Aicardi-Goutières syndrome is an enormously rare, autosomal recessive genetic mutation that causes a genetically heterogeneous developmental disorder in the brains of infants around three months of age and is associated with spasticity and epilepsy in addition to severe motor impairments. A maximum life expectancy of ten years is considered a guideline for severe phenotypes, although milder phenotypes with RNASEH2B mutations may live beyond ten in some circumstances.
What is Aicardi-Goutières syndrome?
Aicardi-Goutières syndrome is the medical term for an autosomal recessive inherited disorder that corresponds to a genetically heterogeneous developmental disorder of the brain in babies around three months of age. Aicardi-Goutières syndrome is an autosomal recessive hereditary disease corresponding to a genetically heterogeneous developmental disorder of the brain in babies aged around three months. Clinically, the syndrome has a similar appearance to an intrauterine infection, i.e. an infection acquired in the womb, but no pathogens can be detected because the cause is genetic. Certain cell nucleus enzymes are less active than usual due to the genetic defect and thus purify the chromosomes significantly less from spurious RNA proteins. This leads to an accumulation of DNA segments in the cells. As the cells die as a result, the immune system becomes active and causes inflammation at the corresponding sites. In 1984, the French physicians Françoise Goutières and Jean François Aicardi described this phenomenon for the first time. Since then, fewer than 150 cases have been reported, so the genetic defect is correspondingly rare. Individual cases have so far been observed mostly concentrated in families, since there is a 25 percent chance that a second child will also develop the syndrome.
Causes
There is no acquired form of Aicardi-Goutières syndrome. The developmental brain disorder is always congenital and results from an autosomal recessive gene mutation that is passed on. In order to trigger an outbreak of the disease, the defective gene must accordingly be present on both sides of the inheritance pathway. However, new mutations are also possible. Five gene loci have been linked to the mutation so far. These include TREX1, RNASEH2A, RNASEH2B and RNASEH2C, and SAMHD1. The first descriptions of the syndrome assume a cause related to the TREX1 gene on chromosome 3p21. The RNASEH2-A genes are gene loci for three different proteins that play a role in the formation of the trimeric cell nuclear enzyme RNase H. This cell nuclear enzyme is in turn responsible for clearing DNA of misplaced RNA molecule building blocks. Without RNase H, early embryonic death occurs. If, on the other hand, the cell nuclear enzyme is present but not fully active, individual fragments of certain genes become incorporated into the body’s cells. In doing so, they cause apoptosis, which triggers an inflammatory process based on the natural immune response.
Symptoms, complaints, and signs
Children with Aicardi-Goutières syndrome are difficult to feed. They exhibit jerky eye movements and fidgeting and suffer from mild fevers and vomiting. Slightly less than half of the affected children lose their previously learned motor skills after about six months. With regard to motor skills, pyramidal signs appear in particular. In addition to spastic paralysis, there may be uncoordinated movements that cause the muscles of both the arms and legs to contract or cause seizures. In some cases, in addition to the disturbance of muscle tone, organs such as the liver and spleen are enlarged. Later, there is an increasing delay in psychomotor development. Occasionally, frostbite-like skin changes also occur.
Diagnosis and course
Differentially, if Aicardi-Goutières syndrome is suspected, the physician must exclude Toxoplasma parasites in particular. Computed tomography shows bilateral calcifications in the basal ganglia in AGS. Brain substance loss and brain substance malformations may also be computed tomographic evidence. Nerve fluid examination shows increased CSF lymphocytosis levels and alpha-interferons, indicating an inflammatory process in the central nervous system. In serum, platelets are decreased in AGS patients and liver enzyme levels are increased at the same time.As far as the course of the disease is concerned, many of those affected die in childhood, with ten years being considered the maximum life expectancy for particularly severe forms of the mutation. Patients with milder forms also often live beyond ten years. These milder phenotypes mostly correspond to RNASEH2B mutations, as they are present in nearly half of all cases. The disease progresses over several months at onset until multiple disabilities are present. However, the disease usually stabilizes to a steady course after these initial months. Although almost all patients older than ten have had severe multiple disabilities to date, much milder courses have also occurred in individual cases.
Complications
Aicardi-Goutières syndrome presents with severe complications that can have a major negative impact on the lives of individuals and children. In most cases, the syndrome is manifested by difficulty feeding and movements of the eyes that are jerky and uncontrolled. As the disease progresses, fever and vomiting become more frequent. In Aicardi-Goutières syndrome, children show spastic paralysis of the arms and legs, so that they cannot coordinate and move them properly. In the worst cases, seizures can occur, which can be dangerous, especially in children. Aicardi-Goutières syndrome also causes mental retardation. In most cases, death occurs in childhood due to the symptoms, so that life expectancy decreases enormously. If the child with Aicardi-Goutières syndrome does not die, there are significant complications and difficulties in everyday life. Due to the physical and psychological limitations, the patient is always dependent on the help of other people and caregivers. Usually, a stay in the hospital is also necessary. Aicardi-Goutières syndrome can also affect the liver and spleen, causing them to enlarge. This usually results in pain in the respective organs.
When should you see a doctor?
In most cases, Aicardi-Goutières syndrome cannot be treated by a doctor. In this case, death of the patient occurs after the first ten years of life. As a rule, the symptoms are already diagnosed by a pediatrician. However, parents can consult a pediatrician in case of noticeable delays in development or development of various spasticities. A visit to the doctor is also necessary in the case of jerky movements and a strong and persistent fever. Usually, the fever and vomiting can be limited by medication. It is not uncommon for children to also suffer from paralysis and convulsions. These can also be limited by treatment, so in these cases a visit to the doctor is also recommended. In acute emergencies or seizures, an emergency doctor may also be called. It is not uncommon for parents to suffer from psychological distress or depression as well. In this case, psychological treatment of the parents is recommended. This should be followed by psychological care, especially after the death of the child from Aicardi-Goutières syndrome.
Treatment and therapy
To date, Aicardi-Goutières syndrome cannot be treated causally, but only symptomatically. In this context, seizures can be prevented, for example, by administering antiepileptic drugs. Physiotherapeutic measures are usually used to reduce spasticity and contractures. Certain ointments and creams can be used to counteract skin symptoms. Therapy options also include early intervention, in the course of which not only the affected children but also, and above all, the parents are cared for.
Outlook and prognosis
Due to Aicardi-Goutières syndrome, there are various deformities and burdens for the patient. Often, the child’s parents in particular are affected by severe psychological distress and depression and therefore require psychological care. The child itself suffers from severe limitations and epileptic seizures. There are intense episodes of fever and vomiting. Often the child also suffers from uncontrollable movements of the eyes and paralysis of different parts of the body. Furthermore, seizures may also occur, which are not infrequently associated with pain. The child’s development is severely restricted by the Aicardi-Goutières syndrome and motor function disorders occur.The central nervous system is also negatively affected by the syndrome. The patient’s quality of life is extremely limited and the affected person is usually dependent on the help of other people in everyday life. Aicardi-Goutières syndrome cannot be treated, which is why only the symptoms can be limited. The epileptic seizures can be reduced relatively well with the help of medication. Furthermore, various therapies are available to the patient.
Prevention
While still in the womb, a fetus can be screened for Aicardi-Goutières syndrome by taking an amniotic fluid sample. In some circumstances, expectant parents may decide not to have the baby as a result. No other preventive measures are available because the syndrome is a mutation.
Follow-up
The options for follow-up care are relatively limited in Aicardi-Goutières syndrome. The patient is always dependent on medical treatment to relieve symptoms and prevent possible complications. As a rule, the syndrome also considerably limits the life expectancy of the affected person. Since the disease is hereditary, it cannot be treated completely. Purely symptomatic treatment is available to the patient. Furthermore, if the patient wishes to have children, genetic counseling can be performed to prevent the recurrence of Aicardi-Goutières syndrome. Affected individuals are usually dependent on taking medications. These must be taken regularly, and possible interactions with other medications should also be considered. The children are given appropriate therapy and support to counteract the spasticity. However, they cannot be completely cured. Often, contact with others affected by Aicardi-Goutières syndrome has a positive effect on the further course of the disease. This often leads to an exchange of information and thus to an easing of everyday life. Furthermore, the parents are often also dependent on psychological treatment. In this context, conversations with friends or with acquaintances can also be helpful.
This is what you can do yourself
Aicardi-Goutières syndrome is a disorder with multiple disabilities. Parents will have to seek permanent medical treatment with their child. The burden on parents is very high and psychological care is highly recommended. Further professional help for the daily care of the child should also be sought without hesitation. If there are other children in the family, the possibility of placement in a care facility should also be discussed. Since the sick child requires intensive care, the burden should not be underestimated. For parents with a sick child, the risk of depression is particularly increased. Taking care of one’s own health – both physical and psychological – should not be neglected. Parents can only be a stable support for their child if they themselves are stable. Seizures and frequent vomiting require constant observation of the child. In all the activities of daily living, the child needs parental or professional care. Parents must provide sufficient exercise through motor exercises, make the child’s diet rich in vital substances and easily digestible, and ensure adequate hydration. Above all, physiotherapeutic support is fundamentally important for reducing spastic seizures and accompanies drug therapy with antiepileptic drugs. Dermatoses can be treated supportively by parents by careful application of creams and ointments.
