According to photionary.com, Joubert syndrome is characterized by a congenital malformation of the brainstem and agenesis (inhibition malformation, missing system, e.g. cerebral cortex, vermiform process). There may also be hypoplasia (underdevelopment) of the cerebellar vermis. Patients suffering from this autosomal recessive gene defect exhibit, among other things, abnormal breathing behavior and ataxia.
What is Joubert Syndrome?
An exact anomaly could not be conclusively verified to this day. However, a mutation of the X chromosome is considered certain.
People with Joubert syndrome suffer from developmental disorders of the central nervous system and the resulting functional disorders. There is a controversial debate in medical research as to whether this genetic disorder should be classified as a disease in its own right.
Affected patients show a variety of different symptoms. For this reason, a conclusive diagnosis is difficult. The JB is characterized by extensive gene locus heterogeneity. So far, multiple gene mutations have been identified. A mutation analysis is very extensive.
Joubert syndrome belongs to the group of primary ciliopathies. With this genetic disorder of the primary cilia, or the basal body, various types of developmental disorders can occur. As special cell extensions, cilia fulfill various tasks. They function as chemo-, mechano- and osmosensors and are involved in many signaling pathways. They also ensure normal organ development.
They maintain 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. Doctors were able to detect malformations in the NPHP6/CEP290 gene (encoding for nephrocystin-6) or in the NPHP8/RPGRIP1L gene (encoding for nephrocystin-8). Other gene mutations are MKS3, ARL13B, AHI1, CC2DA2, TMEM216 and INPP5E. Only a few patients have mutations in NPHP4 and NPHP1.
Symptoms, Ailments & Signs
The pathognomonic feature is the “molar tooth sign” (MTS), which can be detected using “axial T1-weighted brain magnetic resonance imaging”. This trait is characterized by agenesis or hypoplasia of the cerebellar worm or upper cerebellar worm. Furthermore, the posterior interpendicular fossa (pit between the cerebral peduncles) is severely retracted and the cerebellar peduncles show a prominent superior shape due to a midbrain malformation.
In addition to MTS, patients often suffer from respiratory disorders, ataxia, muscular hypotonia and psychomotor retardation. 8 to 19 percent of those affected show postaxial polydactyly (many fingers) and six percent an occipital (meningo) encephalocele, in which the rear brain area has a bulge.
This deformity was first recorded in 1969. The prevalence is approximately 1 in 100,000, a ratio that shows how rare the disease is. Only one hundred cases have been documented since the year of the first medical registration. Since this genetic defect occurs in different forms and variants, doctors assume multiple changes in genetics.
An exact anomaly could not be conclusively verified to this day. However, a mutation of the X chromosome is considered certain. This condition is passed on based on autosomal recessive inheritance. A missing vermis cerebelli (cerebellum, cerebellar vermis), damage to the retina and a conspicuous iris are involved.
Common symptoms and signs during the neonatal period are nystagmus and an irregular breathing pattern as episodic tachypnea and apnea. Young children can develop muscle hypotonia. Balance disorders and an uneven gait (ataxia) develop with advancing age. These main symptoms are also known as motor milestones.
Patients have different cognitive abilities and can be severely impaired, but also show normal intelligence. Oculomotor 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 low-set ears. Uncommon symptoms include nephrophthisis, retinal dystrophy, and polydactyly.
Diagnosis & course of disease
Diagnosis is based on the previously cited characteristic milestones of ataxia, hypotonia, oculomotor apraxia, patent vermis cerebelli after 18 weeks of gestation, and developmental delay. In addition, a characteristic neuroradiological finding in the MRI, the MTS (Molar tooth sign), is made.
This feature, known as the molar sign, is due to malformations of the hindbrain and midbrain as well as hypoplasia of the cerebellum. Differential diagnoses are based on diseases closely related to JS, such as JSRD (Joubert syndrome related disorder), Dandy-Walker malformation (malformed cerebellar vermis without MTS), type 1 and 2 oculomotor apraxia, pontocerebral hypoplasia and atrophy, 3-c syndrome, oro-facio-digital syndromes II and III, and Meckel-Gruber syndrome.
Stage I includes the “next-generation sequencing-based panel analysis” of the genes JBTS5 (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 other JB genes are analyzed by PCR (a method that amplifies gene sequences in the DNA chain in an enzyme-dependent manner) and subsequent Sanger sequencing depending on phenotypic characteristics corresponding to decreasing mutation frequencies.
In order to rule out chromosomal imbalances, the differential diagnostic SNP array analysis is carried out. If there is a blood relationship or if there are several sick people in the family, the doctors carry out the homozygosity screening using linkage analysis in the gene-flanking microsatellite marker and subsequent gene analysis using Sanger sequencing. Two to ten milliliters of EDTA blood are taken from children as diagnostic material, and the amount for adults is five to ten milliliters.
DNA or tissue material is also suitable. Stage I: Genomic DNA material is analyzed by quantitative analysis of the NPHP1 gene for the existence of duplications or deletions using MLPA. Very small amounts of DNA in the genome are examined for deletions and duplications of individual exons (gene sections). Stage II: The encoded exons of the genes identified so far are evaluated by next-generation sequencing. The splice sites are enriched by probe hybridization.
Due to Joubert syndrome, most patients suffer from various symptoms. This usually leads to short stature, breathing disorders and, furthermore, to retardation. The mental development of the child can also be restricted. The breathing difficulties can continue to lead to shortness of breath, which must be treated in any case.
It is not uncommon for the parents of those affected to suffer from severe depression or other mental disorders. Patients also show balance disorders and often suffer from restricted mobility. It is not uncommon for there to be problems with the eyes and ears, resulting in hearing loss or vision problems. The patient’s quality of life is significantly reduced by Joubert syndrome.
Joubert syndrome can be limited and treated with the help of various therapies. Unfortunately, a causal treatment cannot be carried out. Emergency ventilation can also be carried out in emergencies if breathing difficulties should occur. With the treatment itself, there are no special complications. Whether the patient’s life expectancy will be reduced by Joubert syndrome cannot generally 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 the pregnant woman as well as that of the unborn child is examined. Since Joubert syndrome can be diagnosed as early as the 18th week of pregnancy, it is advisable to take advantage of the check-ups provided and recommended by health insurance companies. In addition, if there is a genetic defect in the history of the parental ancestors, genetic counseling and an examination are generally advisable.
In the unlikely event that no irregularities are detected in the womb, the obstetricians and paediatricians carry out automatic check-ups immediately after the birth. These examinations can identify breathing disorders. If the child’s parents later notice unusual discrepancies that previously went undetected, the observations should be discussed with a doctor. If there are physical peculiarities, short stature or deformities, a doctor must be consulted.
If language problems or mental underdevelopment are noticed in direct comparison to children of the same age, a doctor should be consulted. Investigations are necessary to clarify the cause. The sooner a diagnosis is made, the earlier targeted therapies can be initiated to support the child. Consultation with a doctor should therefore be made at the first sign of an abnormality.
Treatment & Therapy
Parents have a right to genetic counseling. The treatment options are as varied as the causes of this disease. In the case of motor development disorders and hypotension, pedagogical support programs, speech, occupational and ergotherapy, which can have a positive influence on the course of the disease, come into play.
Those affected with an abnormal breathing pattern can also be given oxygen substitution or ventilation. Patients with mild symptoms have a positive prognosis. Severely affected patients must be cared for at an expert referral 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 conditions. Researchers and doctors are not legally permitted to alter the genetic conditions of a person through interventions. For this reason, the treatment focuses on the use of therapies that should lead to an improvement in the existing quality of life. Without the use of medical care, the reduced well-being of the patient is further reduced.
The earlier the syndrome can be diagnosed and treated, the better results will be achieved. In emergency situations, emergency ventilation of the person concerned is indicated, as otherwise premature death may occur. Although numerous therapies are put together and applied in an individual treatment plan, the disease can lead to secondary disorders. These worsen the overall prognosis.
Mental illnesses can develop as a result of existing functional disorders or other movement restrictions. Transient or persistent depression, mood swings, or personality changes are documented in many patients. This represents an additional burden for the person affected and the environment. The everyday life of a patient with Joubert syndrome can often only be managed with sufficient help and support from the relatives. Balance disorders and ataxia become more severe with age.
Since an exact genetic cause has not yet been conclusively determined, there are no preventive measures in the clinical sense. The only way to counteract malformations in the human organism is to lead a healthy lifestyle.
In most cases, the patient with Joubert syndrome has no direct or special options for aftercare, so that the person concerned is primarily dependent on a quick and, above all, early diagnosis of the disease. The earlier the disease is detected, the better the further course is, as a rule. It is therefore advisable to contact a doctor as soon as the first symptoms and signs appear.
The person affected with this disease is usually dependent on intensive care and therapy, which can alleviate the symptoms. The help and support of parents and close relatives is also very important in order to enable the affected person to live as normal a life as possible. The exercises from physiotherapy or physiotherapy can often be carried out at home, which can alleviate the symptoms.
The symptoms cannot always be completely alleviated. Contact with other people affected by Joubert syndrome can also be very useful, as it is not uncommon for information to be exchanged. As a rule, the life expectancy of the affected person is not reduced by this disease.
You can do that yourself
Joubert syndrome cannot be cured and everyday help is difficult. The symptoms of the congenital disease are in most cases unavoidable. Still, it is possible that some of them will be alleviated.
Since breathing is particularly disturbed in those affected, this is a starting point. An optimized indoor climate can be helpful. Dry heating air can exacerbate breathing problems. Too cold air has the same effect. Ideally, the room temperature is around 20°C and the humidity around 50 percent. Houseplants in particular can contribute to an optimal indoor climate. Alternatively, damp towels can also be placed in the room to keep the humidity at the desired level. The indoor climate can be monitored using a hygrometer. Another starting point, which also aims at breathing, are breathing exercises. Regular use improves perception of the otherwise automatic process. In this way, rapid breathing and breathing pauses can be prevented.
It also makes sense if those affected do not sleep alone in a room. Relatives may notice breathing pauses during sleep and wake the patient or stimulate breathing. But this is only a precautionary measure.