◎Our reporter Jin Feng

　　At present, doctors mostly use symptomatic treatment and comprehensive behavioral and language therapy to help patients with Fragile X syndrome to improve their condition.

Scholars from various countries are also exploring the use of targeted therapy, gene therapy, protein replacement and other therapies to help patients with Fragile X syndrome get rid of their pain.

　　This is a group of people that are easily overlooked.

When they were young, they looked like children their age, but as they got older, they showed symptoms such as mental retardation, hyperactivity, anxiety and delayed speech, and sometimes seizures.

They are patients with Fragile X Syndrome (FXS), which affects about 1/4000-1/8000 of the population.

　　As a hereditary disease caused by a single gene mutation on the X chromosome, Fragile X syndrome currently has no specific cure.

Due to the lack of awareness of the disease, many families have difficulty in making accurate diagnosis and intervention in the early stages of child development.

　　At present, doctors mostly use symptomatic treatment and comprehensive behavioral and language therapy to help them improve their condition.

Scholars from various countries are also exploring the use of targeted therapy, gene therapy, protein replacement and other therapies.

Some researchers have called for the establishment of guidelines for the diagnosis and treatment of Fragile X syndrome in my country, the construction of a multidisciplinary diagnosis and treatment model, and the improvement of the overall cognition and diagnosis and treatment of Fragile X syndrome.

　　July 22 is Fragile X Syndrome Cares Day.

Where does Fragile X Syndrome come from, how does it work, and what are the latest treatment strategies?

　　Caused by genetic mutation, more common in males

　　"Fragile X syndrome is a rare disease that is more common in men. Among men with mental retardation, the number of patients with Fragile X syndrome is second only to Down syndrome." Department of Children's Health, Children's Hospital Affiliated to Nanjing Medical University Deputy Chief Physician Li Rong has done statistics. Among the 780 boys with mental retardation and autism he treated from December 2019 to June 2021, 15 were diagnosed with Fragile X syndrome.

　　Fragile X syndrome, also known as Martin-Bell syndrome.

In 1943, scholars Martin and Bell discovered that X chromosome abnormalities existed in mentally retarded patients in two generations of a family.

In 1991, some scholars discovered the Fragile X intellectual disability 1 (FMR1) gene located on the X chromosome, which enabled Fragile X syndrome to be diagnosed by genetic diagnosis.

　　"The cause of Fragile X syndrome is mainly the abnormal expansion of the CGG trinucleotide repeat sequence in the promoter region of the FMR1 gene. Normal people have 6-44 CGG repeats in the FMR1 gene, while patients with premutation of the FMR1 gene have 55-200 CGG repeats. There are more than 200 CGG repeats in patients with full mutation." Wu Wei, chief physician of the Reproductive Center of Jiangsu Provincial People's Hospital (The First Affiliated Hospital of Nanjing Medical University), said that compared with normal people, the increase of CGG repeats will make DNA methyl Metabolic abnormality, inactivation of FMR1 gene expression, resulting in the deletion of Fragile X mental retardation protein (FMRP), causing Fragile X syndrome.

　　Fragile X mental retardation protein is a regulator that is abundant in neurons.

Fragile X mental retardation protein controls the expression of several key molecular proteins during brain development.

When Fragile X mental retardation protein is deficient, neurons lose their ability to regulate multiple messenger RNAs, thereby affecting the function of the brains of people with Fragile X syndrome.

　　Familial inheritance, some symptoms are similar to autism

　　Fragile X syndrome is the most common disorder of intellectual disability and autism spectrum disorder, and the clinical manifestations of some patients also have some similarities with autism.

Wei Xing, chairman of the Beijing Fragile X Syndrome Care Center (hereinafter referred to as the Care Center), said: "At present, more than 800 autism susceptibility genes have been found, such as FMR1, MECP2, TSC1/TSC2, PTEN and other gene mutations, which can Cause autism. 5%-7% of children with autism have Fragile X Syndrome." She introduced that the incidence of Fragile X Syndrome in foreign populations is 1/4000-1/8000.

However, in my country, there is no large-scale survey data on the incidence of the general population.

　　Among the fragile X syndrome patients treated by Li Rong, the patients with fragile X syndrome are special, but sometimes lack recognition.

"They are not as easily identified as Down syndrome patients. When they are very young, their body shape and appearance are not much different from normal children, but some still can't speak or walk by the age of two or three, and some are eight years old. At the age of nine, he was taller and heavier than children of the same age, had a big head, big ears, and his testicles were larger than normal when he reached puberty." Li Rong introduced.

　　A reporter from Science and Technology Daily searched and found that there are similar descriptions in many common physical characteristics of patients with Fragile X syndrome: they develop rapidly, their foreheads are prominent, their faces are longer, and the middle of the face is hypoplastic, with large ears and nasal roots. Wide, large and protruding mandible, high arched palate, thick lips and prominent lower lip, with ape lines on the palm lines.

Most people with Fragile X syndrome present with symptoms such as hyperactivity, seizures, anxiety, and delayed speech.

　　It is worth noting that patients with Fragile X syndrome have strong familial aggregation, Li Rong told reporters: "If the mother carries the mutated gene, the son will have a 50% probability of developing Fragile X syndrome, although the daughter may not necessarily be sick. , but if you carry the mutated gene, you may also give birth to children with Fragile X syndrome in the future. Among the patients I treated, there were 9 patients with Fragile X syndrome in 4 families." She recalled, 2019 A mother brought her little son who was more than two years old with mental retardation to see a doctor and was finally diagnosed with Fragile X Syndrome, while her other son also suffered from Fragile X Syndrome.

　　There are three potential therapeutic directions

　　Early detection and early intervention will provide an important time window for disease treatment.

During the interview, a number of doctors and scholars said that with the improvement of the level of genetic testing, doctors can now screen patients with Fragile X syndrome through molecular genetic testing.

Wu Wei introduced: "The diagnosis of fragile X syndrome is mainly based on genetic methods, such as molecular genetic methods such as conventional PCR and methylation-specific PCR, to detect whether the number of CGG repeats is abnormal."

　　However, Wei Xing revealed that at present, the overall diagnosis rate of Fragile X syndrome in China is low. Many clinicians do not know much about Fragile X syndrome, and the clinical manifestations of patients with Fragile X syndrome are different, resulting in a low diagnosis rate and a misdiagnosis rate. high.

"The reason is that on the one hand, there is no diagnostic reagent for Fragile X syndrome in China, which makes it difficult to diagnose; on the other hand, there is still a lack of effective drugs for the treatment of Fragile X syndrome, and only a few drugs are in clinical trials." Wei Xing said.

　　However, scientists have been actively looking for ways to relieve Fragile X syndrome patients.

　　According to Wei Xing, there are currently three potential therapeutic directions in the world: one is the pharmacological reactivation of the FMR1 gene, which can affect DNA methylation and histone modification; the other is the use of non-coding RNA to treat Fragile X syndrome The third is gene therapy, which mainly treats Fragile X syndrome based on changes in the genome.

　　With the clarification of the molecular and biological mechanism of the disease, gene therapy, gene reactivation and protein replacement therapy have been placed high hopes.

　　Targeted therapy has also become a trend in the treatment of Fragile X syndrome, such as class I metabotropic glutamate receptor antagonists and gamma aminobutyric acid receptor agonists.

Studies have shown that the therapy may reverse the loss of Fragile X mental retardation protein, but it is still in the research stage.

　　In addition, the potential of new use of old drugs should not be underestimated, and there are also teams looking for therapeutic opportunities in emerging therapies such as AI-based drug discovery and induced pluripotent stem cells.

　　It is urgent to establish diagnosis and treatment standards and strengthen research

　　Before the arrival of the special drug, will humans be helpless against Fragile X syndrome?

Not also.

　　Wu Wei said: "Maternal inheritance is a common inheritance pattern of Fragile X syndrome, so prenatal screening is the first line of defense to prevent the birth of children with Fragile X syndrome. At present, only a few countries have included FMR1 gene screening in the routine of pregnant women. Check. In my country, the number of prenatal diagnoses for Fragile X syndrome is also much lower than that for Down's screening."

　　"If there have been children with mental retardation, intellectual disability with epilepsy, autism, etc. in the family, it is recommended that women get eugenic counseling and prenatal diagnosis before trying to conceive. If they carry the premutated FMR1 gene, genetic testing can be used to avoid fragility. A child with Syndrome X was born." Wu Wei said.

　　"Clinically speaking, behavioral and language training therapy is the main treatment strategy for Fragile X syndrome." Li Rong said.

　　In Wei Xing's view, there is an urgent need to establish the diagnosis and treatment standards for Fragile X syndrome in my country.

"For example, how to define pre-mutation carriers and full-mutation patients of FMR1 gene, and what tests should be done for the two." She believes that after clarifying the standard, it can not only improve the basic understanding of basic hospital doctors on Fragile X syndrome, but also Help primary hospitals to do referral work.

　　"More importantly, we also need policy support for the diagnosis and treatment of Fragile X Syndrome. At present, how many people in my country have the disease or carry the causative gene of Fragile X Syndrome, and whether it can be included in the management of rare diseases? Research is needed." She said that the inclusion of Fragile X syndrome in the list of rare diseases will provide a basis for the diagnosis and treatment of Fragile X syndrome, which will attract more scholars and enterprises to conduct academic research and clinical trials, and promote drug development and patient rehabilitation.

　　"We also hope to build a multidisciplinary diagnosis and treatment model, increase investment in scientific research, establish a research team and a cooperative training network, and break through the difficulties of clinical treatment." Wei Xing said.