Joubert syndrome is characterized by a congenital malformation of the brain stem as well as agenesis (inhibition malformation, lack of attachment, for example, cerebral bar, vermiform appendix). There may also be hypoplasia (underdevelopment) of the cerebellar vermis. Patients suffering from this autosomal recessive genetic defect exhibit abnormal respiratory behavior and ataxia, among other symptoms.
What is Joubert syndrome?
People with Joubert syndrome suffer from developmental disorders of the central nervous system and subsequent dysfunction. Medical researchers controversially debate 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. JB is characterized by extensive gene locus heterogeneity. So far, multiple gene mutations have been identified. Mutation analysis is very extensive.
Causes
Joubert syndrome belongs to the group of primary ciliophathies. In this genetic disorder of primary cilia, or basal bodies, various types of developmental abnormalities can occur. As special cellular extensions, cilia fulfill various tasks. They function as chemo-, mechano- and osmosensors and are involved in many signaling pathways. Furthermore, they 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, JSRD (Joubert Syndrome Related Disorder) is present. This secondary disease is characterized by more extensive organ manifestations involving the kidneys, liver and eyes. It is a genetically heterogeneous syndrome. Physicians have identified malformations in the NPHP6/CEP290 gene (coding for nephrocystin-6) or in the NPHP8/RPGRIP1L gene (coding for nephrocystin-8). Other gene mutations include FMD3, ARL13B, AHI1, CC2DA2, TMEM216, and INPP5E. Few patients have mutations in NPHP4 and NPHP1.
Symptoms, complaints, and signs
The pathognomonic feature is “molar tooth sign” (MTS), which can be detected by “axial T1-weighted brain magnetic resonance imaging.” This feature is characterized by agenesis or hypoplasia of the cerebellar vermis or cerebellar vermis. Furthermore, the posterior interpendicular fossa (pit between the cerebral peduncles) is severely retracted and the cerebellar peduncles have a prominent superior shape due to a malformation of the midbrain. In addition to MTS, patients in many cases suffer from respiratory disorders, ataxia, muscular hypotonia, and psychomotor retardation. Eight to 19 percent of affected individuals show postaxial polydactyly (multifingeredness) and six percent show an occipital (meningo)-encephalocele, in which the posterior cerebral area has a bulge. This deformity was first recorded in 1969. The prevalence is approximately 1: 100,000, a ratio that shows how rarely the condition appears. Only one hundred cases have been documented since the year of the first medical recording. Since this genetic defect occurs in different forms and variants, physicians assume that there are multiple changes in the genetics. An exact abnormality has not been conclusively verified to date. However, a mutation of the X chromosome is considered certain. This disease is transmitted on the basis of autosomal recessive inheritance. Involved are a missing vermis cerebelli (cerebellum, cerebellar vermis), damage to the retina and a conspicuous iris. Common symptoms and complaints during the neonatal period include nystagmus and an irregular breathing pattern as episodic tachypnea as well as apnea. Infants may develop muscle hypotonia. With advancing age, balance disorders and an irregular gait (ataxia) develop. These major symptoms are also referred to as motor milestones. Patients have varying degrees of cognitive ability and may be severely impaired, but may also show normally developed intelligence. 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 low-set ears. Occasional symptoms include nephrophthisis, retinal dystrophy, and polydactyly.
Diagnosis and disease course
A diagnosis is made based on the previously cited characteristic milestones of ataxia, hypotonia, oculomotor apraxia, overt vermis cerebelli after the 18th week of gestation, and developmental delay. In addition, a hallmark neuroradiologic finding on MRI, the molar tooth sign (MTS), is made. This feature, known as the molar tooth sign, is due to malformations of the rhomboid and midbrain and hypoplasia of the cerebellar vermis. Differential diagnoses are made based on conditions closely related to JS such as JSRD (Joubert syndrome related disorder), Dandy-Walker malformation (malformed cerebellar vermis without MTS), types 1 and 2 of oculomotor apraxia, ponto-cerebral hypoplasia and atrophy, 3-c syndrome, oro-facio-digital syndromes II and III, and Meckel-Gruber syndrome. Stage I involves “next-generation sequencing-based panel analysis” of the JBTS5 (53 coding exons), JBTS3 (26 coding exons), JBTS6 (28 coding exons), and JBTS9 (36 coding exons) genes. The JBTS4 gene is tested for homozygous deletion by multiplex PCR. In stage II, the other JB genes are analyzed by PCR (procedure that amplifies gene sequences in the DNA chain in an enzyme-dependent manner) followed by Sanger sequencing depending on phenotypic characteristics according to decreasing mutation frequencies. To exclude chromosomal imbalances, differential diagnostic SNP array analysis is performed. If there is a blood relationship or if several persons with the disease are known within the family, the physicians perform homozygosity screening by means of linkage analysis in the gene-flanking microsatellite marker and subsequent gene analysis by means of Sanger sequencing. Two to ten milliliters of EDTA blood is taken from children as diagnostic material, and five to ten milliliters from adults. DNA or tissue material is also suitable. Stage I: Genomic DNA material is examined for the existence of duplications or deletions by means of a quantitative analysis of the NPHP1 gene using MLPA. 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 genes detected so far are evaluated by next-generation sequencing. Splice sites are enriched by probe hybridization.
Complications
Due to Joubert syndrome, most patients suffer from various complaints. There is usually short stature, respiratory disorders, and further, retardation. The child’s mental development may also be impaired. The respiratory problems can further lead to respiratory distress, which must be treated in any case. It is not uncommon for the parents of the affected person to also suffer from severe depression or other psychological upsets. Patients also show balance disorders and not infrequently suffer from movement restrictions. It is not uncommon for symptoms to affect 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. Likewise, in emergencies, emergency ventilation can be performed if respiratory distress should occur. No particular complications occur during the treatment itself. Whether the patient’s life expectancy is reduced by Joubert syndrome generally cannot be predicted.
When should you see a doctor?
An expectant mother should attend any checkups offered during pregnancy. The exams examine the health of the pregnant woman as well as that of the unborn child. Since Joubert syndrome can be diagnosed as early as the 18th week of pregnancy, it is advisable to take advantage of the preventive examinations provided and recommended by health insurance companies. In addition, if a genetic defect is present in the history of the parental ancestors, genetic counseling as well as examination is always advisable.In the unlikely event that no irregularity was detected in the womb, automatic check-ups by obstetricians as well as pediatricians take place immediately after delivery. During these examinations, respiratory disorders may be detected. If, in the further course, the child’s parents notice unusual irregularities that previously went undetected, the observations should be discussed with a physician. If physical peculiarities, short stature or deformities occur, a physician should 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 determine the cause. The sooner a diagnosis is made, the sooner targeted therapies can be initiated to support the child. Consultation with a physician should therefore take place at the first signs of an abnormality.
Treatment and therapy
Parents are entitled to genetic counseling. The treatment options are as wide-ranging as the causes of this condition. In the case of motor development disorders and hypotonia, educational support programs, speech therapy, occupational therapy, and occupational therapy take effect and can favorably influence the course of the disease. Affected patients with a conspicuous breathing pattern can also be given oxygen substitution or ventilation. Patients with mild symptoms have a positive prognosis. Severely affected patients need to be managed by an expert referral center.
Outlook and prognosis
The prognosis of Joubert syndrome is unfavorable. This syndrome is a genetic disorder. This is not curable with the current medical, scientific as well as legal conditions. By law, researchers and doctors are not allowed to change the genetic conditions of a person by interventions. For this reason, treatment is focused on the use of therapies that should lead to an improvement in the existing quality of life. Without the use of medical care, the patient’s diminished well-being is further diminished. The earlier the syndrome can be diagnosed and treated, the better the outcomes. In emergency situations, emergency ventilation of the affected person is indicated, as otherwise premature death may occur. Although numerous therapies are compiled and applied in an individual treatment plan, secondary disorders may occur due to the present disease. These worsen the overall prognosis. Psychological disorders may develop due to existing functional disorders or other movement restrictions. In many patients, temporary or persistent depression, mood swings or personality changes are documented. This represents an additional burden for the affected person and the environment. The daily life of a patient with Joubert syndrome can often only be managed with sufficient help and support from relatives. With increasing age, balance disorders as well as ataxia become more severe.
Prevention
Because 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 of the human organism is a healthy lifestyle.
Follow-up
In most cases, the patient with Joubert syndrome has no direct or special options for aftercare, so the affected person is primarily dependent on rapid and, above all, early diagnosis of the disease. As a rule, the earlier the disease is detected, the better its further course. Therefore, it is advisable to contact a doctor at the first symptoms and signs. The person affected by 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 much needed to enable the affected person to lead as normal a life as possible. Often the exercises from physiotherapy can be performed in the patient’s own home, which can alleviate the symptoms. The complaints cannot always be completely alleviated.Contact with other sufferers of Joubert syndrome can also be very useful, as it is not uncommon for this to result in an exchange of information. As a rule, the life expectancy of the affected person is not reduced by this disease.
This is what you can do yourself
There is no cure for Joubert syndrome, and everyday help is also difficult. In most cases, the symptoms of the congenital disorder are not preventable. Nevertheless, it is possible that some of them can be alleviated. Since breathing in particular is disturbed in those affected, this offers a starting point. An optimized room climate can have a helpful effect. Dry heating air can aggravate breathing problems. Air that is too cold has the same effect. Ideally, the room temperature should be around 20°C and the humidity around 50 percent. Indoor plants in particular can contribute to an optimal room climate. Alternatively, damp towels can be placed in the room to keep the humidity at the desired level. A hygrometer can be used to track the indoor climate. Another starting point, which also targets breathing, is breathing exercises. Regular use improves the perception of the otherwise automatic process. In this way, too rapid breathing and breathing pauses can be prevented. In addition, it is useful if affected persons do not sleep alone in a room. Relatives can notice breathing pauses during sleep and wake the patients or stimulate them to breathe. However, this is only a precautionary measure.