Pain, difficulties in social life and obesity: Patients with Fragile X Syndrome live with some limitations. There are no medications – yet. Peptides appear to be a promising new option.
That Fragile-X-Syndrom (FXS) is a mutation in the X chromosome. In addition to cognitive disorders, there are a number of somatic influences such as the shape of the head, the reproductive system, the muscles and joints and an increased tendency to cramps. There is no specific drug treatment. However, the testing of drugs approved for other indications seems hopeful.
First described in 1943, FXS is a genetic X-linked disease resulting from an extension of a cytosine-guanine-guanine (CGG) sequence in the promoter region of the FMR1 gene. In addition to those affected with a fully developed syndrome, there are significantly more carriers of the disease gene. They have no or hardly any symptoms of the disease, but they can pass it on to their children.
FXS is the most common form of hereditary intellectual disability and Autism Spectrum Disorder (ASD) and affects approximately 1 in 4,000 males and 1 in 8,000 females worldwide. The higher rate in males is explained by the X-linked nature of the disease; in addition, about 10% of men with FXS show a phenotype similar to Prader-Willi Syndrome is. Regarding behavioral aspects of the disorder, males with the complete mutation show features of ASD about 90% of the time, with 60% meeting the diagnostic criteria for ASD.
A bit of genetics is a must
The inheritance is complex. Men carry the X and Y sex chromosomes, while women carry X and X. Since men only pass on their possibly affected X chromosome to their daughters, they can therefore inherit the disease. Sons, on the other hand, receive only the Y chromosome from their fathers; they cannot inherit the syndrome from their father. Women with FXS, on the other hand, have a 50 percent risk of passing the disease gene to both their sons and daughters. If a girl has inherited an unchanged X chromosome and a chromosome with the corresponding mutation, she can remain symptom-free if only the healthy X chromosome is active in the body. This is not possible with a son because he only has one X chromosome.
Many of the behavioral characteristics of ASD are also evident in patients with FXS, even when the diagnosis of ASD is not fully met. This includes poor eye contact, difficulties in relationships, performing repetitive tasks, and stress from small changes in daily activities. Patients with FXS may also exhibit self-injurious behavior as a result of this repetition, as well as attempts to relieve stress from external stimuli. Children often wave z. B. with their hands or bite the backs of their hands when they are exposed to particularly stressful situations. People with FXS are easily excitable and prone to violent outbursts of anger, especially when they are young.
Individuals with FXS exhibit pragmatic difficulties in social interaction and communication. This includes Problems with maintaining a topic of conversation, persistence, repetitive speech, impulsiveness, and inappropriate responses. The patients show different physical features such as a long face, prominent jaws and elongated ears in combination with macroorchids.
All of these behavioral, phenotypic, and clinical features of FXS are due to the absence of the protein FMRP, a well-characterized RNA-binding protein that exhibits crucial functions primarily involved in the metabolism of mRNAs related. In addition, over 30% of patients suffer from obesity and gastrointestinal disorders such as gastroösophagealem Reflux. Both men and women with FXS experience chronic neuropathic and musculoskeletal pain. However, women with FXS have significantly more often struggling with chronic pain.
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Characteristics |
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disease name |
Fragile-X-Syndrome |
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Other names |
Marker X Syndrome
Martin-Bell-Syndrom |
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frequency |
1:4,000 males and 1:8,000 females |
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disturbed function |
Cause: genetically caused lack of the protein FMRP cognitive developmental disorder, language and speech problems Learning difficulties, attention problems, behavior problems, aggression, lack of impulse control, anxiety, depression and obsessive-compulsive disorder Autism Spectrum Disorder Early growth spurt Long, narrow face, prominent ears, high palate and forehead testicular enlargement Reflux visual and hearing impairments heart valve defects |
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therapy |
symptom-oriented therapy Possibly. Antiepileptic drugs Behavior therapy, speech therapy Pharmacotherapy under investigation |
Epilepsy as a comorbidity
Epileptic seizures are observed in about 20% of FXS patients. Seizure onset is typically before age 10, with a very small proportion of male patients having seizure onset after age 15. A higher percentage of women have seizures after the age of 15, suggesting a slightly different pattern for seizure onset in women suggests.
Although seizures are not usually spontaneous, they indicate overexcitable cerebral circulation in FXS. They offer a means of valuation of excitability imbalance in research models and for testing therapeutic interventions in FXS.
Drug Therapy: Oldies, but Goldies?
The symptom-oriented drug therapy consists, among other things, of stimulants, selective serotonin reuptake inhibitors and atypical antipsychotic agents. This should be combined with speech therapy, sensory integration, occupational therapy and behavioral interventions.
The limited success of previous clinical trials of FXS has prompted researchers to consider combining different drugs. The aim is to correct the pleiotropic consequences caused by the lack of FMRP. Two drugs that at first glance appear to have nothing to do with FXS have been the subject of multiple investigations. The statin Lovastatin and the antibiotic Minocyclin.
With FXS, the lack of FMRP leads to Hyperphosphorylierung of extracellular signal-regulated kinase (ERK). Lovastatin inhibits the mevalonate pathway and consequently decreases ERK phosphorylation. The behavior of individuals with FXS aged 10 to 40 years associated with 3 to 4 years of therapy will be improved.
A double-blind, placebo-controlled Study demonstrated that minocycline given for 3 months significantly improved the CGI-I (Clinical Global Impressions Scale-Improvement) score in children with FXS (aged 3.5-16 years).
In an open clinical Study by Champigny et al. the combined administration of lovastatin and minocycline was investigated in adolescents and adults with FXS. The aim was to evaluate the safety and efficacy of a combination therapy. The authors hypothesized that the combination of lovastatin and minocycline, each targeting different signaling pathways, might have synergistic effects on cognition and behavior in individuals with FXS without additional side effects. Due to the intrinsic design of the study (open label), outcome measures are susceptible to the placebo effect and bias in observer expectation. Nevertheless, the result was rated as positive. “The combination of lovastatin and minocycline is safe in patients with FXS syndrome and appears to improve multiple elements of behavior,” the authors said.
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All of the strategies mentioned so far target different signaling pathways whose uncontrolled activity appears and continues to be crucial in the pathology of FXS, but also in other neurological diseases and cancers pleiotropen effects. Accordingly, the lack of specificity and selectivity could be the main disadvantages of these approaches.
The use of peptides or Peptidomimetics could be a new option in FXS pharmacotherapy. Most other pharmacological efforts are aimed at compensating for the lack of FMRP protein. Peptides are a promising pharmaceutical option because of their properties, namely high selectivity, safety and tolerability. However, this type of approach has never been used in FXS to restore the imbalance in protein synthesis.
One benefit: peptide therapy would not be a permanent procedure, but these molecules would only be administered for a limited period of time during the first few years of life in FXS children, when the brain is still modulating to allow proper formation of the synaptic network. Therefore it will workedsuggested that peptides/peptidomimetics could compensate for FMRP deficiency by restoring the imbalance in protein synthesis and actin dynamics.
Image source: Thomas Dumortier, unsplash.