Overview
A monogenic disorder caused by mutations in the FMR1 gene. Hereditary mental retardation syndrome is characterized by moderate to severe mental retardation with peculiar facial features such as a prominent forehead and abnormally floppy skin. There is no effective treatment for the Fragile X Mental Retardation Gene 1 (FMR1) mutation, and behavioral and speech therapy is the primary treatment strategy.
Definition
Fragile X syndrome is a monogenic disorder with X-linked incomplete dominant inheritance. It is an inherited mental retardation syndrome caused by mutations in the fragile X mental retardation gene 1 (FMR1).
Fragile X syndrome is second only to Down syndrome in prevalence and is the most common single-gene disorder causing inherited mental retardation and autism spectrum disorders [1].
Incidence
Fragile X syndrome has a prevalence of 0.73 to 0.92 per 100,000 and accounts for 10% to 20% of disorders causing mental retardation in males.
The prevalence is 1/7000~1/5000 in males and 1/6000~1/4000 in females [2].
Etiology
Causes of the disease
More than 95% of Fragile X syndrome is due to repeated amplification mutations and aberrant methylation of the trinucleotide sequence (CGG) n repeat of the non-coding region at the 5′ end of exon 1 of FMR1, located on the X chromosome [1].
In a minority of patients, this is due to FMR1 point mutations or deletion mutations.
Abnormalities in the protein encoded by FMR1 can significantly affect brain and testicular growth, development and function.
Risk factors
Parents who are carriers of the FMR1 mutation gene have an increased likelihood of the disease in the next generation.
People with a family history of fragile X syndrome.
Pathogenesis
FMR1 (CGG)n is polymorphic in the number of CGG repeats n during transmission from parent to self. In the normal population, n is 5-44. Depending on the degree of CGG amplification, FMR1 mutations can be categorized into the following four types [2].
Intermediate critical state
n is 45~54,also known as gray zone.
Usually no fragile X syndrome manifestations, but ataxia, peripheral neuropathy, depression or anxiety can occur. Parental n < 55, offspring do not develop fragile X syndrome.
Pre-mutation
n is 55 to 200.
Depending on environmental and genetic factors, some will show clinical manifestations and others will show normal manifestations.
Primary premature ovarian failure (early menopause before 40 years of age) occurs in about 1/5 of pre-mutant females and tremor/ataxia syndrome in pre-mutant males.
The syndrome has two main clinical manifestations: late-onset, progressive cerebellar ataxia (gait ataxia) and intention tremor.
Parents are pre-mutant and offspring are likely to be full mutant; the n carried by a female parent determines the risk of developing the disease in the offspring, and when n ≥ 100, her offspring are almost exclusively full mutation carriers.
Full mutation
n≥200.
This is manifested by the fact that all males are fragile X syndrome patients, while 30% to 50% of female heterozygotes have varying degrees of mental retardation.
Chimeric
is a variant phenotype.
It occurs in both sexes when carrying a full mutant allele with a combined deletion, and is more prevalent in males.
Symptoms
Main Symptoms
Patients of different ages and genders may present differently. Male patients are more symptomatic than female patients, and the clinical manifestations are usually atypical before puberty.
The main clinical features of adolescent children include intellectual disability, giant testes, peculiar facial features, speech disorders and behavioral abnormalities [2-4].
Intellectual disability
Except for a few male carriers with normal intelligence, most male patients show moderate to severe intellectual disability, and the intelligence quotient (IQ) of patients with full mutation is between 30 and 50.
This is reflected in low levels of abstract thinking, reasoning, concept formation, and ability to complete tasks.
Female patients have a more complex presentation, with 30% having normal intelligence and 70% having varying degrees of mental retardation, of which approximately 25% have an IQ <70.
Macrotesticular Disease
Male patients have significantly larger testes than their peers after puberty.
Specialized facial features
There are special facial features such as prominent forehead, long and narrow face, hypoplasia of the middle part of the face, single ear whorl, large auricle, wide nose root, large and protruding jaw, high palatal arches, thick lips and protruding lower lips.
Speech disorder
All male patients and 60% to 75% of female patients have articulation defects.
There are also speech disorders corresponding to the level of intelligence, slurred speech, tendency to growl when stimulated, and lack of verbal expression.
Behavioral abnormalities
Some children may be autistic, timid, anxious, and withdrawn.
Others may be hyperactive, agitated, manic, inattentive, and have destructive behavior, often tearing clothes, breaking things, or having sudden aggressive behavior.
Some children may make sudden attacks on relatives or people they don’t know, inflicting fatal injuries.
Neurological abnormalities
Difficulty in movement of the limbs, accompanied by clumsy involuntary movements, joint ankylosis, and generalized hyperreflexia may be present.
Connective tissue abnormalities
Flat feet, hyperextension of finger joints, abnormally loose skin and dislocation of joints.
Other symptoms
Affected children tend to be taller and heavier than normal children.
Some patients also have strabismus, ear infections and seizures.
A few female carriers of premutation show primary ovarian dysplasia (no development of sex signs during puberty, no normal menstrual cycle, etc.), anxiety, depression, chronic pain syndromes (fibromyalgia, chronic migraines), hypertension, vertigo, low sense of smell, and hearing loss.
Consultation
Department of Medicine
Pediatrics
If a child develops mental retardation, facial abnormalities, speech disorders, seizures, etc., it is recommended that he or she seek medical attention promptly.
Neurology
Neurology can also be consulted if the above symptoms are present in children or adults.
Preparation
How to prepare for your visit: registering, preparing documents, and frequently asked questions.
Tips for your child’s visit
Parents should keep a record of the time, characteristics, and changes in the child’s symptoms for the doctor’s reference.
Preparation Checklist
Symptom list
Pay special attention to the time of onset of symptoms, special manifestations, etc.
Are there any symptoms such as mental abnormality, behavioral abnormality and speech disorder?
When did the symptoms start to appear?
Are there any symptoms such as difficulty in movement of limbs, joint ankylosis, etc.?
Medical history checklist
Is there a history of Fragile X syndrome in the child’s family?
Does any of the child’s parents carry the FMR1 mutation gene?
Has the child been given prenatal screening and diagnosis? What were the results?
Diagnosis
Basis of Diagnosis
medical history
Child has a family history of fragile X syndrome.
The child’s parents are carriers of the FMR1 mutation gene.
Clinical manifestations
Symptoms
Mental retardation manifestations, e.g., learning disabilities, cognitive deficits.
Language and behavioral disorders, such as dysarthria, late speech, and repetitive speech.
Emotional abnormalities, such as having ADHD, autism, aggressive behavior.
There are cosmetic abnormalities such as prominent forehead, large ears, and protruding jaw.
There are huge testicles, motor difficulties, seizures, etc [2-3].
Laboratory tests
Cytogenetic testing
Chromosomal analysis of peripheral blood cells is performed in medium with low or no folate and thymidine.
＞A >2% is indicative of positivity, but the positivity rate is low and carriers cannot be detected. Cytogenetic testing can make a diagnosis in patients with significant clinical manifestations.
Molecular Genetic Testing
Triple-primer PCR: It can accurately detect n in ( CGG) n with high sensitivity, low DNA sample requirement, reliable and reproducible results. Therefore, triple-primer PCR has become the gold standard for the initial clinical diagnosis of fragile X syndrome [2,7].
Southern blot hybridization: it can detect FMR1 alleles, including normal, premutation, and full mutation, and can detect the methylation status of the FMR1 promoter, but the resolution of the detection of intermediate status and premutation is lower, and there is a certain rate of leakage and misdiagnosis.
PCR amplification method: it can accurately detect (CGG)n repetitions and is suitable for the detection of intermediate state and pre-mutation range, but it is unable to amplify and detect the methylation of FMR1 gene with high degree of amplification. Therefore, PCR combined with Southern blot hybridization can compensate each other’s defects and improve the accuracy of detection.
Gene sequencing: for cases in which (CGG)n repeat testing does not reveal abnormal amplification and the clinical manifestations are highly compatible, gene sequencing can be considered as a method to de-mutate the coding of the FMR1 gene and determine whether there is a disease-causing point mutation or a small fragment insertion/deletion [2].
Differential diagnosis
Prader-Willi syndrome
Also known as hypotonia-hypogonadism-hypogonadism and obesity syndrome, this disorder predominantly affects the central nervous system and is characterized by clinical manifestations such as mild to moderate mental retardation, hypogonadism, obesity, and amygdala.
The disease is autosomal dominant and is due to a deletion or specific abnormality in the near mid-critical region of the long arm of chromosome 15. Laboratory tests are helpful in making the diagnosis.
Sotos syndrome
A congenital overgrowth disorder, generally autosomal dominant, caused mainly by microdeletion 5q35 of the NSDI-containing gene or mutations in the NSD1 gene.
Clinical manifestations include peculiar facial features (raised forehead, wide eye spacing, downward sloping eye fissure, long pointed jaw, high palatal arch, double temporal hair degeneration, etc.), overgrowth, developmental delay, and advanced bone age, etc. Clinical symptoms and laboratory tests are helpful in identifying the disease.
Klinefelter syndrome
Also known as congenital testicular hypoplasia syndrome, it is a highly prevalent sex chromosome disorder that results in testicular hypoplasia and infertility due to an abnormality of the sex chromosomes.
The main manifestations are a long and thin body, delayed pubertal development, inconspicuous male secondary sexual characteristics, no beard, no laryngeal nodes, fair skin, small testes, and a small penis. Most of the affected children have IQ levels within the normal range, but the average IQ is about 10-15 points lower than the normal population [2,5-6].
Treatment
Aims of treatment: to improve the symptoms of mental retardation and social difficulties in children in order to improve their quality of life.
Treatment principle: There is no effective treatment for this disease, and the main treatment strategies include language training and behavioral therapy [8].
Language training
Exercise the language ability, so that children can learn to communicate and exchange with others.
According to the existing language level of the child, develop a training program.
Use simple and clear speech as much as possible.
From recognizing objects, naming to expression, from simple syllables to complete sentences, step by step.
Take care to utilize the child’s preferences for reinforcement and encouragement.
When a certain level is reached, let the child participate in language communication games, such as word solitaire, guessing words, and so on.
Create a language environment, integrate language training into daily life environment, and learn language in play.
Behavioral therapy
Reward good behaviors and punish bad behaviors so that children can gradually develop good behavioral habits and reduce bad behaviors.
Imitation
When a child sees a model being punished for displaying an aggressive behavior, the child realizes that the behavior is forbidden and thus reduces the aggressive behavior.
De-escalation
When a child’s aggressive behavior does not cause harm to others or to his own personal safety, it can be ignored so that the child will gradually reduce his aggressive behavior due to lack of attention and reinforcement.
Token therapy
This refers to taking away a certain number of positive reinforcers, which can be toys or opportunities to watch TV or travel, etc., after the problem behavior occurs.
For example, after a child exhibits aggressive behavior of hitting, the child’s right to play with toys is taken away this time.
Medication
The main symptomatic drug treatment, due to the individual clinical manifestations of large differences, the doctor will choose the appropriate drugs for the individual situation, and at the same time combined with non-pharmacological treatment.
For patients with anxiety and depression, 5-hydroxytryptamine reuptake inhibitors can be applied.
Alpha agonists can improve ADHD, such as colistin and propranolol.
Some studies have shown that minocycline significantly improves anxiety and mood-related abnormal behavior in children with fragile X syndrome [2,9].
Prognosis
Cure.
There is no cure for fragile X syndrome.
Patients with mild cases can return to normal life with early intervention, while patients with severe cases require long-term family care if their condition does not improve.
Hazards
Fragile X syndrome can affect a child’s intelligence and social skills. If the symptoms are severe, the child will not be able to take care of himself or herself and will not be able to socialize normally, and will need family care for the rest of his or her life.
Daily
Daily management
Parents can assist the child in daily life such as eating, dressing and preventing accidents according to the child’s level of self-care.
If the child is unable to eat on his/her own, he/she should be fed patiently to ensure adequate nutritional supply.
When the child has aggressive behavior, the hands and feet can be tied with restraining straps and fixed to the bed, but be careful not to affect blood circulation.
When children have seizures, they need to remove objects around them that may cause injuries and guard them to avoid collisions that may cause skin damage, dislocation or falling out of bed.
Parents should give children care and love, encourage them to communicate with others, and help them build confidence and overcome psychological and behavioral barriers such as low self-esteem and loneliness.
Prevention
Detection of carriers of the causative gene is an important link in the prevention and treatment of fragile X syndrome, and prenatal diagnosis is an important preventive tool to prevent the birth of affected children [3,10].
Patients with fragile X syndrome should be investigated in the family line to detect heterozygosity and undergo genetic counseling and prenatal diagnosis.
High-risk pregnant women should be prenatally examined and pregnancy should be terminated if a male fetus is found to be positive for fragile X syndrome.