X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. In medicine, X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. In this case, someone who expresses an X-linked dominant allele will exhibit the disorder and be considered affected.
X-linked dominant traits do not necessarily affect males more than females (unlike X-linked recessive
traits). The exact pattern of inheritance varies, depending on whether
the father or the mother has the trait of interest. All fathers that are
affected by an X-linked dominant disorder will have affected daughters
but not affected sons. However, if the mother is also affected then sons
will have a chance of being affected, depending on whether a dominant
or recessive X chromosome is passed on. When the son is affected, the
mother will always be affected.
Some scholars have suggested discontinuing the terms dominant and
recessive when referring to X-linked inheritance due to the multiple
mechanisms that can result in the expression of X-linked traits in
females, which include cell autonomous expression, skewed X-inactivation, clonal expansion and somatic mosaicism.
Genetics
As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked
inheritance is determined by the sex of the parent carrying a specific gene and can often seem complex. This is due to the fact that, typically, females have two copies of the X-chromosome, while males have only one copy. The difference between dominant and recessive
inheritance patterns also plays a role in determining the chances of a
child inheriting an X-linked disorder from their parentage.
Males can only get an X chromosome from their mother whilst
females get an X chromosome from both parents. As a result, females tend
to show higher prevalence of X-linked dominant disorders because they
have more of a chance to inherit a faulty X chromosome.
Inheritance
X-linked dominant
inheritance works differently depending upon whether the mother (left
image) or father (right image) is the carrier of a gene that causes a
disease or disorder.
In X-linked dominant inheritance, when the mother alone is the carrier
of a mutated, or defective gene associated with a disease or disorder;
she herself will have the disorder. Her children will inherit the
disorder as follows:
Of her daughters and sons: 50% will have the disorder, 50% will
be completely unaffected. Children of either sex have an even chance of
receiving either of their mother's two X chromosomes, one of which
contains the defective gene in question.
When the father alone is the carrier of a defective gene associated
with a disease or disorder, he too will have the disorder. His children
will inherit the disorder as follows:
Of his daughters: 100% will have the disorder, since all of his daughters will receive one copy of his single X chromosome.
Of his sons: none will have the disorder; sons do not receive an X chromosome from their father.
If both parents were carriers of a defective gene associated with a
disease or disorder, they would both have the disorder. Their children
would inherit the disorder as follows:
Of their daughters: 100% will have the disorder, since all of the daughters will receive a copy of their father's X chromosome.
Of the sons: 50% will have the disorder, 50% will be completely
unaffected. Sons have an equal chance of receiving either of their
mother's X chromosomes.
In such a case, where both parents carry and thus are affected by an
X-linked dominant disorder, the chance of a daughter receiving two
copies of the X chromosome with the defective gene is 50%, since
daughters receive one copy of the X chromosome from both parents. Were
this to occur with an X-linked dominant disorder, that daughter would
likely experience a more severe form.
Some X-linked dominant conditions such as Aicardi syndrome are fatal to boys, therefore only girls with these conditions survive, or boys with Klinefelter's syndrome (and hence have more than one X chromosome).
In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation
in DNA occurs. All of these diseases have neurological symptoms.
Prior to the understanding of the genetic mechanism for anticipation, it
was debated whether anticipation was a true biological phenomenon or
whether the earlier age of diagnosis was related to heightened awareness
of disease symptoms within a family.
Trinucleotide repeats and expansion
Trinucleotide repeats are apparent in a number of loci in the human genome. They have been found in introns, exons and 5' or 3' UTR's. They consist of a pattern of three nucleotides (e.g. CGG) which is repeated a number of times. During meiosis, unstable repeats can undergo triplet expansion (see later section); in this case, the germ cells produced have a greater number of repeats than are found in the somatic tissues.
The mechanism behind the expansion of the triplet repeats is not
well understood. One hypothesis is that the increasing number of repeats
influence the overall shape of the DNA, which can have an effect on its interaction with DNA polymerase and thus the expression of the gene.
Disease mechanisms
For many of the loci, trinucleotide expansion is harmless,
but in some areas expansion has detrimental effects that cause
symptoms. When the trinucleotide repeat is present within the
protein-coding region, the repeat expansion leads to production of a
mutant protein with gain of function. This is the case for Huntington's disease,
where the trinucleotide repeat encodes a long stretch of glutamine
residues. When the repeat is present in an untranslated region, it
could affect the expression of the gene in which the repeat is found (ex. fragile X) or many genes through a dominant negative effect (ex. myotonic dystrophy).
In order to have a deleterious effect, the number of repeats must
cross a certain threshold. For example, normal individuals have between
5 and 30 CTG repeats within the 3' UTR of DMPK, the gene that is altered in myotonic dystrophy.
If the number of repeats is between 50 to 100, the person is only
mildly affected – perhaps having only cataracts. However, meiotic
instability could result in a dynamic mutation
that increases the number of repeats in offspring inheriting the mutant
allele. Once the number of copies reaches over 100, the disease will
manifest earlier in life (although the individual will still reach
adulthood before the symptoms are evident) and the symptoms will be more
severe – including electrical myotonia. As the number progresses upwards past 400, the symptoms show themselves during childhood or infancy.
Fragile X syndrome (FXS) is a genetic disorder. Symptoms often include mild to moderate intellectual disability. The average IQ in males is under 55, while about two thirds of females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common and seizures occur in about 10%. Males are usually more affected than females.
Fragile X syndrome is inherited in an X-linked dominant pattern. Women with a premutation have an increased risk of having an affected child. It is typically due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome. This results in not enough of the fragile X mental retardation protein (FMRP), which is required for the normal development of connections between neurons. Diagnosis requires genetic testing to determine the number of CGG repeats in the FMR1 gene.
Normal is between 5 and 40 repeats, fragile X syndrome occurs with more
than 200, and a premutation is said to be present when an intermediate
number of repeats occurs. Testing for premutation carriers may allow for genetic counseling.
There is no cure. Early intervention is recommended as it provides the most opportunity for developing a full range of skills. These interventions may include special education, speech therapy, physical therapy, or behavioral therapy. Medications may be used to treat associated seizures, mood problems, aggressive behavior, or ADHD. Fragile X syndrome is estimated to occur in 1.4 in 10,000 males and 0.9 in 10,000 females.
Signs and symptoms
Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone.
Most young children do not show any physical signs of FXS. It is not until puberty that physical features of FXS begin to develop. Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone. Recurrent otitis media (middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. Behavioral characteristics may include stereotypic movements
(e.g., hand-flapping) and atypical social development, particularly
shyness, limited eye contact, memory problems, and difficulty with face
encoding. Some individuals with fragile X syndrome also meet the
diagnostic criteria for autism.
Males with a full mutation display virtually complete penetrance
and will therefore almost always display symptoms of FXS, while females
with a full mutation generally display a penetrance of about 50% as a
result of having a second, normal X chromosome. Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males.
Individuals with FXS may present anywhere on a continuum from learning disabilities in the context of a normal intelligence quotient (IQ) to severe intellectual disability, with an average IQ of 40 in males who have complete silencing of the FMR1 gene.
Females, who tend to be less affected, generally have an IQ which is
normal or borderline with learning difficulties. The main difficulties
in individuals with FXS are with working and short-term memory, executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively spared.
Data on intellectual development in FXS are limited. However,
there is some evidence that standardized IQ decreases over time in the
majority of cases, apparently as a result of slowed intellectual
development. A longitudinal study looking at pairs of siblings where one
child was affected and the other was not found that affected children
had an intellectual learning rate which was 55% slower than unaffected
children.
When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.
Autism
Fragile X syndrome co-occurs with autism in many cases and is a suspected genetic cause of the autism in these cases. This finding has resulted in screening for FMR1 mutation to be considered mandatory in children diagnosed with autism. Of those with fragile X syndrome, prevalence of concurrent autism spectrum disorder
(ASD) has been estimated to be between 15 and 60%, with the variation
due to differences in diagnostic methods and the high frequency of
autistic features in individuals with fragile X syndrome not meeting the
DSM criteria for an ASD.
Although individuals with FXS have difficulties in forming
friendships, those with FXS and ASD characteristically also have
difficulties with reciprocal conversation with their peers. Social
withdrawal behaviors, including avoidance and indifference, appear to be
the best predictors of ASD in FXS, with avoidance appearing to be
correlated more with social anxiety while indifference was more strongly
correlated to severe ASD.
When both autism and FXS are present, a greater language deficit and
lower IQ is observed as compared to children with only FXS.
Genetic mouse models of FXS have also been shown to have autistic-like behaviors.
Social interaction
FXS is characterized by social anxiety,
including poor eye contact, gaze aversion, prolonged time to commence
social interaction, and challenges forming peer relationships.
Social anxiety is one of the most common features associated with FXS,
with up to 75% of males in one series characterized as having excessive
shyness and 50% having panic attacks.
Social anxiety in individuals with FXS is related to challenges with
face encoding, the ability to recognize a face that one has seen before.
It appears that individuals with FXS are interested in social
interaction and display greater empathy than groups with other causes of
intellectual disability, but display anxiety and withdrawal when placed
in unfamiliar situations with unfamiliar people.
This may range from mild social withdrawal, which is predominantly
associated with shyness, to severe social withdrawal, which may be
associated with co-existing autism spectrum disorder.
Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal. In addition, premutation in females has been found to be associated with social anxiety.
Individuals with FXS show decreased activation in the prefrontal regions of the brain.
Mental health
Attention deficit hyperactivity disorder
(ADHD) is found in the majority of males with FXS and 30% of females,
making it the most common psychiatric diagnosis in those with FXS. Children with fragile X have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal.
Hyperactivity and disruptive behavior peak in the preschool years and
then gradually decline with age, although inattentive symptoms are
generally lifelong.
Aside from the characteristic social phobia features, a range of
other anxiety symptoms are very commonly associated with FXS, with
symptoms typically spanning a number of psychiatric diagnoses but not
fulfilling any of the criteria in full.
Children with FXS pull away from light touch and can find textures of
materials to be irritating. Transitions from one location to another can
be difficult for children with FXS. Behavioral therapy can be used to
decrease the child's sensitivity in some cases. Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety.
Perseveration
is a common communicative and behavioral characteristic in FXS.
Children with FXS may repeat a certain ordinary activity over and over.
In speech, the trend is not only in repeating the same phrase but also
talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches. Although only a minority of FXS cases will meet the criteria for obsessive–compulsive disorder
(OCD), a significant majority will have symptoms of obsession. However,
as individuals with FXS generally find these behaviors pleasurable,
unlike individuals with OCD, they are more frequently referred to as
stereotypic behaviors.
Mood symptoms in individuals with FXS rarely meet diagnostic
criteria for a major mood disorder as they are typically not of
sustained duration.
Instead, these are usually transient and related to stressors, and may
involve labile (fluctuating) mood, irritability, self-injury and
aggression.
Ophthalmologic problems include strabismus. This requires early identification to avoid amblyopia.
Surgery or patching are usually necessary to treat strabismus if
diagnosed early. Refractive errors in patients with FXS are also common.
Neurology
Individuals with FXS are at a higher risk of developing seizures, with rates between 10% and 40% reported in the literature. In larger study populations the frequency varies between 13% and 18%, consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures. The seizures tend to be partial, are generally not frequent, and are amenable to treatment with medication.
Individuals who are carriers of premutation alleles are at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease.
It is seen in approximately half of male carriers over the age of 70,
while penetrance in females is lower. Typically, onset of tremor occurs in the sixth decade of life, with subsequent progression to ataxia (loss of coordination) and gradual cognitive decline.
Working memory
From
their 40s onward, males with FXS begin developing progressively more
severe problems in performing tasks that require the central executive
of working memory.
Working memory involves the temporary storage of information 'in mind',
while processing the same or other information. Phonological memory (or
verbal working memory) deteriorates with age in males, while
visual-spatial memory is not found to be directly related to age. Males
often experience an impairment in the functioning of the phonological
loop. The CGG length is significantly correlated with central executive
and the visual–spatial memory. However, in a premutation individual, CGG
length is only significantly correlated with the central executive, not
with either phonological memory or visual–spatial memory.
Fertility
About
20% of women who are carriers for the fragile X premutation are
affected by fragile X-related primary ovarian insufficiency (FXPOI),
which is defined as menopause before the age of 40. The number of CGG repeats correlates with penetrance and age of onset. However premature menopause
is more common in premutation carriers than in women with the full
mutation, and for premutations with more than 100 repeats the risk of
FXPOI begins to decrease.
Fragile X-associated primary ovarian insufficiency (FXPOI) is one of
three Fragile X-associated Disorders (FXD) caused by changes in the FMR1
gene. FXPOI affects female premutation carriers of Fragile X syndrome,
which is caused by the FMR1 gene, when their ovaries are not functioning
properly. Women with FXPOI may develop menopause-like symptoms but they
are not actually menopausal. Women with FXPOI can still get pregnant in
some cases because their ovaries occasionally release viable eggs.
Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.
In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats. Between 45-54 repeats is considered a "grey zone", with a premutation allele
generally considered to be between 55 and 200 repeats in length.
Individuals with fragile X syndrome have a full mutation of the FMR1 allele, with over 200 CGG repeats. In these individuals with a repeat expansion greater than 200, there is methylation of the CGG repeat expansion and FMR1promoter, leading to the silencing of the FMR1 gene and a lack of its product.
This methylation of FMR1 in chromosome band Xq27.3 is
believed to result in constriction of the X chromosome which appears
'fragile' under the microscope at that point, a phenomenon that gave the
syndrome its name. One study found that FMR1 silencing is mediated by
the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract
as part of the 5' untranslated region, which hybridizes to the
complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA
duplex.
A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in FMR1. This subset lacked the CGG repeat expansion in FMR1 traditionally associated with fragile x syndrome.
Inheritance
Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity and possibly reduced penetrance. However, due to genetic anticipation and X-inactivation
in females, the inheritance of Fragile X syndrome does not follow the
usual pattern of X-linked dominant inheritance, and some scholars have
suggested discontinuing labeling X-linked disorders as dominant or
recessive. Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation.
Before the FMR1 gene was discovered, analysis of pedigrees
showed the presence of male carriers who were asymptomatic, with their
grandchildren affected by the condition at a higher rate than their
siblings suggesting that genetic anticipation was occurring. This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985. Due to this, male children often have a greater degree of symptoms than their mothers.
The explanation for this phenomenon is that male carriers pass on
their premutation to all of their daughters, with the length of the FMR1 CGG repeat typically not increasing during meiosis, the cell division that is required to produce sperm. Incidentally, males with a full mutation only pass on premutations to their daughters.
However, females with a full mutation are able to pass this full
mutation on, so theoretically there is a 50% chance that a child will be
affected.
In addition, the length of the CGG repeat frequently does increase
during meiosis in female premutation carriers due to instability and so,
depending on the length of their premutation, they may pass on a full
mutation to their children who will then be affected. Repeat expansion is considered to be a consequence of strand slippage either during DNA replication or DNA repair synthesis.
Pathophysiology
FMRP is found throughout the body, but in highest concentrations within the brain and testes. It appears to be primarily responsible for selectively binding to around 4% of mRNA in mammalian brains and transporting it out of the cell nucleus and to the synapses of neurons. Most of these mRNA targets have been found to be located in the dendrites of neurons, and brain tissue from humans with FXS and mouse models shows abnormal dendritic spines,
which are required to increase contact with other neurons. The
subsequent abnormalities in the formation and function of synapses and
development of neural circuits result in impaired neuroplasticity, an integral part of memory and learning. Connectome changes have long been suspected to be involved in the sensory pathophysiology
and most recently a range of circuit alterations have been shown,
involving structurally increased local connectivity and functionally
decreased long-range connectivity.
In addition, FMRP has been implicated in several signalling
pathways that are being targeted by a number of drugs undergoing
clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes mGluR1 and mGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (LTP), both of which are important mechanisms in learning.
The lack of FMRP, which represses mRNA production and thereby protein
synthesis, leads to exaggerated LTD. FMRP also appears to affect dopamine
pathways in the prefrontal cortex which is believed to result in the
attention deficit, hyperactivity and impulse control problems associated
with FXS. The downregulation of GABA
pathways, which serve an inhibitory function and are involved in
learning and memory, may be a factor in the anxiety symptoms which are
commonly seen in FXS.
Diagnosis
Cytogenetic
analysis for fragile X syndrome was first available in the late 1970s
when diagnosis of the syndrome and carrier status could be determined by
culturing cells in a folate deficient medium and then assessing for "fragile sites" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome.
This technique proved unreliable, however, as the fragile site was
often seen in less than 40% of an individual's cells. This was not as
much of a problem in males, but in female carriers, where the fragile
site could generally only be seen in 10% of cells, the mutation often
could not be visualised.
Since the 1990s, more sensitive molecular techniques have been used to determine carrier status. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using polymerase chain reaction (PCR) and methylation status using Southern blot analysis.
By determining the number of CGG repeats on the X chromosome, this
method allows for more accurate assessment of risk for premutation
carriers in terms of their own risk of fragile X associated syndromes,
as well as their risk of having affected children. Because this method
only tests for expansion of the CGG repeat, individuals with FXS due to missense mutations or deletions involving FMR1
will not be diagnosed using this test and should therefore undergo
sequencing of the FMR1 gene if there is clinical suspicion of FXS.
Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable.
Early diagnosis of fragile X syndrome or carrier status is
important for providing early intervention in children or fetuses with
the syndrome, and allowing genetic counselling with regards to the
potential for a couple's future children to be affected. Most parents
notice delays in speech and language skills, difficulties in social and
emotional domains as well as sensitivity levels in certain situations
with their children.
Management
There is no cure for the underlying defects of FXS. Management of FXS may include speech therapy, behavioral therapy, sensory integration occupational therapy, special education,
or individualised educational plans, and, when necessary, treatment of
physical abnormalities. Persons with fragile X syndrome in their family
histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.
Medication
Current
trends in treating the disorder include medications for symptom-based
treatments that aim to minimize the secondary characteristics associated
with the disorder. If an individual is diagnosed with FXS, genetic
counseling for testing family members at risk for carrying the full
mutation or premutation is a critical first-step. Due to a higher
prevalence of FXS in boys, the most commonly used medications are
stimulants that target hyperactivity, impulsivity, and attentional
problems.
For co-morbid disorders with FXS, antidepressants such as selective
serotonin reuptake inhibitors (SSRIs) are utilized to treat the
underlying anxiety, obsessive-compulsive behaviors, and mood disorders.
Following antidepressants, antipsychotics such as risperidone and quetiapine
are used to treat high rates of self-injurious, aggressive and aberrant
behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants
are another set of pharmacological treatments used to control seizures
as well as mood swings in 13%–18% of individuals suffering from FXS.
Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are
linked with synaptic plasticity are especially beneficial for targeted
symptoms of FXS.
Lithium is also currently being used in clinical trials with humans,
showing significant improvements in behavioral functioning, adaptive
behavior, and verbal memory. Few studies suggested using folic acid, but
more researches are needed due to the low quality of that evidence.
Alongside pharmacological treatments, environmental influences such as
home environment and parental abilities as well as behavioral
interventions such as speech therapy, sensory integration, etc. all
factor in together to promote adaptive functioning for individuals with
FXS.
While metformin may reduce body weight in persons with fragile X
syndrome, it is uncertain whether it improves neurological or
psychiatric symptoms.
Current pharmacological treatment centers on managing problem
behaviors and psychiatric symptoms associated with FXS. However, as
there has been very little research done in this specific population,
the evidence to support the use of these medications in individuals with
FXS is poor.
ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants.
However, the use of stimulants in the fragile X population is
associated with a greater frequency of adverse events including
increased anxiety, irritability and mood lability. Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using SSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior. Atypical antipsychotics
can be used to stabilise mood and control aggression, especially in
those with comorbid ASD. However, monitoring is required for metabolic
side effects including weight gain and diabetes, as well as movement
disorders related to extrapyramidal side effects such as tardive dyskinesia. Individuals with coexisting seizure disorder may require treatment with anticonvulsants.
Prognosis
A
2013 review stated that life expectancy for FXS was 12 years lower than
the general population and that the causes of death were similar to
those found for the general population.
Research
Fragile X syndrome is the most translated neurodevelopmental disorder under study.
The increased understanding of the molecular mechanisms of disease in
FXS has led to the development of therapies targeting the affected
pathways. Evidence from mouse models shows that mGluR5 antagonists
(blockers) can rescue dendritic spine abnormalities and seizures, as
well as cognitive and behavioral problems, and may show promise in the
treatment of FXS. Two new drugs, AFQ-056 (mavoglurant) and dipraglurant, as well as the repurposed drug fenobam are currently undergoing human trials for the treatment of FXS. There is also early evidence for the efficacy of arbaclofen, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD.
In addition, there is evidence from mouse models that minocycline, an antibiotic used for the treatment of acne,
rescues abnormalities of the dendrites. An open trial in humans has
shown promising results, although there is currently no evidence from controlled trials to support its use.
The first complete DNA sequence of the repeat expansion in
someone with the full mutation was generated by scientists in 2012 using
SMRT sequencing.
History
In 1943, James Purdon Martin and Julia Bell described a pedigree of X-linked mental disability, without considering the macroorchidism (larger testicles). In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental disability. In 1970, Frederick Hecht coined the term "fragile site". And, in 1985, Felix F. de la Cruz
outlined extensively the physical, psychological, and cytogenic
characteristics of those afflicted in addition to prospects for therapy. Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.
The
multitude of neurodevelopmental disorders span a wide range of
associated symptoms and severity, resulting in different degrees of
mental, emotional, physical, and economic consequences for individuals,
and in turn families, social groups, and society.
Causes
Development of the nervous system
is tightly regulated and timed; it is influenced by both genetic
programs and the environment. Any significant deviation from the normal
developmental trajectory early in life can result in missing or abnormal
neuronal architecture or connectivity.
Because of the temporal and spatial complexity of the developmental
trajectory, there are many potential causes of neurodevelopmental
disorders that may affect different areas of the nervous system at
different times and ages. These range from social deprivation, genetic and metabolic diseases, immune disorders, infectious diseases, nutritional factors, physical trauma, and toxic and environmental factors. Some neurodevelopmental disorders, such as autism and other pervasive developmental disorders, are considered multifactorial syndromes which have many causes that converge to a more specific neurodevelopmental manifestation.
Social deprivation
Deprivation from social and emotional care causes severe delays in brain and cognitive development. Studies with children growing up in Romanian orphanages during Nicolae Ceauşescu's regime reveal profound effects of social deprivation and language deprivation
on the developing brain. These effects are time dependent. The longer
children stayed in negligent institutional care, the greater the
consequences. By contrast, adoption at an early age mitigated some of
the effects of earlier institutionalization (abnormal psychology).
Less commonly known genetically determined neurodevelopmental disorders include Fragile X syndrome. Fragile X syndrome was first described in 1943 by J.P. Martin and J. Bell, studying persons with family history of sex-linked "mental defects". Rett syndrome, another X-linked disorder, produces severe functional limitations. Williams syndrome is caused by small deletions of genetic material from chromosome 7.
The most common recurrent Copy Number Variannt disorder is 22q11.2 deletion syndrome (formerly DiGeorge or velocardiofacial syndrome), followed by Prader-Willi syndrome and Angelman syndrome.
Immune dysfunction
Immune reactions during pregnancy, both maternal and of the
developing child, may produce neurodevelopmental disorders. One typical
immune reaction in infants and children is PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection. Another disorder is Sydenham's chorea,
which results in more abnormal movements of the body and fewer
psychological sequellae. Both are immune reactions against brain tissue
that follow infection by Streptococcus bacteria. Susceptibility to these immune diseases may be genetically determined, so sometimes several family members may suffer from one or both of them following an epidemic of Strep infection.
Infectious diseases
Systemic
infections can result in neurodevelopmental consequences, when they
occur in infancy and childhood of humans, but would not be called a
primary neurodevelopmental disorder per se, as for example HIV
Infections of the head and brain, like brain abscesses, meningitis or
encephalitis have a high risk of causing neurodevelopmental problems and
eventually a disorder. For example, measles can progress to subacute sclerosing panencephalitis.
A number of infectious diseases
can be transmitted congenitally (either before or at birth), and can
cause serious neurodevelopmental problems, as for example the viruses
HSV, CMV, rubella (congenital rubella syndrome), Zika virus, or bacteria like Treponema pallidum in congenital syphilis, which may progress to neurosyphilis if it remains untreated. Protozoa like Plasmodium or Toxoplasma which can cause congenital toxoplasmosis with multiple cysts in the brain and other organs, leading to a variety of neurological deficits.
Some cases of schizophrenia may be related to congenital infections though the majority are of unknown causes.
In a child, type 1 diabetes can produce neurodevelopmental damage by the effects of excess or insufficient glucose. The problems continue and may worsen throughout childhood if the diabetes is not well controlled. Type 2 diabetes may be preceded in its onset by impaired cognitive functioning.
A non-diabetic fetus can also be subjected to glucose effects if its mother has undetected gestational diabetes.
Maternal diabetes causes excessive birth size, making it harder for the
infant to pass through the birth canal without injury or it can
directly produce early neurodevelopmental deficits. Usually the
neurodevelopmental symptoms will decrease in later childhood.
Phenylketonuria,
also known as PKU, can induce neurodevelopmental problems and children
with PKU require a strict diet to prevent mental retardation and other
disorders. In the maternal form of PKU, excessive maternal phenylalanine
can be absorbed by the fetus even if the fetus has not inherited the
disease. This can produce mental retardation and other disorders.
Nutrition
Nutrition disorders and nutritional deficits may cause neurodevelopmental disorders, such as spina bifida, and the rarely occurring anencephaly, both of which are neural tube defects with malformation and dysfunction of the nervous system
and its supporting structures, leading to serious physical disability
and emotional sequelae. The most common nutritional cause of neural tube
defects is folic acid deficiency in the mother, a B vitamin usually found in fruits, vegetables, whole grains, and milk products.
(Neural tube defects are also caused by medications and other
environmental causes, many of which interfere with folate metabolism,
thus they are considered to have multifactorial causes.) Another deficiency, iodine deficiency,
produces a spectrum of neurodevelopmental disorders ranging from mild
emotional disturbance to severe mental retardation.
Excesses in both maternal and infant diets may cause disorders as
well, with foods or food supplements proving toxic in large amounts.
For instance in 1973 K.L. Jones and D.W. Smith of the University of Washington Medical School in Seattle
found a pattern of "craniofacial, limb, and cardiovascular defects
associated with prenatal onset growth deficiency and developmental
delay" in children of alcoholic mothers, now called fetal alcohol syndrome, It has significant symptom overlap with several other entirely unrelated neurodevelopmental disorders. It has been discovered that iron supplementation in baby formula can be linked to lowered I.Q. and other neurodevelopmental delays.
Brain trauma in the developing human is a common cause (over 400,000
injuries per year in the US alone, without clear information as to how
many produce developmental sequellae) of neurodevelopmental syndromes. It may be subdivided into two major categories, congenital injury (including injury resulting from otherwise uncomplicated premature birth) and injury occurring in infancy or childhood. Common causes of congenital injury are asphyxia (obstruction of the trachea), hypoxia (lack of oxygen to the brain) and the mechanical trauma of the birth process itself.
Diagnosis
Neurodevelopmental
disorders are diagnosed by evaluating the presence of characteristic
symptoms or behaviors in a child, typically after a parent, guardian,
teacher, or other responsible adult has raised concerns to a doctor.
