The XLAG syndrome is one of the reduction malformations of the brain and corresponds to an extremely rare hereditary disease. Only male individuals are affected by the causative mutations. A causal treatment of the symptom complex is not yet available.
What is XLAG Syndrome?
Medicine summarizes diseases whose cause lies in a disturbed embryonic development of the central nervous system as reduction deformities of the brain. The congenital malformations of the brain can correspond to different characteristics. A rather strong manifestation consists in the missing formation of individual brain sections. For meaning of api in English, please visit sportingology.com.
However, reductions in the size of individual brain areas are also regarded as reduction malformations of the brain. Lissencephaly is based on a reduction malformation of the gyration. If there is no gyration at all, it is called agyria. Doctors speak of microgyria when the cerebral convolutions are reduced. All enlargements are considered macrogyria in medical circles.
Pachygyria is a mixed form that is based on reduced gyration with thickened cerebral convolutions. Lissencephaly, in the sense of a reduction malformation of the brain, is the main clinical feature of syndromes such as XLAG syndrome. The term XLAG corresponds to an acronym for X-linked lissencephaly with genital abnormalities.
Patients with the congenital hereditary disease therefore suffer from lissencephaly, corpus callosum agenesis and deformed genitals. XLAG syndrome was first described in 1999 by US pediatrician WB Dobyns and his associates.
XLAG syndrome only affects genetically male patients. In 2002, mutations in the X-chromosomal ARX gene of the gene locus Xp21.3 turned out to be the primary cause of the malformations. The gene reaches highest expression in the dorsal-ventral telencephalon as well as the germinal zone and the neo-cortical ventricular zone of the eminent ganglion.
It reaches lower levels of expression in the subventricular zone and the cortical plate, as well as in the hippocampus, basal ganglia and ventral thalamus. If the gene is missing, the tangential migration including the differentiation of all GABAergic interneurons within the eminence ganglion and the neocortex is affected. In a sequence arise the clinical features of XLAG syndrome.
The ARX mutations essentially correspond to chain termination mutations in the sense of larger deletions, frameshift mutations, nonsense mutations or splicesite mutations. In contrast, missense mutations associated with XLAG are rather rare and rarely lead to severe forms of XLAG syndrome.
Clinical pictures such as Proud’s and Partington’s syndromes are regarded as XLAG-related syndromes with similar mutations. There are no precise figures on the frequency of XLAG syndrome. So far, around 30 affected families have been documented in studies.
Symptoms, Ailments & Signs
Patients with XLAG syndrome show different symptoms depending on the severity of the symptoms. What they have in common is abnormal genitals and a neurological disorder that is usually severe. Lissencephaly with a postero-anterior gradient is present in almost all cases and is accompanied by mild cortical enlargement.
Agenesis in the sense of a missing corpus callosum completes the neurological picture. Most of those affected already show severe forms of epilepsy when they are newborns. The functioning of the hypothalamus is affected by disorders. For this reason, many of the patients suffer from disturbed temperature regulation with sweating or chills.
Intermediate genitalia with cryptorchidism or micropenis accompany the neurological symptoms. The clinical picture of patients with XLAG syndrome therefore differs significantly from that of classic lissencephaly patients. XLAG syndrome not only causes additional symptoms compared to classic lissencephaly.
Also, the cortex thickness for XLAG patients is only between six and seven millimeters, while the mutations in the PAFAH1B1 and DCX genes in classic lissencephaly lead to cortex thicknesses of 15 to 20 millimeters. The severity of the neurological manifestations differs from case to case in patients with XLAG syndrome and is related to the precise expression of the causative mutations.
Diagnosis & course of disease
Diagnosis of XLAG syndrome is based on neuroimaging, urological evaluation, and molecular genetic testing. Malformations of the brain sometimes leave those affected at the developmental stage of a baby. Depending on the severity of the epilepsy and other neurological symptoms, the life expectancy of those affected may be subject to more or less severe restrictions.
Due to the XLAG syndrome, patients suffer from a number of different malformations that have a very negative effect on the patient’s everyday life and quality of life. Those affected suffer from very large genitals and also from a neurological disorder.
Epilepsy can also occur as a result of illness, and in the worst case it can lead to death from an epileptic seizure. Many of those affected suffer from a disturbed sense of temperature, which can lead to injuries or an incorrect assessment of dangers. XLAG syndrome can lead to severe depression or psychological problems, especially in children, since they are often teased or bullied because of the deformities.
Speech development disorders are also not uncommon with this syndrome and are accompanied by swallowing difficulties, which can also significantly limit the intake of food and liquids. Since the treatment is always based on the symptoms of the XLAG syndrome and cannot be causal, there are usually no complications. However, complete healing cannot be achieved. Whether the syndrome has a negative effect on the life expectancy of those affected cannot be generally predicted.
When should you go to the doctor?
If a member of the family has a known diagnosis of XLAG syndrome, consultation with a doctor should always be sought when planning offspring. Since this disease is a hereditary health disorder, the possible risk of disease in the offspring can be discussed with a doctor in advance. In most cases, birth takes place in an inpatient setting. Doctors or obstetricians who are present carry out the initial examinations of the newborn in a routine process.
At this point, at the latest, the first visual abnormalities are noticed and documented. Further investigations are initiated until a diagnosis is made. In many cases, parents and relatives do not have to take action themselves. If, contrary to expectations, no health impairment is detected within the first few days of life, a doctor should be consulted as soon as irregularities occur in the child’s growth process.
Movement disorders, irregularities in eating and digestion should be discussed with a doctor. If there are optical flaws, you should also consult a doctor. Since this disease leads to disturbances in brain activity, general functional disorders of the organism occur. So that no complications develop, a doctor’s visit is already necessary at the first signals and indications.
Treatment & Therapy
Medicine does not have a causal therapy for patients with XLAG syndrome. The treatment of those affected is therefore exclusively symptomatic. There is currently no prospect of a cure, but it could be achieved in the future through gene therapy. The focus of treatment for patients with XLAG syndrome is currently the preservation of all vital bodily functions.
If the neurological impairments prevent the affected person from eating independently, the treating doctor inserts a nasal gastric tube. A PEG diet is also within the realm of possibility. The therapy counteracts language development problems through logopedic care and early support approaches.
Motor problems require physiotherapy and ergotherapeutic care, which in many cases continues throughout the life of those affected. Patients’ epilepsy receives special attention during treatment. Therapy with drugs is not possible in most cases, since the form of epilepsy is based on malformations of the brain. In individual cases, slight improvements can be achieved through brain surgery, which extends the life expectancy of the patient.
The XLAG syndrome cannot be prevented so far. Genetic counseling can help affected families with further family planning. A prenatal possibility of diagnosis for the rare syndrome is not yet available.
In most cases, those affected with XLAG syndrome have very few and only very limited measures and options for aftercare. For this reason, the affected person should consult a doctor very early on in order to prevent the occurrence of further complications or symptoms, since this usually does not lead to an independent healing.
Since the XLAG syndrome can also be inherited by the descendants, the affected person should definitely have a genetic examination and counseling carried out if they wish to have children in order to prevent this. Most of those affected with XLAG syndrome are dependent on physiotherapy and physiotherapy to relieve the symptoms. Many of the exercises can also be performed at home, which speeds up healing.
The help and support of one’s own family is also very important, with psychological support being particularly important. In some cases, contact with other people affected by this disease can also be very useful. This results in an exchange of information, which can make everyday life much easier. The disease may also reduce the life expectancy of those affected, although a general prediction is not possible.
You can do that yourself
The disease is associated with such malformation of the brain that there are no possibilities of self-help to bring about relief or recovery.
In everyday life, the relatives in particular must learn how to deal well with the person affected and the disease. Due to the health impairments, the patient himself is not in a position to take any opportunities to improve the situation. The clinical picture characterizes a patient who has the mental development level of a small child throughout his life. Above all, the parents have to deal intensively with the entire clinical picture and its effects. You need strategies to deal with the situation. Mental strengthening is of enormous importance for those affected and their relatives.
The focus should be on positive lifestyle choices. The quality of life and well-being must be optimized for everyone involved. Leisure activities and time together should be characterized by respect, rest and pleasant activities. Dealing openly with the disease helps to reduce situations of shame or mental overload.
Clarification of the clinical picture and the cause of optical abnormalities can bring people in the immediate vicinity to refrain from unpleasant comments. Therefore, situations of conflict or disagreement should be prevented in time.