Genetics is the study of genes and tries to explain what they are and how they work. Genes are how living organisms inherit features or traits
from their ancestors; for example, children usually look like their
parents because they have inherited their parents' genes. Genetics tries
to identify which traits are inherited and to explain how these traits
are passed from generation to generation.
Some traits are part of an organism's physical appearance, such as eyecolor or height. Other sorts of traits are not easily seen and include blood types or resistance to diseases.
Some traits are inherited through genes, which is the reason why tall
and thin people tend to have tall and thin children. Other traits come
from interactions between genes and the environment, so a child who
inherited the tendency of being tall will still be short if poorlynourished.
The way our genes and environment interact to produce a trait can be
complicated. For example, the chances of somebody dying of cancer or heart disease seems to depend on both their genes and their lifestyle.
Genes are made from a long molecule called DNA, which is copied and inherited across generations. DNA is made of simple units that line up in a particular order within it, carrying genetic information. The language used by DNA is called genetic code,
which lets organisms read the information in the genes. This
information is the instructions for the construction and operation of a
living organism.
The information within a particular gene is not always exactly
the same between one organism and another, so different copies of a gene
do not always give exactly the same instructions. Each unique form of a
single gene is called an allele.
As an example, one allele for the gene for hair color could instruct
the body to produce much pigment, producing black hair, while a
different allele of the same gene might give garbled instructions that
fail to produce any pigment, giving white hair. Mutations
are random changes in genes and can create new alleles. Mutations can
also produce new traits, such as when mutations to an allele for black
hair produce a new allele for white hair. This appearance of new traits
is important in evolution.
Genes and inheritance
A section of DNA; the sequence of the plate-like units (nucleotides) in the center carries information.
Genes are pieces of DNA that contain information for the synthesis of ribonucleic acids (RNAs) or polypeptides.
Genes are inherited as units, with two parents dividing out copies of
their genes to their offspring. Humans have two copies of each of their
genes, but each egg or sperm cell only gets one of those copies for each gene. An egg and sperm join to form a zygote
with a complete set of genes. The resulting offspring has the same
number of genes as their parents, but for any gene, one of their two
copies comes from their father and one from their mother.
Example of mixing
The effects of mixing depend on the types (the alleles)
of the gene. If the father has two copies of an allele for red hair,
and the mother has two copies for brown hair, all their children get the
two alleles that give different instructions, one for red hair and one
for brown. The hair color of these children depends on how these alleles
work together. If one allele dominates the instructions from another, it is called the dominant allele, and the allele that is overridden is called the recessive allele. In the case of a daughter with alleles for both red and brown hair, brown is dominant and she ends up with brown hair.
A Punnett square showing how two brown haired parents can have red or brown haired children. 'B' is for brown and 'b' is for red.Red hair is a recessive trait.
Although the red color allele is still there in this brown-haired
girl, it doesn't show. This is a difference between what is seen on the
surface (the traits of an organism, called its phenotype) and the genes within the organism (its genotype).
In this example, the allele for brown can be called "B" and the allele
for red "b". (It is normal to write dominant alleles with capital
letters and recessive ones with lower-case letters.) The brown hair
daughter has the "brown hair phenotype" but her genotype is Bb, with one
copy of the B allele, and one of the b allele.
Now imagine that this woman grows up and has children with a
brown-haired man who also has a Bb genotype. Her eggs will be a mixture
of two types, one sort containing the B allele, and one sort the b
allele. Similarly, her partner will produce a mix of two types of sperm
containing one or the other of these two alleles. When the transmitted
genes are joined up in their offspring, these children have a chance of
getting either brown or red hair, since they could get a genotype of BB =
brown hair, Bb = brown hair or bb = red hair. In this generation, there
is, therefore, a chance of the recessive allele showing itself in the
phenotype of the children—some of them may have red hair like their
grandfather.
Many traits are inherited in a more complicated way than the
example above. This can happen when there are several genes involved,
each contributing a small part to the result. Tall people tend to have
tall children because their children get a package of many alleles that
each contribute a bit to how much they grow. However, there are not
clear groups of "short people" and "tall people", like there are groups
of people with brown or red hair. This is because of the large number of
genes involved; this makes the trait very variable and people are of
many different heights. Despite a common misconception, the green/blue eye traits are also inherited in this complex inheritance model.
Inheritance can also be complicated when the trait depends on the
interaction between genetics and environment. For example, malnutrition
does not change traits like eye color, but can stunt growth.
The function of genes is to provide the information needed to make molecules called proteins in cells.
Cells are the smallest independent parts of organisms: the human body
contains about 100 trillion cells, while very small organisms like bacteria
are just a single cell. A cell is like a miniature and very complex
factory that can make all the parts needed to produce a copy of itself,
which happens when cells divide.
There is a simple division of labor in cells—genes give instructions
and proteins carry out these instructions, tasks like building a new
copy of a cell, or repairing the damage.
Each type of protein is a specialist that only does one job, so if a
cell needs to do something new, it must make a new protein to do this
job. Similarly, if a cell needs to do something faster or slower than
before, it makes more or less of the protein responsible. Genes tell
cells what to do by telling them which proteins to make and in what
amounts.
Genes are expressed by being transcribed into RNA, and this RNA then translated into protein.
Proteins are made of a chain of 20 different types of amino acid
molecules. This chain folds up into a compact shape, rather like an
untidy ball of string. The shape of the protein is determined by the
sequence of amino acids along its chain and it is this shape that, in
turn, determines what the protein does.
For example, some proteins have parts of their surface that perfectly
match the shape of another molecule, allowing the protein to bind to
this molecule very tightly. Other proteins are enzymes, which are like tiny machines that alter other molecules.
The information in DNA is held in the sequence of the repeating units along the DNA chain. These units are four types of nucleotides (A, T, G and C) and the sequence of nucleotides stores information in an alphabet called the genetic code. When a gene is read by a cell the DNA sequence is copied into a very similar molecule called RNA (this process is called transcription). Transcription is controlled by other DNA sequences (such as promoters),
which show a cell where genes are, and control how often they are
copied. The RNA copy made from a gene is then fed through a structure
called a ribosome,
which translates the sequence of nucleotides in the RNA into the
correct sequence of amino acids and joins these amino acids together to
make a complete protein chain. The new protein then folds up into its
active form. The process of moving information from the language of RNA
into the language of amino acids is called translation.
If the sequence of the nucleotides in a gene changes, the sequence of
the amino acids in the protein it produces may also change—if part of a
gene is deleted, the protein produced is shorter and may not work
anymore.
This is the reason why different alleles of a gene can have different
effects on an organism. As an example, hair color depends on how much of
a dark substance called melanin
is put into the hair as it grows. If a person has a normal set of the
genes involved in making melanin, they make all the proteins needed and
they grow dark hair. However, if the alleles for a particular protein
have different sequences and produce proteins that can't do their jobs,
no melanin is produced and the person has white skin and hair (albinism).
Genes are copied each time a cell divides into two new cells. The process that copies DNA is called DNA replication.
It is through a similar process that a child inherits genes from its
parents when a copy from the mother is mixed with a copy from the
father.
DNA can be copied very easily and accurately because each piece
of DNA can direct the assembly of a new copy of its information. This is
because DNA is made of two strands that pair together like the two
sides of a zipper. The nucleotides are in the center, like the teeth in
the zipper, and pair up to hold the two strands together. Importantly,
the four different sorts of nucleotides are different shapes, so for the
strands to close up properly, an A nucleotide must go opposite a T nucleotide, and a G opposite a C. This exact pairing is called base pairing.
When DNA is copied, the two strands of the old DNA are pulled
apart by enzymes; then they pair up with new nucleotides and then close.
This produces two new pieces of DNA, each containing one strand from
the old DNA and one newly made strand. This process is not predictably
perfect as proteins attach to a nucleotide while they are building and
cause a change in the sequence of that gene. These changes in the DNA
sequence are called mutations.
Mutations produce new alleles of genes. Sometimes these changes stop
the functioning of that gene or make it serve another advantageous
function, such as the melanin genes discussed above. These mutations and
their effects on the traits of organisms are one of the causes of evolution.
A population of organisms evolves when an inherited trait becomes more common or less common over time.
For instance, all the mice living on an island would be a single
population of mice: some with white fur, some gray. If over generations,
white mice became more frequent and gray mice less frequent, then the
color of the fur in this population of mice would be evolving. In terms of genetics, this is called an increase in allele frequency.
Alleles become more or less common either by chance in a process called genetic drift or by natural selection.
In natural selection, if an allele makes it more likely for an organism
to survive and reproduce, then over time this allele becomes more
common. But if an allele is harmful, natural selection makes it less
common. In the above example, if the island were getting colder each
year and snow became present for much of the time, then the allele for
white fur would favor survival since predators would be less likely to
see them against the snow, and more likely to see the gray mice. Over
time white mice would become more and more frequent, while gray mice
less and less.
Mutations create new alleles. These alleles have new DNA sequences and can produce proteins with new properties.
So if an island was populated entirely by black mice, mutations could
happen creating alleles for white fur. The combination of mutations
creating new alleles at random, and natural selection picking out those
that are useful, causes an adaptation. This is when organisms change in ways that help them to survive and reproduce. Many such changes, studied in evolutionary developmental biology, affect the way the embryo develops into an adult body.
Inherited diseases
Some diseases are hereditary and run in families; others, such as infectious diseases, are caused by the environment. Other diseases come from a combination of genes and the environment. Genetic disorders are diseases that are caused by a single allele of a gene and are inherited in families. These include Huntington's disease, cystic fibrosis or Duchenne muscular dystrophy. Cystic fibrosis, for example, is caused by mutations in a single gene called CFTR and is inherited as a recessive trait.
Other diseases are influenced by genetics, but the genes a person
gets from their parents only change their risk of getting a disease.
Most of these diseases are inherited in a complex way, with either
multiple genes involved, or coming from both genes and the environment.
As an example, the risk of breast cancer
is 50 times higher in the families most at risk, compared to the
families least at risk. This variation is probably due to a large number
of alleles, each changing the risk a little bit. Several of the genes have been identified, such as BRCA1 and BRCA2,
but not all of them. However, although some of the risks are genetic,
the risk of this cancer is also increased by being overweight, heavy
alcohol consumption and not exercising.
A woman's risk of breast cancer, therefore, comes from a large number
of alleles interacting with her environment, so it is very hard to
predict.
Since traits come from the genes in a cell, putting a new piece of DNA into a cell can produce a new trait. This is how genetic engineering works. For example, rice can be given genes from a maize and a soil bacteria so the rice produces beta-carotene, which the body converts to vitamin A. This can help children with Vitamin A deficiency. Another gene being put into some crops comes from the bacterium Bacillus thuringiensis; the gene makes a protein that is an insecticide. The insecticide kills insects that eat the plants but is harmless to people.
In these plants, the new genes are put into the plant before it is
grown, so the genes are in every part of the plant, including its seeds. The plant's offspring inherit the new genes, which has led to concern about the spread of new traits into wild plants.
The kind of technology used in genetic engineering is also being developed to treat people with genetic disorders in an experimental medical technique called gene therapy.
However, here the new, properly working gene is put in targeted cells,
not altering the chance of future children inheriting the disease
causing alleles.
Transcortical sensory aphasia (TSA) is a kind of aphasia that involves damage to specific areas of the temporal lobe of the brain,
resulting in symptoms such as poor auditory comprehension, relatively
intact repetition, and fluent speech with semantic paraphasias present. TSA is a fluent aphasia similar to Wernicke's aphasia (receptive aphasia), with the exception of a strong ability to repeat words and phrases. The person may repeat questions rather than answer them ("echolalia").
In all of these ways, TSA is very similar to a more commonly
known language disorder, receptive aphasia. However, transcortical
sensory aphasia differs from receptive aphasia in that patients still
have intact repetition and exhibit echolalia, or the compulsive repetition of words. Transcortical sensory aphasia cannot be diagnosed through brain imaging techniques such as functional magnetic resonance imaging
(fMRI), as the results are often difficult to interpret. Therefore,
clinicians rely on language assessments and observations to determine if
a patient presents with the characteristics of TSA. Patients diagnosed
with TSA have shown partial recovery of speech and comprehension after
beginning speech therapy. Speech therapy methods for patients with any subtype of aphasia are based on the principles of learning and neuroplasticity.
Clinical research on TSA is limited because it occurs so infrequently
in patients with aphasia that it is very difficult to perform systematic
studies.
TSA should not be confused with transcortical motor aphasia
(TMA), which is characterized by nonfluent speech output, with good
comprehension and repetition. Patients with TMA have impaired writing
skills, difficulty speaking and difficulty maintaining a clear thought
process. Furthermore, TMA is caused by lesions in cortical motor areas of the brain as well as lesions in the anterior portion of the basal ganglia, and can be seen in patients with expressive aphasia.
Affected brain areas
Damage to the inferior left temporal lobe, which is shown in green, is associated with TSA.
Transcortical sensory aphasia is caused by lesions in the inferior left temporal lobe of the brain located near Wernicke's area, and is usually due to minor hemorrhage or contusion in the temporal lobe, or infarcts of the left posterior cerebral artery (PCA). One function of the arcuate fasciculus is the connection between Wernicke’s and Broca’s area.
In TSA Wernicke’s and Broca’s areas are spared, meaning that lesions do
not occur in these regions of the brain. However, since the arcuate
fasciculus, Wernicke's area, and Broca's area are secluded from the rest
of the brain in TSA, patients still have intact repetition (as
information from the arcuate fasciculus is relayed to Broca’s area), but
cannot attach meaning to words, either spoken or heard.
Characteristics
Transcortical sensory aphasia is characterized as a fluent aphasia. Fluency
is determined by direct qualitative observation of the patient’s speech
to determine the length of spoken phrases, and is usually characterized
by a normal or rapid rate; normal phrase length, rhythm, melody, and articulatory agility; and normal or paragrammatic speech. Transcortical sensory aphasia is a disorder in which there is a discrepancy between phonological processing, which remains intact, and lexical-semantic processing, which is impaired.[6]
Therefore, patients can repeat complicated phrases, however they lack
comprehension and propositional speech. This disconnect occurs since
Wernicke’s area is not damaged in patients with TSA, therefore
repetition is spared while comprehension is affected. Patients with
intact repetition can repeat both simple and complex phrases spoken by
others, e.g. when asked if the patient would like to go for a walk, he
or she would respond "go for walk." Although patients can respond
appropriately, due to the extent of their TSA, it is most likely that
they do not comprehend what others ask them. In addition to problems in
comprehension, transcortical sensory aphasia is further characterized
based on deficits in naming and paraphasia.
Verbal comprehension
Impaired
verbal comprehension can be the result a number of causes such as
failure of speech sound discrimination, word recognition, auditory working memory,
or syntactic structure building. When clinically examined, patients
with TSA will exhibit poor comprehension of verbal commands.Based on the extent of the comprehension deficiency, patients will have
difficulty following simple commands, e.g. “close your eyes.” Depending
on the extent of affected brain area, patients are able to follow
simple commands but may not be able to comprehend more difficult,
multistep commands, e.g. “point to the ceiling, then touch your left ear
with your right hand."
Verbal commands as such, that require the patient to cross over the
midline of their body are typically more taxing than commands that
involve solely the right or left side. When increasing the complexity of
verbal commands comprehension is often tested by varying the
grammatical structure of the command to determine whether or not the
patient understands different grammatical variations of the same
sentence. Commands involving the passive voice or possessive, e.g. "If
the snake killed the mouse, which one is still alive," usually result in
comprehension problems in those who can understand simple questions.
Naming
Naming
involves the ability to recall an object. Patients with TSA, as well as
patients with all other aphasia subtypes, exhibit poor naming.
Clinical assessment of naming involves the observer first asking the
patient to name high frequency objects such as clock, door, and chair.
TSA patients who name common objects with ease generally have difficulty
naming both uncommon objects and specific parts of objects such as
lapel, or the dial on a watch.
Paraphasia
Patients
with TSA typically exhibit paraphasia; their speech is fluent but often
error-prone. Their speech is often unintelligible as they tend to use
the wrong words, e.g. tree instead of train or uses words in senseless
and incorrect combinations.
Diagnosis
Clinical assessment
Sensory aphasia is typically diagnosed by non-invasive evaluations. Neurologists, neuropsychologists or speech pathologists will administer oral evaluations to determine the extent of a patient’s comprehension and speech capability. Initial assessment will determine if the cause of linguistic deficiency is aphasia. If the diagnosis is then confirmed, testing will next address the type of aphasia and its severity. The Boston Diagnostic Aphasia Examination
specializes in determining the severity of a sensory aphasia through
the observation of conversational behaviors. Several modalities of
perception and response are observed in conjunction with the subject’s
ability to process sensory information.
The location of the brain lesion and type of the aphasia can then be
inferred from the observed symptoms. The Minnesota Test for Differential
Diagnosis is the most lengthy and thorough assessment of sensory
aphasia. It pinpoints weaknesses in the auditory and visual senses, as
well as reading comprehension. From this differential diagnosis, a
patient’s course of treatment can be determined. After treatment
planning, the Porch Index of Communicative Ability is used to evaluate
prognosis and the degree of recovery.
Imaging
fMRI
is a measure of the increase in blood flow to localized areas of the
brain that coincide with neural activity and is used to image brain
activity related to a specific task or sensory process. It is a commonly
used method for imaging brain activity in aphasia patients.
Sensory aphasia cannot be diagnosed through the use of imaging techniques. Differences in cognition between asymptomatic subjects and affected patients can be observed via functional magnetic resonance imaging (fMRI).
However, these results only reveal temporal differences in cognition
between control and diagnosed subjects. The degree of progression during
therapy can also be surveyed through cognition tests monitored by fMRI.
Many patients’ progress is assessed over time via repeated testing and
corresponding cerebral imaging by fMRI.
Management
Due
to advances in modern neuroimaging, scientists have been able to gain a
better understanding of how language is learned and comprehended.
Based on the new data from the world of neuroscience, improvements can be made in coping with the disorder.
Therapists have been developing multiple methods of improving
speech and comprehension. These techniques utilize three general
principles: maximizing therapy occurrences, ensuring behavioral and
communicative relevance, and allowing patients to focus on the language
tools that are still available in his or her repertoire.
Many of the following treatment techniques are used to improve auditory comprehension in patients with aphasia:
Concise and grammatically simple sentences as opposed to lengthy sentences
Speaking slowly, repeating oneself several times when conversing with aphasic patients
Using gestures
A relatively new method of language therapy involves coincidence
learning. Coincidence learning focuses on the simultaneous learning of
two or more events and stipulates that these events are wired together
in the brain, strengthening the learning process.
Therapists use coincidence learning to find and improve language
correlations or coincidences that have been either damaged or deleted by
severe cases of aphasia, such as transcortical sensory aphasia.
This technique is important in brain function and recovery, as it
strengthens associated brain areas that remain unaffected after brain
damage. It can be achieved with intensive therapy hours in order to
maximize time where correlation is emphasized.
Through careful analysis of neuroimaging studies, a correlation
has been developed with motor function and the understanding of action
verbs.
For example, leg and motor areas were seen to be activated words such
as "kick", leading scientists to understand the connection between motor
and language processes in the brain. This is yet another example of
using relationships that are related in the brain for the purpose of
rehabilitating speech and comprehension.
Of huge importance in aphasia therapy is the need to start practicing as soon as possible.[citation needed] Greater recovery occurs when a patient attempts to improve their comprehension and speaking soon after aphasia occurs. There is an inverse relationship between the length of time spent not practicing and level of recovery.
The patient should be pushed to their limits of verbal communication
in order for them to practice and build upon their remaining language
skills.
One effective therapy technique is using what are known as language games in order to encourage verbal communication.
One famous example is known as "Builder's Game", where a 'builder' and
a 'helper' must communicate in order to effectively work on a project.
The helper must hand the builder the tools he or she may need, which
requires effective oral communication. The builder succeeds by
requesting tools from the assistant by usually using single word
utterances, such as 'hammer' or 'nail'. Thus, when the helper hands the
tool to the builder, the game incorporates action with language, a key
therapy technique. The assistant would then hand the builder the
requested tool. Success of the game occurs when the builder's requests
are specific to ensure successful building.
Ultimately, regardless of therapy plan or method, improvement in
speech does not appear overnight; it requires a significant time
investment by the patient as well as a dedicated speech therapist
seeking to ensure that the patient is focusing on the correct speech
tasks outside of the clinic.Furthermore, the patient must collaborate with friends and family
members during their free time in order to maximize the efficacy of the
treatment.
Regions of the left hemisphere that can give rise to aphasia when damaged.
In neuropathy, primary progressive aphasia (PPA) is a type of neurological syndrome in which language capabilities slowly and progressively become impaired. As with other types of aphasia, the symptoms that accompany PPA depend on what parts of the brain's left hemisphere are significantly damaged.
However, unlike most other aphasias, PPA results from continuous
deterioration in brain tissue, which leads to early symptoms being far
less detrimental than later symptoms.
Those with PPA slowly lose the ability to speak, write, read, and
generally comprehend language. Eventually, almost every patient becomes
mute and completely loses the ability to understand both written and spoken language. Although it was first described as solely impairment of language capabilities while other mental functions remain intact, it is now recognized that many, if not most of those with PPA experience impairment of memory, short-term memory formation and loss of executive functions.
It was first described as a distinct syndrome by M. Marsel Mesulam in 1982. PPAs have a clinical and pathological overlap with the frontotemporal lobar degeneration spectrum of disorders and Alzheimer's disease. Unlike those affected by Alzheimer's, people with PPA are generally able to maintain self-sufficiency.
Causes
Currently, the specific causes for PPA and other degenerative brain disease similar to PPA are viewed as idiopathic
(unknown). Autopsies have revealed a variety of brain abnormalities in
people who had PPA. These autopsies, as well as imaging techniques such
as CT scans, MRI, EEG, single photon emission computed tomography, and positron emission tomography, have generally revealed abnormalities to be almost exclusively in the left hemisphere.
Risk factors
There
have been no large epidemiological studies on the incidence and
prevalence of the PPA variants. Though it most likely has been
underestimated, onset of PPA has been found to occur in the sixth or
seventh decade.
There are no known environmental risk factors for the progressive
aphasias. However, one observational, retrospective study suggested
that vasectomy could be a risk factor for PPA in men. These results have yet to be replicated or demonstrated by prospective studies.
PPA is not considered a hereditary disease. However, relatives of a person with any form of frontotemporal lobar degeneration (FTLD), including PPA, are at slightly greater risk of developing PPA or another form of the condition.
In a quarter of patients diagnosed with PPA, there is a family history
of PPA or one of the other disorders in the FTLD spectrum of disorders.
It has been found that genetic predisposition varies among the different
PPA variants, with progressive nonfluent aphasia (PNFA) being more commonly familial in nature than semantic dementia (SD).
The most convincing genetic basis of PPA has been found to be a mutation in the GRN gene. Most patients with observed GRN mutations present clinical features of PNFA, but the phenotype can be atypical.
Diagnosis
Diagnostic criteria
The following diagnosis criteria were defined by Mesulam:
As opposed to having followed trauma to the brain, a patient
must show an insidious onset and a gradual progression of aphasia,
defined as a disorder of sentence and/or word usage, affecting the
production and comprehension of speech.
The disorder in question must be the only determinant on functional impairment in the activities of the patient's daily living.
On the basis of diagnostic procedures, the disorder in question must be unequivocally attributed to a neurodegenerative process.
Whether or not PPA and other aphasias are the only source of
cognitive impairment in a patient is often difficult to assess because:
1) as with other neurologically degenerative diseases, such as Alzheimer's disease,
there are currently no reliable non-invasive diagnostic tests for
aphasias, and thus neuropsychological assessments are the only tool
physicians have for diagnosing patients; and 2) aphasias often affect
other, non-language portions of these neuropsychological tests, such as
those specific for memory.
Classification
In
2011, the classification of primary progressive aphasia was updated to
include three clinical variants. Patients must first be diagnosed with
PPA, and then divided into variants based on speech production features,
repetition, single- word and syntax comprehension, confrontation
naming, semantic knowledge, and reading/spelling.
In the classical Mesulam criteria for primary progressive aphasia,
there are two variants: a non-fluent type PNFA and a fluent type SD.
A third variant of primary progressive aphasia, LPA was then added,
and is an atypical form of Alzheimer's disease. For PNFA, the core
criteria for diagnosis include agrammatism and slow and labored speech.
Inconsistent speech sound errors are also very common, including
distortions, deletions, and insertions. In terms of comprehension, there
are deficits in syntax and sentence comprehension due to grammatical
complexity, but single- word and object comprehension is relatively
maintained.
The second variant, SD, presents with deficits in single-word and
object comprehension. Naming impairments can be severe, specially for
low-frequency objects, and can eventually lead to a more widespread
semantic memory deficiency over time. The ability to read and write can
also be impaired if there are irregularities between pronunciation and
spelling. However, repetition and motor speech is relatively preserved.
The logopenic variant involves impairments in word retrieval, sentence repetition, and phonological paraphasias, comparable to conduction aphasia.
Compared to the semantic variant, single word comprehension and naming
is spared, however, sentence comprehension presents difficulty because
of length and grammatical complexity. Speech will include incomplete
words, hesitations preceding content words, and repetition.
However, these PPA subtypes differ from similar aphasias, as these
subtypes do not occur acutely following trauma to the brain, such as
following a stroke, due to differing functional and structural
neuroanatomical patterns of involvement and the progressive nature of
the disease.
Unlike those affected by Alzheimer's, people with PPA are
generally able to maintain the ability to care for themselves, remain
employed, and pursue interests and hobbies. Moreover, in diseases such
as Alzheimer's disease, Pick's disease, and Creutzfeldt–Jakob disease,
progressive deterioration of comprehension and production of language
is just one of the many possible types of mental deterioration, such as
the progressive decline of memory, motor skills, reasoning, awareness,
and visuospatial skills.
Treatment
Due
to the progressive, continuous nature of the disease, improvement over
time seldom occurs in patients with PPA as it often does in patients
with aphasias caused by trauma to the brain.
In terms of medical approaches to treating PPA, there are
currently no drugs specifically used for patients with PPA, nor are
there any specifically designed interventions for PPA. A large reason
for this is the limited research that has been done on this disease.
However, in some cases, patients with PPA are prescribed the same drugs
Alzheimer's patients are normally prescribed.
The primary approach to treating PPA has been with behavioral
treatment, with the hope that these methods can provide new ways for
patients to communicate in order to compensate for their deteriorated
abilities.
Speech therapy can assist an individual with strategies to overcome
difficulties. There are three very broad categories of therapy
interventions for aphasia: restorative therapy approaches, compensatory
therapy approaches, and social therapy approaches. Examples include word retrieval therapy and script training, communication partner training and group therapy.
Rapid and sustained improvement in speech and dementia in a
patient with primary progressive aphasia utilizing off-label perispinal etanercept, an anti-TNF treatment strategy also used for Alzheimer's, has been reported. A video depicting the patient's improvement was published in conjunction with the print article. These findings have not been independently replicated and remain controversial.
History
M. Marsel Mesulam coined the term primary progressive aphasia.
Motor neuron diseases affect both children and adults. While each motor neuron disease affects patients differently, they all cause movement-related symptoms, mainly muscle weakness. Most of these diseases seem to occur randomly without known causes, but some forms are inherited. Studies into these inherited forms have led to discoveries of various genes (e.g. SOD1) that are thought to be important in understanding how the disease occurs.
Symptoms of motor neuron diseases can be first seen at birth or
can come on slowly later in life. Most of these diseases worsen over
time; while some, such as ALS, shorten one's life expectancy, others do
not. Currently, there are no approved treatments for the majority of motor neuron disorders, and care is mostly symptomatic.
Signs and symptoms
A man with amyotrophic lateral sclerosis
(ALS). (A) He needs assistance to stand. (B) Advanced atrophy of the
tongue. (C) There is upper limb and truncal muscle atrophy with a
positive Babinski sign. (D) Advanced thenar muscle atrophy.
Signs and symptoms depend on the specific disease, but motor neuron
diseases typically manifest as a group of movement-related symptoms.
They come on slowly, and worsen over the course of more than three
months. Various patterns of muscle weakness are seen, and muscle cramps
and spasms may occur. One can have difficulty breathing with climbing
stairs (exertion), difficulty breathing when lying down (orthopnea), or even respiratory failure if breathing muscles become involved. Bulbar symptoms, including difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and excessive saliva production (sialorrhea), can also occur. Sensation, or the ability to feel, is typically not affected. Emotional disturbance (e.g. pseudobulbar affect) and cognitive and behavioural changes (e.g. problems in word fluency, decision-making, and memory) are also seen.
There can be lower motor neuron findings (e.g. muscle wasting, muscle
twitching), upper motor neuron findings (e.g. brisk reflexes, Babinski reflex, Hoffman's reflex, increased muscle tone), or both.
Motor neuron diseases are seen both in children and adults.
Those that affect children tend to be inherited or familial, and their
symptoms are either present at birth or appear before learning to walk.
Those that affect adults tend to appear after age 40. The clinical course depends on the specific disease, but most progress or worsen over the course of months. Some are fatal (e.g. ALS), while others are not (e.g. PLS).
Patterns of weakness
Various patterns of muscle weakness occur in different motor neuron diseases.
Weakness can be symmetric or asymmetric, and it can occur in body parts
that are distal, proximal, or both. According to Statland et al., there
are three main weakness patterns that are seen in motor neuron
diseases, which are:
Asymmetric distal weakness without sensory loss (e.g. ALS, PLS, PMA, MMA)
Symmetric weakness without sensory loss (e.g. PMA, PLS)
Motor neuron diseases are on a spectrum in terms of upper and lower motor neuron involvement.
Some have just lower or upper motor neuron findings, while others have a
mix of both. Lower motor neuron (LMN) findings include muscle atrophy and fasciculations, and upper motor neuron (UMN) findings include hyperreflexia, spasticity, muscle spasm, and abnormal reflexes.
Pure upper motor neuron diseases, or those with just UMN findings, include PLS.
Pure lower motor neuron diseases, or those with just LMN findings, include PMA.
Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS.
Causes
Most cases are sporadic and their causes are usually not known. It is thought that environmental, toxic, viral, or genetic factors may be involved.
DNA damage
TAR DNA-binding protein 43 (TDP-43), is a critical component of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNAdouble-strand breaks in pluripotent stem cell-derived motor neurons. TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the XRCC4-DNA ligase
protein complex that then acts to repair double-strand breaks. About
95% of ALS patients have abnormalities in the nucleus-cytoplasmic
localization in spinal motor neurons of TDP43. In TDP-43 depleted human
neural stem cell-derived motor neurons, as well as in sporadic ALS patients' spinal cord specimens there is significant double-strand break accumulation and reduced levels of NHEJ.
Associated risk factors
In adults, men are more commonly affected than women.
Diagnosis
Differential
diagnosis can be challenging due to the number of overlapping symptoms,
shared between several motor neuron diseases.
Frequently, the diagnosis is based on clinical findings (i.e. LMN vs.
UMN signs and symptoms, patterns of weakness), family history of MND,
and a variation of tests, many of which are used to rule out disease
mimics, which can manifest with identical symptoms.
Classification
Corticospinal tract.
Upper motor neurons originating in the primary motor cortex synapse to
either lower motor neurons in the anterior horn of the central gray
matter of the spinal cord (insert) or brainstem motor neurons (not
shown). Motor neuron disease can affect either upper motor neurons
(UMNs) or lower motor neurons (LMNs).
Motor neuron disease describes a collection of clinical disorders,
characterized by progressive muscle weakness and the degeneration of the
motor neuron on electrophysiological testing.
The term "motor neuron disease" has varying meanings in different
countries. Similarly, the literature inconsistently classifies which
degenerative motor neuron disorders can be included under the umbrella
term "motor neuron disease". The four main types of MND are marked (*)
in the table below.
All types of MND can be differentiated by two defining characteristics:
Sporadic or acquired MNDs occur in patients with no family history of
degenerative motor neuron disease. Inherited or genetic MNDs adhere to
one of the following inheritance patterns: autosomal dominant, autosomal recessive, or X-linked.
Some disorders, like ALS, can occur sporadically (85%) or can have a
genetic cause (15%) with the same clinical symptoms and progression of
disease.
UMNs are motor neurons that project from the cortex down to the brainstem or spinal cord. LMNs originate in the anterior horns of the spinal cord and synapse on peripheral muscles.
Both motor neurons are necessary for the strong contraction of a
muscle, but damage to an UMN can be distinguished from damage to a LMN
by physical exam.
Cerebrospinal fluid (CSF) tests: Analysis of the fluid from around the brain and spinal cord could reveal signs of an infection or inflammation.
Magnetic resonance imaging
(MRI): An MRI of the brain and spinal cord is recommended in patients
with UMN signs and symptoms to explore other causes, such as a tumor,
inflammation, or lack of blood supply (stroke).
Electromyogram (EMG) & nerve conduction study
(NCS): The EMG, which evaluates muscle function, and NCS, which
evaluates nerve function, are performed together in patients with LMN
signs.
For patients with MND affecting the LMNs, the EMG will show evidence
of: (1) acute denervation, which is ongoing as motor neurons
degenerate, and (2) chronic denervation and reinnervation of the muscle, as the remaining motor neurons attempt to fill in for lost motor neurons.
By contrast, the NCS in these patients is usually normal. It can show a low compound muscle action potential (CMAP), which results from the loss of motor neurons, but the sensory neurons should remain unaffected.
Tissue biopsy:
Taking a small sample of a muscle or nerve may be necessary if the
EMG/NCS is not specific enough to rule out other causes of progressive
muscle weakness, but it is rarely used.
Treatment
There are no known curative treatments for the majority of motor neuron disorders.
Physiotherapy helps maintain movement and function when someone is affected by
disability, injury or illness. This is achieved through movement and exercise, manual
therapy, education and advice. Although physiotherapy can’t reverse the effects of
MND, or Kennedy’s disease, it can help maintain range of movement and comfort
for as long as possible.
Prognosis
The table below lists life expectancy for patients who are diagnosed with MND.
Type
Median survival time from start of symptoms
Amyotrophic lateral sclerosis (ALS)
2–5 years
Primary lateral sclerosis (PLS)
8–10 years
Progressive muscular atrophy (PMA)
2–4 years
Progressive bulbar palsy (PBP)
6 months – 3 years
Pseudobulbar palsy
No change in survival
Terminology
In the United States and Canada, the term motor neuron disease usually refers to the group of disorders while amyotrophic lateral sclerosis is frequently called Lou Gehrig's disease. In the United Kingdom and Australia, the term motor neuron(e) disease is used for amyotrophic lateral sclerosis, although is not uncommon to refer to the entire group.
While MND refers to a specific subset of similar diseases, there are numerous other diseases of motor neurons that are referred to collectively as "motor neuron disorders", for instance the diseases belonging to the spinal muscular atrophies group. However, they are not classified as "motor neuron diseases" by the 11th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-11), which is the definition followed in this article.
Para-sagittal MRI of the head in a patient with benign familial macrocephaly
Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system.
Their underlying causes are extremely variable and complicated by
various genetic and/or environmental factors. These diseases cause
progressive deterioration of the neuron resulting in decreased signal transduction
and in some cases even neuronal death. Peripheral nervous system
diseases may be further categorized by the type of nerve cell (motor, sensory,
or both) affected by the disorder. Effective treatment of these
diseases is often prevented by lack of understanding of the underlying
molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.
Neurodengenerative diseases of motor neurons
can cause degeneration of motor neurons involved in voluntary muscle
control such as muscle contraction and relaxation. This article will
cover the epigenetics and treatment of amyotrophic lateral sclerosis
(ALS) and spinal muscular atrophy (SMA). See the Motor Neuron Fact Sheet for details regarding other motor neuron diseases. Neurodegenerative diseases of the central nervous system can affect the brain and spinal cord. This article will cover the epigenetics and treatment of Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease
(PD). These diseases are characterized by chronic and progressive
neuronal dysfunction, sometimes leading to behavioral abnormalities (as
with PD), and, ultimately, neuronal death, resulting in dementia.
Neurodegenerative diseases of sensory neurons can cause
degeneration of sensory neurons involved in transmitting sensory
information such as hearing and seeing. The main group of sensory neuron diseases are hereditary sensory and autonomic neuropathies (HSAN) such as HSAN I, HSAN II, and Charcot-Marie-Tooth Type 2B (CMT2B).
Though some sensory neuron diseases are recognized as
neurodegenerative, epigenetic factors have not yet been clarified in the
molecular pathology.
Epigenetics and epigenetic drugs
The nucleus of a human cell showing the location of euchromatin
The term epigenetics refers to three levels of gene regulation: (1) DNA methylation, (2) histone modifications, and (3) non-coding RNA (ncRNA) function. Briefly, histone-mediated transcriptional control occurs by the wrapping of DNA around a histone core. This DNA-histone structure is called a nucleosome;
the more tightly the DNA is bound by the nucleosome, and the more
tightly a string of nucleosomes are compressed among each other, the
greater the repressive effect on transcription
of genes in the DNA sequences near or wrapped around the histones, and
vice versa (i.e. looser DNA binding and relaxed compaction leads to a
comparatively derepressed state, resulting in facultative heterochromatin or, even further derepressed, euchromatin).
At its most repressive state, involving many folds into itself and
other scaffolding proteins, DNA-histone structures form constitutive
heterochromatin. This chromatin structure is mediated by these three
levels of gene regulation. The most relevant epigenetic modifications to
treatment of neurodegenerative diseases are DNA methylation and histone
protein modifications via methylation or acetylation.
In mammals, methylation occurs on DNA and histone proteins. DNA methylation occurs on the cytosine of CpG dinucleotides
in the genomic sequence, and protein methylation occurs on the amino
termini of the core histone proteins – most commonly on lysine residues.
CpG refers to a dinucleotide composed of a cytosine deoxynucleotide
immediately adjacent to a guanine deoxynucleotide. A cluster of CpG
dinucleotides clustered together is called a CpG island,
and in mammals, these CpG islands are one of the major classes of gene
promoters, onto or around which transcription factors may bind and
transcription can begin. Methylation of CpG dinucleotides and/or
islands within gene promoters is associated with transcriptional
repression via interference of transcription factor binding and recruitment of transcriptional repressors with methyl binding domains. Methylation of intragenic regions is associated with increased transcription. The group of enzymes responsible for addition of methyl groups to DNA are called DNA methyltransferases (DNMTs). The enzyme responsible for removal of methyl group are called DNA demethylases. The effects of histone methylation
are residue dependent (e.g. which amino acid on which histone tail is
methylated) therefore the resulting transcriptional activity and chromatin regulation can vary. The enzymes responsible for the addition of methyl groups to histones are called histone methyltransferases (HMTs). The enzymes responsible for the removal of methyl groups from histone are histone demethylases.
Acetylation
occurs on the lysine residues found at the amino N-terminal of histone
tails. Histone acetylation is most commonly associated with relaxed
chromatin, transcriptional derepression, and thus actively transcribed
genes. Histone acetyltransferases (HATs) are enzymes responsible for the addition of acetyl groups, and histone deacetylases
(HDACs) are enzymes responsible for the removal of acetyl groups.
Therefore, the addition or removal of an acetyl group to a histone can
alter the expression of nearby genes. The majority of drugs being
investigated are inhibitors of proteins that remove acetyl from histones
or histone deacetylases (HDACs).
Briefly, ncRNAs are involved in signaling cascades with epigenetic marking enzymes such as HMTs, and/or with RNA interference(RNAi) machinery. Frequently these signaling cascades result in epigenetic repression (for one example, see X-chromosome inactivation), though there are some cases in which the opposite is true. For example, BACE1-AS ncRNA expression is upregulated in Alzheimer's disease patients and results in increased stability of BACE1 – the mRNA precursor to an enzyme involved in Alzheimer's disease.
Epigenetic drugs target the proteins responsible for modifications on
DNA or histone. Current epigenetic drugs include but are not limited
to: HDAC inhibitors (HDACi), HAT modulators, DNA methyltransferase inhibitors, and histone demethylase inhibitors.
The majority of epigenetic drugs tested for use against
neurodegenerative diseases are HDAC inhibitors; however, some DNMT
inhibitors have been tested as well. While the majority of epigenetic
drug treatments have been conducted in mouse models, some experiments
have been performed on human cells as well as in human drug trials (see
table below). There are inherent risks in using epigenetic drugs as
therapies for neurodegenerative disorders as some epigenetic drugs (e.g.
HDACis such as sodium butyrate)
are non-specific in their targets, which leaves potential for
off-target epigenetic marks causing unwanted epigenetic modifications.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's
disease, is a motor neuron disease that involves neurogeneration. All
skeletal muscles in the body are controlled by motor neurons that
communicate signals from the brain to the muscle through a neuromuscular junction.
When the motor neurons degenerate, the muscles no longer receive
signals from the brain and begin to waste away. ALS is characterized by
stiff muscles, muscle twitching, and progressive muscle weakness from
muscle wasting. The parts of the body affected by early symptoms of ALS
depend on which motor neurons in the body are damaged first, usually the
limbs. As the disease progresses most patients are unable to walk or
use their arms and eventually develop difficulty speaking, swallowing
and breathing. Most patients retain cognitive function and sensory
neurons are generally unaffected. Patients are often diagnosed after the
age of 40 and the median survival time from onset to death is around
3–4 years. In the final stages, patients can lose voluntary control of
eye muscles and often die of respiratory failure or pneumonia
as a result of degeneration of the motor neurons and muscles required
for breathing. Currently there is no cure for ALS, only treatments that
may prolong life.
Genetics and underlying causes
To
date, multiple genes and proteins have been implicated in ALS. One of
the common themes between many of these genes and their causative
mutations is the presence of protein aggregates in motor neurons. Other common molecular features in ALS patients are altered RNA metabolism and general histone hypoacetylation.
Chromosome 21
SOD1
The SOD1 gene on chromosome 21 that codes for the superoxide dismutase protein is associated with 2% of cases and is believed to be transmitted in an autosomal dominant manner.
Many different mutations in SOD1 have been documented in ALS patients
with varying degrees of progressiveness. SOD1 protein is responsible for
destroying naturally occurring, but harmful superoxide radicals produced by the mitochondria.
Most of the SOD1 mutations associated with ALS are gain-of-function
mutations in which the protein retains its enzymatic activity, but
aggregate in motor neurons causing toxicity. Normal SOD protein is also implicated in other cases of ALS due to potentially cellular stress. An ALS mouse model through gain-of-function mutations in SOD1 has been developed.
c9orf72
A gene called c9orf72 was found to have a hexanucleotide repeat in the non-coding region of the gene in association with ALS and ALS-FTD.
These hexanucleotide repeats may be present in up 40% of familial ALS
cases and 10% of sporadic cases. C9orf72 likely functions as a guanine exchange factor for a small GTPase, but this is likely not related to the underlying cause of ALS. The hexanucleotide repeats are likely causing cellular toxicity after they are spliced out of the c9orf72 mRNA transcripts and accumulate in the nuclei of affected cells.
UBQLN2
The UBQLN2 gene encodes the protein ubiquilin 2 which is responsible for controlling the degradation of ubiquitinated
proteins in the cell. Mutations in UBQLN2 interfere with protein
degradation resulting in neurodegeneration through abnormal protein
aggregation. This form of ALS is X chromosome-linked and dominantly inherited and can also be associated with dementia.
Epigenetic treatment with HDAC inhibitors
ALS patients and mouse models show general histone hypoacetylation that can ultimately trigger apoptosis of cells.
In experiments with mice, HDAC inhibitors counteract this
hypoacetylation, reactivate aberrantly down-regulated genes, and
counteract apoptosis initiation. Furthermore, HDAC inhibitors are known to prevent SOD1 protein aggregates in vitro.
Sodium phenylbutyrate
Sodium phenylbutyrate
treatment in a SOD1 mouse model of ALS showed improved motor
performance and coordination, decreased neural atrophy and neural loss,
and increased weight gain. Release of pro-apoptotic factors was also abrogated as well as a general increase in histone acetylation.
A human trial using phenylbuturate in ALS patients showed some increase
in histone acetylation, but the study did not report whether ALS
symptoms improved with treatment.
Valproic scid
Valproic acid
in mice studies restored histone acetylation levels, increased levels
of pro-survival factors, and mice showed improved motor performance. However, while the drug delayed the onset of ALS, it did not increase lifespan or prevent denervation. Human trials of valproic acid in ALS patients did not improve survival or slow progression.
Trichostatin A
Trichostatin A
trials in mouse ALS models restored histone acetylation in spinal
neurons, decreased axon demyelination, and increased survival of mice.
Alpha motor neurons are derived from the basal plate (basal lamina).
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the SMN1 gene.
Symptoms vary greatly with each subset of SMA and the stage of the
disease. General symptoms include overall muscle weakness and poor
muscle tone including extremities and respiratory muscles leading to
difficulty walking, breathing, and feeding. Depending on the type of
SMA, the disease can present itself from infancy through adulthood. As
SMN protein generally promotes the survival of motor neurons, mutations
in SMN1 results in slow degeneration motor neurons leading to
progressive system-wide muscle wasting. Specifically, over time,
decreased levels of SMN protein results in gradual death of the alpha motor neurons in the anterior horn of the spinal cord
and brain. Muscles depend on connections to motor neurons and the
central nervous system to stimulate muscle maintenance and therefore
degeneration of motor neurons and subsequent denervation of muscles lead
to loss of muscle control and muscle atrophy. The muscles of the lower
extremities are often affected first followed by upper extremities and
sometimes the muscles of respiration and mastication. In general,
proximal muscle is always affected more than distal muscle.
Genetic cause
Spinal
muscular atrophy is linked to genetic mutations in the SMN1 (Survival
of Motor Neuron 1) gene. The SMN protein is widely expressed in neurons
and serves many functions within neurons including spliceosome construction, mRNA axon transport, neurite outgrowth during development, and neuromuscular junction formation. The causal function loss in SMA is currently unknown.
SMN1 is located in a telomeric region of human chromosome 5 and also contains SMN2 in a centromeric region. SMN1 and SMN2 are nearly identical except for a single nucleotide change
in SMN2 resulting in an alternative splicing site where intron 6 meets
exon 8. This single base pair change leads to only 10–20% of SMN2
transcripts resulting in fully functional SMN protein and 80–90% of
transcripts leading to a truncated protein that is rapidly degraded.
Most SMA patients have 2 or more copies of the SMN2 gene with more
copies resulting in a decrease in disease severity. Most SMA patients have either point mutations
or a deletion in exon 7 often leading to a protein product similar to
the truncated and degraded version of the SMN2 protein. In SMA patients
this small amount of functional SMN2 protein product allows for some
neurons to survive.
Epigenetic treatment through SMN2 gene activation
Although
SMA is not caused by an epigenetic mechanism, therapeutic drugs that
target epigenetic marks may provide SMA patients with some relief,
halting or even reversing the progression of the disease. As SMA
patients with higher copy numbers of the SMN2 gene have less severe
symptoms, researchers predicted that epigenetic drugs that increased
SMN2 mRNA expression would increase the amount of functional SMN protein
in neurons leading to a reduction in SMA symptoms. Histone deacetylase
(HDAC) inhibitors are the main compounds that have been tested to
increase SMN2 mRNA expression. Inhibiting HDACs would allow for
hyperacetylation of the SMN2 gene loci theoretically resulting in an
increase in SMN2 expression.
Many of these HDAC inhibitors (HDACi) are first tested in mouse models
of SMA created through a variety of mutations in the mouse SMN1 gene. If
the mice show improvement and the drug does not cause very many side
effects or toxicity, the drug may be used in human clinical trials.
Human trials with all of the below HDAC inhibitors are extremely
variable and often impacted by the patient's exact SMA subtype.
Quisinostat (JNJ-26481585)
Quisinostat
is effective at low doses resulting in some improved neuromuscular
function in mouse model of SMA, but survival was not increased. No human trials have been conducted.
Sodium butyrate
Sodium butyrate
was the first HDAC inhibitor tested in SMA mouse models. It prolonged
SMA mouse life span by 35% and showed increased levels of SMN protein in
spinal cord tissue. However, sodium butyrate has not been used in human trials to date.
Sodium phenylbutyrate
Sodium phenylbutyrate increases SMN2 full length mRNA transcripts in cell culture but drug application must be repeated in order to maintain results. Human trials show mixed results with one study showing increased SMA transcript levels in blood and improved motor function, but a larger trial showing no effects on disease progression or motor function.
Valproic acid
Valproic acid added to cells from SMA patients increased SMN2 mRNA and protein levels and that the drug directly activates SMN2 promoter.
In a SMA mouse model, valproic acid was added to the drinking water
and restored motor neuron density and increased motor neuron number over
a period of 8 months.
Human trials are extremely variable showing increased SMN2 levels and
increased muscle strength in some trials and absolutely no effects in
other trials.
M344
M344 is a benzamide that shows promising results in fibroblast cell
culture and increases level of splicing factors known to modulate SMN2
transcripts, but the drug was determined toxic and research has not
progressed to in vivo testing.
Trichostatin A
Trichostatin A
treatment shows promising results in mice. In one study, Trichostatin A
combined with extra nourishment in early onset mouse SMA models
resulted in improved motor function and survival and delays progressive
denervation of muscles. A second study in a SMA mouse model showed increased SMN2 transcripts with daily injections. No human trials have been conducted.
Vorinostat (SAHA)
Vorinostat is a second generation inhibitor that is fairly non-toxic and found to be effective in cell culture at low concentrations and increases histone acetylation at the SMN2 promoter.
In a SMA mouse model, SAHA treatment resulted in weight gain, increased
SMN2 transcripts levels in muscles and spinal cord, and motor neuron
loss and denervation were halted. No human trials have been conducted.
Myasthenia gravis
Myasthenia
gravis is an autoimmune disease affecting synapses at the neuromuscular
junction, whereby antibodies produced primarily in the thymus gland by
B-cells associate with postsynaptic nicotinic acetylcholine receptors
(AChR), along with other NMJ post-synaptic receptors (MuSK-R and
low-density lipoprotein receptor). These antibodies include
acetylcholine receptor antibodies, MuSK antibodies, and low-density
lipoprotein receptor related protein 4 antibodies (LRP4-Ab).
Antibody binding to their respective receptors causes the destruction
of those receptors, leading to a reduction in the number of postsynaptic
acetylcholinergic receptors and a reduction in overall acetylcholine
transport. Disease symptoms include muscular weakness that fatigues due
to overuse, but improves with rest. Hallmark symptoms due to muscular
weakness include ptosis, double vision, dysphagia, as well as aberrant
speech.
Myasthenia gravis is a relatively rare disease, occurring in
about 3–30 individuals per 100,000, but has been rising over the past
couple decades. There exists two variations of myasthenia gravis with
respect to age and gender demographics: early-onset myasthenia gravis,
which has a higher incidence among females, and late-onset myasthenia
gravis, which has a higher incidence among males.
Epigenetic factors
There
has been extensive research on the genetic basis of myasthenia gravis,
however evidence does not suggest that it is an inherited disease. There has also been extensive research on the epigenetic contribution to myasthenia gravis.
DNA methylation and noncoding RNA, such as miRNA (micro RNA) and long
noncoding RNA (lncRNA), are epigenetic factors that play a significant
role in increasing the likelihood of acquiring myasthenia gravis. In
addition, the thymus is a key organ in the immune response that is often
negatively affected by abnormal miRNA expression and DNA methylation.
miRNA
Micro
RNA (miRNA) are single-stranded non-coding RNAs that bind their target
mRNAs. From there, they can regulate gene expression by inhibiting
translation or degrading the mRNA strand, oftentimes in B-cells and
T-cells of the immunological process. With respect to myasthenia gravis,
abnormal miRNA function is associated with immunoregulatory
pathogenesis, and each miRNA has its own unique downstream effects.
The thymus is an important endocrine organ implicated in
myasthenia gravis. In normal, healthy development, the thymus shrinks in
size over time. In those with thymus-associated myasthenia gravis there
are correlations with thymomas in late-onset myasthenia gravis as well
as thymic hyperplasia with germinal centers in early-onset myasthenia
gravis, and each of these conditions can be attributed partly to
irregular miRNA function.
In late-onset myasthenia gravis subjects, it was shown that
miRNA-12a-5p expression was increased in thymoma-associated myasthenia
gravis. MiRNA-12a-5p inhibits expression of the gene FoxP3, a gene known
to be associated with normal thymus development and whose alteration is
attributed to thymomas.
Additionally, an association between thymoma-associated myasthenia
gravis and decreased miR-376a/miR-376c expression was found. Autoimmune
regulation is known to be downregulated in thymoma-associated myasthenia
gravis, and in thymus cells with downregulated autoimmune regulation
there was simultaneous downregulation in miR-376a, miR-376c, and
miRNA-12a-5p expression.
In early-onset myasthenia gravis patients, 61 miRNA's were found to be
either significantly downregulated or upregulated. The most
downregulated miRNA was found to be miR-7-5p, whose target gene is
CCL21. CCL21 is known to aberrantly recruit B-cells in the thymus of
early-onset myasthenia gravis patients, and was found to be highly
expressed in early-onset myasthenia gravis patients, potentially
explaining the abnormally large amounts of B cells found in thymic
hyperplasia.
Aside from miRNA's corresponding to altered thymus function,
there are other several key miRNA's that are correlated with myasthenia
gravis. MiR-15 cluster (miR-15a, miR-15b, and miR-15c) was shown to be
associated with autoimmunity, in that its downregulation increased
CXCL10 expression, a target gene involved in T-cell signaling. CXCL10
expression was also shown to be increased in the thymus of myasthenia
gravis patients.
Additionally, miR-146 was found to be upregulated in myasthenia gravis
patients. In these patients with upregulated miR-146, there was a
concurrent increase in proteins that correspond to a wide array of
immune responses, specifically TLR4, CD40, and CD80.
DNA methylation
DNA
methylation is the epigenetic process by which methyl groups are added
to either adenine or cytosine bases, which results in the repression of
that sequence when cytosine methylation occurs.
DNA methylation was found to be a factor in increasing the likelihood
of acquiring myasthenia gravis, albeit this topic has not been widely
researched. Research in China has identified the gene CTLA-4 (cytotoxic T
lymphocyte antigen-4) as being highly methylated in myasthenia gravis
patients compared to control groups throughout the entire span of the
disease. The CTLA-4 gene produces an antigen of the same name that is
presented on killer T-cells and allows for the suppression of the immune
response. Methylation of this gene represses production of the antigen
CTLA-4—a pattern seen in a significant majority of myasthenia gravis
patients—and can explain the elevated immune response seen in myasthenia
gravis. Furthermore, myasthenia gravis patients with thymic abnormalities (approximately 10–20% of all myasthenia gravis patients)
had even higher levels of CTLA-4 methylation than other myasthenia
gravis patients. It is not extensively researched why certain genes are
hypermethylated in these cases, but information on myasthenia gravis
largely points to upregulation of the DNA methyltransferase genes DNMT1,
DNMT3A, and DNMT3B in patients with myasthenia gravis.
In addition to CTLA-4 methylation, hypermethylation of the growth
hormone secretagogue receptor gene was seen in patients with
thymoma-associated late-onset myasthenia gravis.
Growth hormone secretagogue receptor hypermethylation is detected in a
wide variety of cancers, however only recently has been correlated with
the development of thymoma-associated myasthenia gravis. Although it is
seen in approximately 1/4 of thymoma-associated myasthenia gravis
subjects, it is not a reliable biomarker for the disease, and its
relevance to disease progression is not well known.
Long ncRNA
Long
ncRNA (lncRNA) are a second type of non-coding RNA that are key
post-transcriptional modifiers of protein-coding gene expression. These
also play a significant role in myasthenia gravis. Their aberrant
regulation can cause differential expression in downstream genes. For
instance, the differential expression of lncRNA interferon gamma
antisense RNA negatively regulates the expression of HLA-DRB and
HLA-DOB, two genes implicated in the body's autoimmune response by differentiating endogenous and foreign proteins.
As seen in myasthenia gravis patients with downregulated lethal (let)-7
lncRNA, it was also found that the level of let-7 lncRNA was negatively
correlated with levels of interleukin (IL)-10, a gene responsible for
inhibiting cytokine secretion/activation, antigen presentation, and
macrophage activity, but also for exhibiting anti-tumor effects.
Therefore, the negative correlation between let-7 lncRNA and IL-10
levels and its specific effects on myasthenia gravis development are
ambiguous.
In addition to aberrant regulation of downstream target genes,
lncRNA also affect expression by acting as competing endogenous RNA
(ceRNA). The competing endogenous RNA theory states that transcripts
sharing common miRNA binding sites can compete to bind these identical
miRNAs, and in this way lncRNAs can bind miRNAs, regulating their
downstream binding activity and affecting their function. In the case of
myasthenia gravis, the lncRNA small nucleolar RNA host gene (SNHG) 16
regulates the expression of IL-10 by adsorbing let-7c-5p, a miRNA that
commonly associates with IL-10, as a competing endogenous RNA.
Epigenetic treatments
Diagnosis
of myasthenia gravis, individual prognosis, and the level of treatment
needed can be determined by detecting the amounts of circulating miRNA.
Immunosuppressants represent a large category in clinical studies
for myasthenia gravis treatment, as they reduce the hyperactive
immunological response in T-cells presenting acetylcholine
receptor-binding antigens.
By overexpressing miR-146, studies show that patients with early-onset
myasthenia gravis can have antigen-specific suppressive effects. This
has implications in reducing the immune response of myasthenia gravis
patients and improving prognosis. Likewise, miR-155 is proven to be
correlated with myasthenia gravis-associated thymic inflammation and
immune response. Research is being conducted whereas repression of
miR-155 could reduce these aberrant effects.
Lastly, the miRNA's miR-150-5p and miR-21-5p are consistently shown to
be elevated in myasthenia gravis patients with acetylcholinergic
receptor antibodies (in contrast to the MuSK-binding variant of
myasthenia gravis), therefore these two miRNA's are reliable biomarkers
in detecting this variant of myasthenia gravis.
Neurodegenerative diseases of the central nervous system
Alzheimer's disease (AD) is the most prevalent form of dementia among
the elderly. The disease is characterized behaviorally by chronic and
progressive decline in cognitive function, beginning with short-term
memory loss, and neurologically by buildup of misfolded tau protein and associated neurofibrillary tangles, and by amyloid-beta senile plaques amyloid-beta senile plaques. Several genetic factors have been identified as contributing to AD, including mutations to the amyloid precursor protein (APP) and presenilins 1 and 2 genes, and familial inheritance of apolipoprotein E
allele epsilon 4. In addition to these common factors, there are a
number of other genes that have shown altered expression in Alzheimer's
disease, some of which are associated with epigenetic factors.
Epigenetic factors
Brain-derived neurotrophic factor
ncRNA
ncRNA that is encoded antisense from an intron within the beta-amyloid cleaving enzyme gene, BACE1, is involved in AD. This ncRNA, BACE1-AS (for antisense), which overlaps exon 6 of BACE1, is involved in increasing the stability of the BACE1
mRNA transcript. As that gene's name suggests, BACE1 is an enzymatic
protein that cleaves the amyloid precursor protein into the insoluble
amyloid beta form, which then aggregates into senile plaques. With
increased stability of BACE1 mRNA resulting from BACE1-AS, more BACE1 mRNA is available for translation into BACE1 protein.
miRNA
factors have not consistently been shown to play a role in
progression of AD. miRNAs are involved in post-transcriptional gene
silencing via inhibiting translation or involvement in RNAi
pathways. Some studies have shown upregulation of miRNA-146a, which
differentially regulates neuroimmune-related Interleukin-1R associated
kinases IRAK1 and IRAK2 expression, in human AD brain, while other
studies have shown upregulation or downregulation of miRNA-9 in brain.
DNA methylation
In Alzheimer's disease cases, global DNA hypomethylation and
gene-specific hypermethylation has been observed, though findings have
varied between studies, especially in studies of human brains.
Hypothetically, global hypomethylation should be associated with global
increases in transcription, since CpG islands are most prevalent in gene
promoters; gene-specific hypermethylation, however, would indicate that
these hypermethylated genes are repressed by the methylation marks.
Generally, repressive hypermethylation of genes related to learning and
memory has been observed in conjunction with derepressive
hypomethylation of neuroinflammatory genes and genes related to
pathological expression of Alzheimer's disease. Reduced methylation has
been found in the long-term memory-associated temporal neocortex neurons
in monozygotic twins with Alzheimer's disease compared to the healthy
twin. Global hypomethylation of CpG dinucleotides has also been observed in hippocampus and in entorhinal cortex layer II
of human AD patients, both of which are susceptible to AD pathology.
These results, found by probing with immunoassays, have been challenged
by studies that interrogate DNA sequence by bisulfite sequencing,
a CpG transformation technique which is sensitive to CpG methylation
status, in which global hypomethylation has been observed.
COX-2
At the individual gene level, hypomethylation and thus derepression of COX-2 occurs, inhibition of which reduces inflammation and pain, and hypermethylation of BDNF, a neurotrophic factor important for long-term memory.[85] Expression of CREB, an activity-dependent transcription factor involved in regulating BDNF among many other genes, has also been shown to be hypermethylated, and thus repressed, in AD brains, further reducing BDNF transcription. Furthermore, synaptophysin (SYP),
the major synaptic vesicle protein-encoding gene, has been shown to be
hypermethylated and thus repressed, and transcription factor NF-κB, which is involved in immune signaling, has been shown to be hypomethylated and thus derepressed.
Taken together, these results have elucidated a role for dysregulation
of genes involved in learning and memory and synaptic transmission, as
well as with immune response.
Hypomethylation
has been observed in promoters of presenilin 1, GSK3beta, which phosphorylates tau protein, and BACE1,
an enzyme that cleaves APP into the amyloid-beta form, which in turn
aggregates into insoluble senile plaques. Repressive hypermethylation
caused by amyloid-beta has been observed at the promoter of NEP, the gene for neprilysin, which is the major amyloid-beta clearing enzyme in the brain.
This repression of NEP could result in a feed-forward buildup of
senile plaques; combined with the observed increase in AD brains of BACE1-AS and corresponding increases in BACE1 protein and amyloid beta,
multiple levels of epigenetic regulation may be involved in controlling
amyloid-beta formation, clearance or aggregation, and senile plaque
deposition. There may be some effect of age in levels of DNA methylation
at specific gene promoters, as one study found greater levels of
methylation at APP promoters in AD patients up to 70 years old, but lower levels of methylation in patients greater than 70 years old.
Studies on differential DNA methylation in human AD brains remain
largely inconclusive possibly owing to the high degree of variability
between individuals and to the numerous combinations of factors that may
lead to AD.
Histone marks
Acetylation of lysine residues on histone tails is typically
associated with transcriptional activation, whereas deacetylation is
associated with transcriptional repression. There are few studies
investigating specific histone marks in AD. These studies have
elucidated a decrease in acetylation of lysines 18 and 23 on N-terminal
tails of histone 3 (H3K18 and H3K23, respectively) and increases in HDAC2 in AD brains
- both marks related to transcriptional repression. Age-related
cognitive decline has been associated with deregulation of H4K12
acetylation, a cognitive effect that was restored in mice by induction
of this mark.
Treatments
Treatment
for prevention or management of Alzheimer's disease has proven
troublesome since the disease is chronic and progressive, and many
epigenetic drugs act globally and not in a gene-specific manner. As
with other potential treatments to prevent or ameliorate
symptoms of AD, these therapies do not work to cure, but only
ameliorate symptoms of the disease temporarily, underscoring the
chronic, progressive nature of AD, and the variability of methylation in
AD brains.
Folate and other B vitamins
B vitamins are involved in the metabolic pathway that leads to SAM
production. SAM is the donor of the methyl group utilized by DNA
methyltransferases (DNMTs) to methylate CpGs. Using animal models, Fuso
et al. have demonstrated restoration of methylation at previously
hypomethylated promoters of presenilin 1, BACE1 and APP
– a hypothetically stable epigenetic modification that should repress
those genes and slow the progression of AD. Dietary SAM supplementation
has also been shown to reduce oxidative stress and delay buildup of
neurological hallmarks of AD such as amyloid beta and phosphorylated tau
protein in transgenic AD mice.
AZA
Khan and colleagues have demonstrated a potential role for neuroglobinin attenuating amyloid-related neurotoxicity. 5-aza-2' deoxycitidine
(AZA, or decitabine), a DNMT inhibitor, has shown some evidence for
regulating neuroglobin expression, though this finding has not been
tested in AD models.
Histone-directed treatments
Though studies of histone marks in AD brains are few in number,
several studies have looked at the effects of HDACis in treatment of
Alzheimer's disease. Class I and II HDAC inhibitors such as
trichostatin A, vorinostat, and sodium butyrate, and Class III HDACis,
such as nicotinamide, have been effective at treating symptoms in animal
models of AD. While promising as a therapeutic in animal models,
studies on the long-term efficacy of HDACis and human trials have yet to
be conducted.
Sodium butyrate
Sodium butyrate is a class I and II HDACi and has been shown to recover learning and memory after 4 weeks, decrease phosphorylated tau protein, and restore dendritic spine density in the hippocampus of AD transgenic mice.
Histone acetylation resulting from diffuse sodium butyrate application
is especially prevalent in the hippocampus, and genes involved in
learning and memory showed increased acetylation in AD mice treated with
this drug.
Trichostatin A
Trichostatin A is also a class I and II HDACi that rescues fear
learning in a fear conditioning paradigm in transgenic AD mice to wild
type levels via acetylation on histone 4 lysine tails.
Vorinostat
Vorinostat is a class I and II HDACi that has been shown to be
especially effective at inhibiting HDAC2 and restoring memory functions
in non-AD models of learning deficits. One study showed vorinostat is effective at reversing contextual memory deficits in transgenic AD mice.
This is a transverse section of the striatum from a structural MR image. The striatum, in red, includes the caudate nucleus (top), the putamen (right), and, when including the term 'corpus' striatum, the globus pallidus (lower left).
Huntington's disease (HD) is an inherited disorder that causes progressive degeneration of neurons within the cerebral cortex and striatum of the brain
resulting in loss of motor functions (involuntary muscle contractions),
decline in cognitive ability (eventually resulting in dementia), and
changes in behavior.
Genetics and underlying causes
Huntington's is caused by an autosomal dominant mutation expanding the number of glutamine codon repeats (CAG) within the Huntingtin gene (Htt).
The Htt gene encodes for the huntingtin protein which plays a role in
normal development but its exact function remains unknown.
The length of this CAG repeat correlates with the age-of-onset of the
disease. The average person without Huntington's has less than 36 CAG
repeats present within the Htt gene. When this repeat length exceeds 36,
the onset of neuronal degradation and the physical symptoms of
Huntington's can range from as early as 5 years of age (CAG repeat >
70) to as late as 80 years of age (CAG repeat < 39).
This CAG expansion results in mRNA downregulation of specific
genes, decreased histone acetylation, and increased histone methylation.
The exact mechanism of how this repeat causes gene dysregulation is
unknown, but epigenome modification may play a role. For early-onset
Huntington's (ages 5–15), both transgenic mice and mouse striatal cell
lines show brain specific histone H3 hypoacetylation and decreased
histone association at specific downregulated genes within the striatum
(namely Bdnf, Cnr1, Drd2 – dopamine 2 receptor, and Penk1 –
preproenkephalin).
For both late- and early-onset Huntington's, the H3 and H4 core
histones associated with these downregulated genes in Htt mutants have
hypoacetylation (decreased acetylation) compared to wild-type Htt. This hypoacetylation is sufficient to cause tighter chromatin packing and mRNA downregulation.
Along with H3 hypoacetylation, both human patients and mice with
the mutant Htt have increased levels of histone H3 lysine 9
trimethylation.
This increase in H3-K9 trimethylation is linked to an increased
expression of the methyltransferase ESET/SETDB1 (ERG-associated protein
with SET domain (ESET)), which targets and trimethylates H3-K9 residues. It is proposed that this hypermethylation may account for the onset of specific gene repression in Htt mutants.
HDAC inhibitors
Huntington patients and both mouse and Drosophila
models show histone H3 and H4 hypoacetylation. There are currently no
treatments for the disease but numerous HDAC inhibitors have been tested
and shown to reverse the certain symptoms caused by the Htt mutation.
Sodium butyrate
Sodium butyrate treatment slowed neuronal degeneration in Drosophila models. Sodium butyrate treatment also increased histone H3 acetylation and normalized mRNA levels for mutant Htt downregulated genes.
Valproic acid
Valproic acid treatment increased mutant Htt H3 and H4 acetylation levels comparable to wild-type Htt in Drosophila models.
Sodium phenylbutyrate
Sodium phenylbutyrate phase II human trials with 12 to 15 g/day
showed restored mRNA levels of Htt mutant repressed genes but also had
adverse side effects such as nausea, headaches, and gain instability.
Phenylbutyrate has also been shown to increase histone acetylation,
decrease histone methylation, increase survival rate, and decrease the
rate of neuronal degradation in Htt mutant mouse models.
Trichostatin A
Trichostatin A (TSA) treatment increased mutant Htt H3 and H4
acetylation levels comparable to wild-type Htt in Drosophila models.
TSA treatment has also been shown to increase alpha-tubulin lysine 40
acetylation in mouse striatal cells and increase intracellular transport
of BDNF, a brain-derived neurotrophic factor that function in nerve
growth and maintenance within the brain.
Vorinostat (SAHA)
Vorinostat treatment slowed photoreceptor degeneration and improved longevity of adult Htt mutant Drosophila.
Like TSA, SAHA treatment increased alpha-tubulin lysine 40 acetylation
in mouse striatal cells and also increased intracellular transport of
BDNF.
Parkinson's disease (PD) is characterized by progressive degeneration
of dopaminergic neurons in the substantia nigra by causes unknown.
Several genes and environmental factors (e.g. pesticide exposure) may
play a role in onset of PD. Hallmarks include mutations to the
alpha-synuclein gene, SNCA, as well as PARK2, PINK1, UCHL1, DJ1, and LRRK2 genes, and fibrillar accumulation of Lewy bodies
from misfolded alpha-synuclein. Symptoms are most noticeably manifested
in disorders of movement, including shaking, rigidity, deficits in
making controlled movements, and slow and difficult walking. The late
stages of the disease result in dementia and depression. Levodopa and
dopaminergic therapy may ameliorate symptoms, though there is no
treatment to halt progression of the disease.
Epigenetic factors
ncRNA
Reductions of miR-133b correlated to decreased numbers of dopaminergic neurons in the midbrain of PD patients. miR-132, meanwhile, is negatively correlated with dopaminergic neuron differentiation in the midbrain. miR-7 and miR-153 act to reduce alpha-synuclein levels (a hallmark of PD) but are reduced in PD brain.
DNA methylation
Neurons of PD patients show hypomethylation of tumor necrosis factor (TNF) alpha encoding sequence, overexpression of which leads to apoptosis of neurons. Cerebrospinal fluid of PD patients also shows elevated TNF alpha. Research indicates there may be a link between DNA methylation and SNCA expression.
Furthermore, human and mouse models have shown reduction of nuclear
DNMT1 levels in PD subjects, resulting in hypomethylated states
associated with transcriptional repression.
Histone marks
alpha-synuclein, the protein encoded by SNCA, can associate with histones and prevent their acetylation in concert with the HDACs HDAC1 and Sirt2. Furthermore, it has been demonstrated that alpha-synuclein binds histone 3 and inhibits its acetylation in Drosophila.
Dopamine depletion in Parkinson's disease is associated with
repressive histone modifications, including reduced H3K4me3, and lower
levels of H3 and H4 lysine acetylation after levodopa therapy (a common
treatment of PD).
Treatments
Epigenetic
treatments tested in models of PD are few, though some promising
research has been conducted. Most treatments investigated thus far are
directed at histone modifications and analysis of their roles in
mediating alpha-synuclein expression and activity. Pesticides and
paraquat increase histone acetylation, producing neurotoxic effects
similar to those seen in PD, such as apoptosis of dopaminergic cells. Despite this, treatment with HDACis seems to have a neuroprotective effect.
Sodium butyrate
Several studies using different animal models have demonstrated that
sodium butyrate may be effective in reducing alpha-synuclein-related
neurotoxicity. In Drosophila, sodium butyrate improved locomotor impairment and reduced early mortality rates.
Valproic acid
In an inducible rat model of PD, valproic acid had a neuroprotective
effect by preventing translocation of alpha-synuclein into cell nuclei.
Vorinostat
In an alpha-synuclein overexpressing Drosophila model of PD, vorinostat (as well as sodium butyrate) reduced alpha-synuclein-mediated neurotoxicity.
siRNA inhibition of SIRT2
Treatment with SIRT2 inhibiting siRNA leads to reduced alpha-synuclein neurotoxicity AK-1 or AGK-2.
Multiple sclerosis
Multiple
sclerosis (MS) is a demyelinating neurodegenerative disease that does
not have a confirmed cause, but is widely considered to be an autoimmune
disease in nature.
It is indicated by demyelination of the nerves of the brain and spinal
cord. Its symptoms are unique in nature and vary, but include those that
have degenerative effects in the eyes and limbs. These can present
themselves as numbness or atrophy, shock like sensations, paralysis, as
well as lack of coordination or tremors, within the extremities. Within
the eye, multiple sclerosis can cause blurriness, double vision, pain,
or vision loss. Multiple sclerosis effects can be presented throughout
other realms of the body, but is largely characterized by these main
symptoms. Some of these can include loss of sexual or excretory function
and epilepsy. While there are a few subcategories of multiple
sclerosis, in most instances, the disease afflicts in a relapsing
nature, where relapses of symptoms might not occur for extended periods
of time, yielding more to the uncertainty of the disease. There is no
known cure for MS, but measures can be taken post relapse to regain loss
of function and the symptoms can be mitigated via therapeutic or
medicinal means.
Epigenetic factors
Because
of the outside factors that precede multiple sclerosis and the
heritability typically occurring within the mother, it is thought to
have an epigenetic cause. Some factors that may increase the incidence
of MS are smoking, vitamin deficiency, and a history of some viral
infections—which are factors that can induce epigenetic change.
Human leukocyte antigen-DRB1*15 allele
Human
leukocyte antigen-DRB1*15 haplotype is a potential risk factor of MS.
Because of the increased likelihood of the mother's human leukocyte
antigen-DRB1*15 allele being passed onto their children, this
contributes to the instances of MS being more prevalent from the mother.
HLA-DRB1 is thought to be regulated via epigenetic means. The
correlation of MS and this allele is speculated to be due to the
presence of hypomethylation in the CpG island of HLA-DRB1, and those
that carry the allele tend to exhibit this hypomethylation. HLA-DRB1
exon 2 is a particular region where evidence has shown that methylation
is shown to be important in regulation. Research has furthered the
evidence that variation in HLA-DRB1 DMR, which is a mechanism that is
methylation regulated, that in turn regulates increased HLA-DRB1
expression, displays an increased risk for MS, and the exhibition of the
disease.
miRNA
Higher
levels of expression of specific types of miRNA are often seen in the
brain of those afflicted, showing an association of these types of miRNA
and MS. Higher expression of miR-155 and miR-326 is often associated
with CD4+T cell differentiation, and with this differentiation,
instances of autoimmune encephalitis occur, which is the link with which
it is thought that smoking can induce epigenetic changes that increase
susceptibility to MS. Higher expression levels of miR-18b, miR-493,
miR-599, and miR-96 are often seen in patients diagnosed with MS.
miR-145 detection appears to be a promising future diagnostic tool due
to its high specificity of 90% and sensitivity of 89.5% in whole blood
testing due to its capability of distinguishing healthy patients versus
those with MS. A symptom associated with MS patients is white matter
lesions in the brain, and these lesions when biopsied showed higher
expression of miR-155, miR-326 and miR-34a. These are especially notable
due to the fact that overexpression of these miRNA's cause
downregulation of CD47, leading to myelin phagocytosis, because of
CD47's role of inhibiting macrophage activity.
DNA methylation
MS
patients can be identified through observation of abnormal DNA
methylation patterns in genes responsible for inflammation and
myelination factor expression. Methylation occurs in the genomic region,
CpG island, and is imperative in regulation of transcription. A
methylated CpG region typically is the mechanism that will silence a
gene, whereas a hypomethylated region is able to induce transcription.
Using methylation inhibitors it has been shown that allowing higher
proliferation of T cells can be achieved by preventing silencing.
Abnormalities in methylation patterns increase the generation of CD4+T
auto reactive. Hypomethylation of CpG regions of the PAD2 gene, a
regulator of MBP which in turn regulates myelin, is also associated with
higher instances of MS. This hypomethylation leads to overexpression of
the PAD2 gene. These patterns have been observed in the white matter of
patients with MS. While methylation is an indicator of MS, its effects
are more specialized to location in MS, for example, where these
patterns are observed in white matter.
Histone modifications
Association
of abnormal histone modification in MS patients can be found in lesions
located in the brain, with most instances of this being observed in
patients over time and in lesions located in the frontal lobe. Higher
instance of histone acetylation can be seen in patients afflicted over
time, but this is counteracted by lower instances of histone acetylation
in lesions found on the brain early in the course of the disease. The
mechanisms by which histone modifications work in the progression of MS
are unconfirmed, but changes in acetylation are often associated with
the disease.
Treatments
HDAC inhibitors
Trichostatin
Positive responses were observed in animal trials utilizing this
HDAC inhibitor, associated with mediation of inflammatory pathways and
thus resulting in lower instances of inflammatory responses in the
brain. It was also shown to be effective in decreasing levels of
disability when the mice were in a relapsing stage of MS. Trichostatin's
mediation of symptoms is not well known but is thought to work in
increasing acetylation at the H3 and H4 histones in CD4+T cells where MS
patients often display differences in acetylation levels at these
histones that control patients do not.
Vorinostat
Animal trials were utilized along with the testing of human
myeloid dendritic cells. Not much is known about the mechanisms of
vorinostat; however regulation of Th1/Th17 cytokine expression, which
are responsible for inducing inflammation, were observed, thereby
decreasing instances of inflammation and demyelination. Decreased
patterns of T cell proliferation were also observed, similar to how
trichostatin mediates disease symptoms.
Valpropic acid
Valpropic acid has been shown to have positive results in animal trials,
in the mitigation of the disease by regulating the severity and
duration of MS. Its mechanism is decreasing the presentation of miRNA.
Its mechanism for such has been observed in rats by shifting Th1 and
Th17 to Th2 (responsible for inducing inflammation), thereby
downregulating miRNA expression in inflammatory cytokines, tumor
mediating mechanisms, and the spine. This is another instance in which T
cell expression regulation is present, by preventing proliferation
through interference of its pathway, similar to trichostatin and
vorinostat. Another effect of VPA is its prevention of macrophage and
lymphocyte proliferation in the spinal cords of MS rats. Currently, no
HDAC inhibitors are in use for the mitigation of symptoms in MS
patients; however, some are in pre-clinical trials at this time.
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