Joubert syndrome is a rare genetically heterogeneous hereditary disease characterized by a violation of the formation of the cerebellum and brain stem structures with the development of appropriate neurological symptoms. The symptoms of this pathology show significant variability in their severity, respiratory disorders, oculomotor disorders and muscle weakness are most often observed, hearing disorders and lag in intellectual development are possible. Diagnosis of Joubert syndrome is made on the basis of neurological examination of the patient, magnetic resonance imaging of the brain, molecular genetic studies. There is no specific treatment at the moment, supportive and symptomatic measures are used.
Joubert syndrome is a rather rare genetic pathology, which is characterized by a violation of the embryonic development of important brain structures, which leads to various neurological problems. The disease was first described by Canadian pediatrician Marie Joubert in 1969. She identified four children whose parents were related by blood, respiratory disorders, hearing disorders, muscle weakness and signs of mental retardation. Since 1977, such disorders have been isolated into a separate nosological unit called “Joubert syndrome”. In the future, geneticists were able to determine the significant genetic heterogeneity of the disease – at least 20 genes are known at the moment, mutations of which could be associated with this pathology. At the same time, in almost half of the cases of Joubert syndrome, its molecular genetic mechanisms remain unknown. According to the latest data, the incidence of this disease is approximately 1 case per 1 million newborns, the transmission mechanism is autosomal recessive, boys and girls are affected with the same frequency. There were no national, racial or regional peculiarities in the distribution of Joubert syndrome.
Causes and classification
As the study of Joubert syndrome reveals more and more genes, mutations of which can lead to the development of this disease. To date, almost two dozen such genes have been identified, while in about half of the clinical cases of Joubert syndrome, it is not possible to determine genetic disorders, which indicates the role of other, not yet studied defects. Gene mutations leading to this disease occur on different chromosomes, but are always inherited by an autosomal recessive mechanism. Also, all these genes are united by participation in the embryonic development of brain structures, it is this circumstance that causes the appearance of the characteristic symptoms of Joubert syndrome.
It has been established that mutations of some genes lead to the development of the disease somewhat more often than others. One of them is the AHI1 gene, which is located on the 6th chromosome. According to medical statistics, defects in this gene cause 10-12% of all cases of Joubert syndrome. The AHI1 gene encodes a specific protein that is actively involved in the formation of certain elements of the brain stem and retina. Another common cause of Joubert syndrome is considered to be a defect in the CEP290 gene, localized on the 12th chromosome. It encodes a sequence of proteins involved in the formation of cellular centrosomes and cilia in various organs of the body (brain, retina, heart, lungs, kidneys). Mutations of the CEP290 gene are detected in about 10% of patients with Joubert syndrome.
Approximately with the same frequency (9-10% of all cases of the disease), mutations of the CC2D2A gene located on the 4th chromosome are detected in patients. In addition to Joubert syndrome, defects in this gene can lead to Meckel syndrome. The protein encoded by CC2D2A participates in the development of cilia and elements of the cytoskeleton of cells, in addition, it has the ability to attach calcium ions. Another common form of genetic disorders in Joubert syndrome are defects in the TMEM67 gene localized on the 8th chromosome. Like the above genes, TMEM67 expresses a protein that regulates the formation of centrosomes and cilia in many cells of the human body.
In addition, mutations of genes such as TCTN1 and TCTN2 (12th chromosome), TMEM138 and TMEM216 (11th chromosome), TMEM237, TTC21B and NPHP1 (2nd chromosome), ARL13B (5th chromosome) and a number of others can lead to Joubert syndrome. They occur with a frequency of several percent of all cases of the disease, for many the relative prevalence is unknown. Those genes whose functions have been established also control the development of cilia, centrioles or cytoskeleton, which allows us to consider Joubert syndrome as a manifestation of disorders in the formation of these structures. Mutations of all of the above genes are inherited by an autosomal recessive mechanism, but in recent years there have been indications of the possibility of gender-linked transmission. It is assumed that this form of Joubert syndrome is caused by a mutation of the OFD1 gene localized on the X chromosome.
The phenotypic manifestations of Joubert syndrome are generally similar in different genetic varieties of the disease. However, there are minor differences. The severity of symptoms can vary significantly even within the same family. Currently, the reasons why the severity of the course of Joubert syndrome differs in different patients are not reliably known. In the vast majority of cases, it is possible to suspect the presence of the disease in the first days of a child’s life – muscle hypotension, abnormal eye movements are detected, coloboma (a defect in the membranes of the eye) is often determined. A characteristic feature of Joubert syndrome is respiratory disorders – rhythm instability (tachypnea, bradypnea), possible respiratory arrest during sleep (night apnea).
As the child grows, there is a slight progression of the disease – muscle hypotension flows into cerebellar ataxia, there is a lag in motor and intellectual development. At the same time, the spectrum of intellectual disabilities in Joubert syndrome varies very widely – from normal to deep mental retardation. There may be hearing disorders (up to sensorineural deafness) and vision (caused by both oculomotor anomalies and retinal dystrophy). Approximately half of patients with Joubert syndrome develop various abnormalities of internal organs – liver fibrosis, polycystic kidney disease, congenital heart defects. Less often, encephalocele occurs (through a large occipital opening or defects in the cranial vault), hydrocephalus, hamartomas of the oral cavity.
Due to the significant range of manifestations of Joubert syndrome, the risks of death and various complications are rather uncertain. In the most severe cases, death of patients in infancy is possible due to respiratory and neurological disorders. With a less severe course of Joubert syndrome, patients can live to adulthood and even old age, while they are usually unable to walk due to cerebellar ataxia. The main risks in such cases are caused by lesions and abnormalities of the development of internal organs – the heart, kidneys, liver.
Diagnosis and treatment
To determine the Joubert syndrome, the following diagnostic techniques are used: neurological examination of patients, magnetic resonance imaging of the brain, additional studies of the eyes, hearing and the work of internal organs. Molecular genetic diagnostics in most modern laboratories is possible for the four most common types of the disease – caused by mutations of the genes AHI1, CEP290, CC2D2A and TMEM67. When examining patients with Joubert syndrome, muscle weakness is determined, signs of cerebellar ataxia and coordination disorders, the main tendon reflexes are sharply reduced. Almost always there is a lag in motor development, in some cases – a different degree of mental retardation.
The most typical diagnostic sign of Joubert syndrome is the presence of the so–called “molar tooth symptom” – characteristic changes on the MRI of the brain, outwardly similar to a tooth incision. This manifestation indicates the presence of disorders in the formation of brain stem elements. Also, magnetic resonance imaging often determines the underdevelopment of the cerebellar worm, hypoplasia of the corpus callosum, hydrocephalus, ventricular dilation, encephalocele and other abnormalities of brain development. In adult patients with Joubert syndrome, signs of internal organ damage are often detected – polycystic kidney disease, liver fibrosis, cardiac arrhythmias. When examined by an ophthalmologist, involuntary abnormal eye movements (nystagmus), coloboma, dystrophy and degeneration of the retina are often detected.
With the help of modern genetics methods, molecular genetic diagnosis of Joubert syndrome is possible, which is caused by mutations of the AHI1, CEP290, CC2D2A and TMEM67 genes. In total, defects in these genes cause about 40% of all cases of the disease. For this reason, a negative result of genetic tests is not a reason for the guaranteed exclusion of Joubert syndrome. An auxiliary role in determining pathology is played by the study of the patient’s hereditary history in order to confirm autosomal recessive transmission. With the help of direct automatic sequencing, it is possible to detect the carrier of the pathological form of the gene in the relatives of the patient or with heredity burdened by this condition.
There is no specific treatment for Joubert syndrome, medical care for this disease is reduced to palliative and symptomatic measures. To alleviate neurological symptoms, nootropic drugs are used – their regular intake, started from an early age, can significantly improve the prognosis for the intellectual development of the patient. Also, with Joubert syndrome, various methods of physiotherapy are used, special exercises to improve coordination of movements and reduce the manifestations of ataxia. At an early age, it is often necessary to monitor the patient’s breathing in order to avoid potentially dangerous apnea.
Prognosis and prevention
The prognosis of Joubert syndrome is often uncertain, since it depends on the severity of symptoms and the severity of the clinical course of the disease. In the most severe cases, a fatal outcome is possible even in early childhood due to respiratory disorders and neurological pathologies. In most cases, patients live to adulthood and even old age, although the combination of ataxia, pathologies of internal organs, visual and hearing disorders often leads to profound disability. Mental development can be preserved, but there are also various degrees of mental retardation. Prevention of Joubert syndrome is possible only as a prenatal diagnosis of the disease and determination of the carrier of the pathological form of the gene in persons with burdened heredity.