Fragile X syndrome is a hereditary disease characterized by persistent intellectual decline, autism spectrum disorders and specific phenotypic features. The key symptom is a lack of cognitive functions. Hyperactivity, lack of communicative abilities, isolation are noted. The face is elongated, the auricles are large, the forehead is protruding, the tip of the nose is curved. Diagnosis is based on clinical and anamnestic data and the results of biogenetic analysis. Treatment is symptomatic, includes the use of medications and psychological and pedagogical correction.
ICD 10
Q99.2 Brittle X chromosome
General information
Fragile X syndrome (Martin-Bell syndrome) got its name from the surnames of the researchers who first described the pathology. In 1943, physiologists from Great Britain D. Martin and D. Bell studied 11 cases of oligophrenia in men from the same family, in which women had normal intellectual development. The genetic basis of the disease was identified in 1969 by the American geneticist G. Labs. The synonymous name is the syndrome of the brittle X chromosome. The prevalence among boys is 1:4,000, among girls – 1:6,000. According to the data of geneticists, the frequency of Fragile X syndrome in male patients with mental retardation reaches 1.9-5.9%.
Causes
Fragile X syndrome is the result of a defect in the FMR1 gene located on the X chromosome. Inheritance occurs according to a dominant gender-linked type with incomplete penetrance. Men have one X chromosome, so the mutant allele always provokes the disease. Women have two X-type sex chromosomes: one is active, the other is redundant, inactivated. Thus, in the presence of a mutation in one of the two FMR1 genes, the disease manifests itself or not depending on the activity of the altered chromosome. Men with a brittle X chromosome cannot pass it on to their sons, but they pass it on to all daughters who either get sick or remain healthy carriers of the mutation. Women with a defective chromosome pass it on to children of both sexes with a 50% probability. The inheritance of the syndrome increases from generation to generation, this phenomenon is called the Sherman paradox.
Pathogenesis
Sequencing of the FMR1 gene revealed that the basis of the symptoms and cytogenetically determined fragility of chromosome X is a multiple increase in the number of single trinucleotides of CGT. This leads to the suppression of transcription and the subsequent insufficient production of the FMR1 protein responsible for the development of the central nervous system, namely, for the formation of axons and synapses, the appearance and complication of neural connections, the success of learning and memorization processes.
A section of chromosomes subject to structural changes in hereditary Fragile X syndrome can be in four states characterized by various elongation of repeating sequences of trinucleotides. In the absence of illness and carrier, the normal number of repetitions is determined – from 6 to 39. In the intermediate state, 40-60 repetitions are diagnosed, in the premutation state – 55-200. In both cases, the disease is absent. Since the expansion of trinucleotides is possible only during gametogenesis, premutation can turn into a complete mutation. This happens during the transmission of an altered maternal gene, the allele “becomes heavier” during ovogenesis. With a complete mutation, more than 200 CGG repeats are detected, most often from 230 to 4,000.
Symptoms
Children are born with an increased body weight, on average – 3.5-4 kg. The phenotypic features of infants are the first to attract attention. Macroorchism is characteristic – testicular enlargement without endocrine disease. The circumference of the head is larger than normal or corresponds to its upper limits. The forehead is high and wide, the face is elongated with a flattened middle part. The nose has a slightly beak-shaped bend, the auricles are large, located low. The joints are characterized by good mobility, the bones of the hands and feet are wide. The skin is often hyperelastic, the hair and irises of the eyes are a light shade. Phenotypic signs can be expressed in different ways, from one or two barely defined to a complete complex.
The key clinical manifestation of the disease is mental retardation. Persistent intellectual decline is manifested by the weak development of complex forms of thinking and memory. Patients cannot understand abstract-logical statements and phenomena, use categories, establish analogies. Comparison, analysis and generalization can be carried out at a simple level, for example, in specific everyday situations. The vocabulary is depleted. Many boys have an IQ of 40-50 points, less often reaches 70-79. Nominative speech and visual perception are relatively preserved. In girls, cognitive decline is less pronounced, corresponds to a mild degree of oligophrenia or a borderline level of intellectual development.
Another typical symptom of the disease is the peculiarity of speech. It is accelerated, confused, replete with repetitions, echolalia and perseverations. Autistic disorders are represented by communication difficulties and behavioral disorders. Children often show aggressiveness and isolation when trying to establish contact. In severe cases, mutism develops – a complete absence of speech as a means of communication. Motor disinhibition, hyperactivity, stereotypes, self-harm prevail in behavior. Patients avoid eye contact, do not allow touching, but compared to patients with autism, there is an interest in communication. Stereotypical movements include hand clapping, jumping, rotating around its axis, shaking hands, running in circles, grimacing and monotonous whimpering. There are difficulties in planning and controlling behavior, switching attention and spatial coordination.
Neurological symptoms are nonspecific. A slight decrease in muscle tone, motor discoordination is determined. Insufficient development of fine motor skills makes it difficult to master writing, some gaming and household skills (assembling a designer, drawing, sewing, etc.). Some patients have oculomotor disorders, increased tendon reflexes, extrapyramidal parakinesis, for example, closing eyes, frowning eyebrows, grimacing. In severe forms of the syndrome, epileptic seizures occur. 25% of patients with premutation condition develop primary ovarian insufficiency.
Diagnostics
With pronounced phenotypic changes, the disease can be detected from the first months of a child’s life – neonatologists and pediatricians pay attention to the enlarged size of the testicles and the characteristic features of the face. In other cases, suspicion of mental retardation occurs at the age of six months to 2-3 years. During this period, there is a lag in mental development, behavioral and speech disorders. Differential diagnosis is aimed at excluding ASD, in particular early childhood autism, as well as mental retardation of another origin (not related to the fragility of the X chromosome). The examination is carried out by psychiatrists, neurologists and geneticists, includes:
- Clinical survey, examination. In a conversation with a child, a decrease in intelligence, hyperactivity and disinhibition of behavior, a violation of communication skills come to the fore. The level of mental development does not correspond to age, the methods of intelligence research reveal oligophrenia (IQ – 40-79 points). Externally, characteristic phenotypic signs are observed, neurological examination reveals muscle hypotension, enhanced tendon reflexes, parakinesis.
- Genealogical analysis. Unlike other forms of oligophrenia, Fragile X syndrome has a hereditary transmission of the disease. As a rule, the patient has relatives with this disease, more often men (grandfather, uncle, brother). Sometimes signs of mild intellectual decline are found in the mother, but her diagnosis is often not established (not confirmed).
- Genetic research. In laboratory conditions, the structure of DNA is studied: the number of CGT repeats and the status of methylation are determined. PCR and cytogenetic method are used. The diagnosis is confirmed if the number of triplet repeats is more than 200. With a result of 60-199, mild phenotypic manifestations of the disease are possible, the risk of developing pathology in the next generation (if the indicator is diagnosed in a woman).
Treatment
There are currently no methods of specific therapy of the syndrome. Symptomatic drug treatment and psychological and pedagogical correction are carried out. The efforts of doctors and special psychologists are aimed at minimizing emotional and behavioral deviations, mastering the skills of walking, speech and communication, reading and writing. Drug therapy includes the use of psychostimulants, antidepressants, nootropics, antiepileptic drugs and hormonal drugs (for primary ovarian insufficiency). Patients are trained according to special correctional and developmental programs. Methods of cognitive behavioral therapy and group trainings are used to improve social skills.
Prognosis and prevention
Fragile X syndrome has no complications and does not shorten the life expectancy of patients, therefore, with timely and adequate medical, psychological and pedagogical assistance, the prognosis is quite favorable: patients master communication and self-service skills, study in special schools, sometimes master working professions. Prevention is based on medical and genetic counseling of couples from risk groups and prenatal diagnosis of the syndrome. These measures are necessary for women with premature ovarian depletion syndrome, families in which FMR1 premutation conditions have been diagnosed or cases of intellectual disability in boys and men have been identified.