The Joubert syndrome is characterized by a congenital malformation of the brain stem and agenesis (inhibition malformation, lack of attachment, for example brain beam, appendix) out. There may also be hypoplasia (underdevelopment) of the cerebellar vermis. Patients suffering from this autosomal recessive gene defect have abnormal respiratory behavior and ataxia, among others.

What is Joubert syndrome?

An exact anomaly could not be conclusively verified to this day. However, a mutation of the X chromosome is considered safe.
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People with Joubert syndrome suffer from developmental disorders of the central nervous system and the resulting dysfunction. The medical research controversially discusses whether this genetic disorder is classified as a distinct disease.

The affected patients have a variety of different symptoms. For this reason, a final diagnosis is difficult. The JB is characterized by a far-reaching gene locus heterogeneity. So far, multiple gene mutations could be detected. A mutation analysis is very extensive.

causes

Joubert syndrome belongs to the group of primary ciliophates. In this genetic disorder of the primary cilia, or the basal body, various types of developmental disorders can occur. Cilia fulfill different tasks as special cell processes. They function as chemo-, mechano- and osmosensors and are involved in many signaling pathways. Furthermore, they ensure a normal organ development.

They maintain the tissue homeostasis of basic developmental processes. A large number of the proteins involved form a complicated network through interaction. If other organs are affected in addition to the main symptoms, the JSRD (Joubert Syndrome Related Disorder) is present. This secondary disease is characterized by further organ manifestations involving the kidneys, liver and eyes.

It is a genetically heterogeneous syndrome. Physicians were able to detect malformations in the NPHP6 / CEP290 gene (coding for nephrozystin-6) or in the NPHP8 / RPGRIP1L gene (coding for nephrozystin-8). Other gene mutations include MKS3, ARL13B, AHI1, CC2DA2, TMEM216 and INPP5E. Few patients have mutations in NPHP4 and NPHP1.

Symptoms, complaints & signs

The pathognomonic feature is the "molar tooth sign" (MTS), which can be determined by means of the "axial T1-weighted brain magnetic resonance tomography". This feature is characterized by agenesis or hypoplasia of the cerebellar or cerebellar vermis. Furthermore, the posterior fossa inter-oralis (pit between the cerebral thighs) is heavily retracted and the cerebellar peduncles have a prominent superior shape due to malformation of the midbrain.

In addition to MTS, patients often suffer from respiratory disorders, ataxia, muscular hypotension and psychomotor retardation. 8 to 19 percent of those affected show a postaxial polydactyly (multiple fingerings) and six percent an occipital (Meningo) encephalocele, in which the rear part of the brain has a Ausackung.

This deformity was recorded for the first time in 1969. The prevalence is approximately 1: 100, 000, a ratio that shows how rare the disease is. Since the first year of medical coverage, only one hundred cases have been documented. Since this genetic defect occurs in different forms and variants, physicians assume that there are multiple changes in genetics.

An exact anomaly could not be conclusively verified to this day. However, a mutation of the X chromosome is considered safe. This disease is transmitted on the basis of autosomal recessive heredity. Involved are a missing Vermis cerebelli (cerebellum, cerebellar vermis), damage to the retina and a conspicuous iris.

Common symptoms and symptoms during the neonatal period include nystagmus and an irregular respiratory pattern as episodic tachypnoea and apnea. Infants may develop hypotonia. As you age, balance disorders and uneven gait (ataxia) develop. These main symptoms are also referred to as motor milestones.

Patients have different cognitive abilities and may be severely impaired, but also have a normal intelligence. An oculo-motor apraxia (movement disorder) is also possible.

Characteristic of this genetic defect are craniofacial anomalies such as a large head, rounded and high eyebrows, a prominent (protruding) forehead, a deformed mouth, a rhythmically moving and protruding tongue, and deep-seated ears. Occasional symptoms include nephrophthis, retinal dystrophy and polydactyly.

Diagnosis & disease course

A diagnosis is made on the basis of the above-cited characteristic milestones ataxia, hypotension, oculomotor apraxia, open vermis cerebelli after the 18th week of pregnancy and developmental delay. In addition, a characteristic neuroradiological finding in MRI, the MTS (molar tooth sign), made.

This feature, known as the molar tooth, is due to malformations of the rhomboids and midbrain, as well as the hypoplasia of the cerebellar vermis. Differential diagnoses include JSRD (Joubert Syndrome Related Disorder), Dandy-Walker Malformation (malformed cerebellar worm without MTS), type 1 and 2 oculomotor apraxia, ponto-cerebral hypoplasia and atrophy, 3-c Syndrome, Oro-fazio-digital syndromes II and III and Meckel-Gruber syndrome.

Stage I includes the next generation sequencing-based panel analysis of JBTS5 genes (53 coding exons), JBTS3 (26 coding exons), JBTS6 (28 coding exons) and JBTS9 (36 coding exons). The JBTS4 gene is tested for homozygous deletion by multiplex PCR. In stage II, the analysis of the other JB genes is carried out by PCR (method which amplifies enzyme-dependent gene sequences in the DNA chain) and subsequent Sanger sequencing depending on phenotypic features corresponding to decreasing mutation frequencies.

In order to exclude chromosomal imbalances, differential diagnostic SNP array analysis is performed. If there is a consanguinity or if several persons are known within the family, the physicians carry out homozygosity screening by means of coupling analysis in the gene-flanking microsatellite marker and subsequent gene analysis by means of Sanger sequencing. Children are taken as a diagnostic material two to ten milliliters of EDTA blood, in adults, the amount is five to ten milliliters.

In addition, DNA or tissue material is suitable. Stage I: Genomic DNA material is assayed for the existence of duplications or deletions using MLPA by quantitative analysis of the NPHP1 gene. Very small amounts of DNA in the genome are examined for deletions and duplications of individual exons (gene segments). Stage II: The encoded exons of the previously identified genes are evaluated by Next-Generation-Frequencing. The splice sites are enriched by probe hybridization.

complications

Due to the Joubert syndrome, most patients suffer from various ailments. It usually comes to dwarfism, disorders of breathing and also to a retardation. The mental development of the child can also be limited. The breathing difficulties can still lead to respiratory distress, which must be treated in any case.

Not infrequently also suffer the parents of the person affected by severe depression or other mental disorders. The patients also show balance disorders and often suffer from movement restrictions. Not infrequently there are also complaints to the eyes and the ears, so that it comes to a hearing loss or to visual problems. The quality of life of the patient is significantly reduced by the Joubert syndrome.

With the help of various therapies Joubert syndrome can be limited and treated. Unfortunately, a causal treatment can not be carried out. Likewise, emergency breathing can be carried out in case of emergency respiratory distress. There are no special complications during the treatment itself. Whether the life expectancy of the patient is reduced by the Joubert syndrome can generally not be predicted.

When should you go to the doctor?

An expectant mother should take part in all check-ups offered during pregnancy. In the examinations, the state of health of both the pregnant and the unborn child is examined. Since the Joubert syndrome can be diagnosed as early as the 18th week of pregnancy, it is recommended that you use the health insurance plans and recommended check-ups. In addition, in the case of an existing genetic defect in the history of parental ancestors, genetic counseling and examination are generally advisable.

In the unlikely event that there is no evidence of an irregularity in the womb, automatic check-ups of obstetricians and pediatricians take place immediately after delivery. In these examinations disturbances of the respiration can be determined. If, later on, the child's parents notice unusual disagreements that have previously gone undetected, the observations should be discussed with a physician. If it comes to physical features, a short stature or deformities, a doctor is to consult.

If linguistic problems or mental underdevelopment are noticed in direct comparison to children of the same age, a doctor should be consulted. To clarify the cause, investigations are necessary. The sooner a diagnosis is made, the earlier targeted therapies for promoting the child can be initiated. Consultation with a doctor should therefore be made at the first sign of an abnormality.

Treatment & Therapy

The parents are entitled to genetic counseling. As diverse as the causes of this disease are, so are the treatment options. In the case of motor developmental disorders and hypotension access educational support programs, speech, occupational and occupational therapy, which can influence the course of the disease favorably.

Affected individuals with conspicuous respiratory patterns may also be given oxygen replacement or ventilation. Patients with mild discomfort have a positive prognosis. Severely affected patients must be cared for by a specialized reference center.

Outlook & Forecast

The prognosis of Joubert syndrome is unfavorable. This syndrome is a genetic disease. This is not curable with the current medical, scientific and legal requirements. Legally, researchers and physicians are not allowed to change the genetic conditions of a human by intervention. For this reason, the treatment is based on the use of therapies, which should lead to an improvement of the existing quality of life. Without the use of a medical care, the reduced well-being of the patient is reduced by another.

The earlier the syndrome can be diagnosed and treated, the better the results are achieved. In emergency situations an emergency ventilation of the person concerned is indicated, as otherwise it can lead to premature death. Although many therapies are put together and used in an individualized treatment plan, secondary complications may occur due to the present condition. These worsen the overall forecast.

Due to existing dysfunctions or other movement restrictions, mental illnesses can develop. Many patients report transient or persistent depression, mood swings or personality changes. This represents an additional burden for the person concerned and the environment. The daily routine of a patient with Joubert syndrome can often only be managed with sufficient help and support from the relatives. With age, balance disorders and ataxia become stronger.

prevention

Since an exact genetic causation has not yet been conclusively established, there are no preventive measures in the clinical sense. The only way to counter malformations of the human organism is a healthy lifestyle.

aftercare

In most cases, the patient has no direct or special aftercare options for Joubert syndrome, so the person primarily depends on a quick and, above all, on an early diagnosis of the disease. The sooner the disease is recognized, the better is usually the further course. Therefore, it is recommended to contact a doctor at the first symptoms and signs.

The person concerned is usually dependent on intensive care and therapy for this disease, which can alleviate the symptoms. The help and the support of the parents and the close relatives is very much in demand, in order to enable the affected person to live as normally as possible. Frequently, the exercises from physiotherapy or physiotherapy can also be carried out in one's own home, which can alleviate the symptoms.

Not always the symptoms can be completely alleviated. Contact with other people affected by Joubert's syndrome can also make a lot of sense, as information is often exchanged. As a rule, the life expectancy of the person affected by this disease is not reduced.

You can do that yourself

The Joubert syndrome is not curable and everyday help is difficult. The symptoms of congenital disease are unavoidable in most cases. Nevertheless, it is possible that some of them are alleviated.

Since especially the breathing is disturbed in the affected, here is a starting point. An optimized room climate can be helpful. Dry heating air can aggravate breathing problems. Too cold air has the same effect. Ideally, the room temperature is about 20 ° C, the humidity is about 50 percent. Above all indoor plants can contribute to an optimal room climate. Alternatively, wet towels can be placed in the room to keep the humidity at the desired level. A hygrometer can be used to monitor the indoor climate. Another approach that also aims at breathing is breathing exercises. Regular use improves the perception of the otherwise automatic process. In this way, too fast breathing and breathing interruptions can be prevented.

In addition, it makes sense if those affected do not sleep alone in a room. Relatives may notice respiratory failure during sleep and wake or stimulate the patient to breathe. But that's just a precaution.

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