One study has shown that there was an increased expression of glial fibrillary acidic protein (GFAP) after chronic PCP administration in rats [17]. Therefore, it is important to address the neuroinflammatory changes in the PCP-induced mouse model of schizophrenia.

PKD is the most widely recognized type of paroxysmal dyskinesia characterized by involuntary convulsion and variability in manifestations. The PKD incidence is rare among the population account to be 1/150,000 around the world. Genome wide linkage analysis and fine-mapping have enabled to identify susceptibility genes including PRRT2 in PKD/IC appearance (Szpetowski, Rochette et al. 1997; Lee, Tay et al. 1998). The PRRT2 gene encodes transmembrane protein consisting of N-terminal extracellular domain and C- cytoplasmic domain. Two recent studies have shown that the PRRT2 is profoundly expressed in neural cell development during the early embryonic stages subsequently takes an interest in synaptic function. Therefore, low of expression or