The Joubert syndrome is a genetic disorder characterized decreased muscle tone, coordination problems, abnormal eye movements, breathing patterns and altered mental retardation (Joubert Syndrome Foundation, 2016).
All these alterations are due to an autosomal genetic transmission that will lead to important brain abnormalities, cerebellar vermis reduction (Joubert Syndrome Foundation, 2016), as well as abnormalities in the structure of the brainstem (National Institute of Neurological Disorders and Stroke, 2016).
In addition, Joubert syndrome is part of a group of disorders called “ciliopathies”. which occur with dysfunction of a part of the cells called cilia. Joubert Syndrome Foundation, 2016).
The initial description of this pathology was made by Marie Joubert and collaborarodes in 1968, in which four cases were described. The patients presented partial or total absence of cerebellar vermis, neonatal episodic ampneal hyper- ine syndrome, abnormal eye movements, ataxia and mental retardation (Angemi and Zucotti, 2012).
In addition, this syndrome was also associated with different multiorgan disorders such as hepatic fibrosis, polydactyly, nephronoptisis or retinal dystrophy (Angemi and Zucotti, 2012).
As for treatment, there is currently no cure for Joubert’s syndrome. Therapeutic interventions are aimed at symptomatic control and support, infant physical and intellectual stimulation, and occupational therapy (National Institute of Neurological Disorders and Stroke, 2016).
Characteristics of Joubert’s syndrome
The Joubert syndrome ( SJ ) is a type of disease of genetic origin characterized by a congenital malformation in areas of the brain stem and agenesis (partial or complete absence) or hypoplasia (incomplete development) of the cerebellar vermis, which can cause (Ophatnet, 2009).
More specifically, at the anatomical level is characterized by the so-called ?? molar sign ?? of the mesencephalon: agenesis or hypoplasia of the cerebellar vermis, narrowing of the superior cerebellar peduncles with indentation, elongation and lack of decussation, and deep interpeduncular fossa (Angemi and Zuccoti, 2012).
It is a disorder that can affect many areas and organs of the body, so the signs and symptoms vary considerably among people affected (US National Library of Medicine, 2011).
Most affected suffer from weakened muscle tone (hypotonia) and motor coordination difficulties (ataxia). Other characteristic features are episodes of altered breathing, nystagmus (involuntary and arrhythmic movement of the eyes), delayed motor development, and variable intellectual difficulties (US National Library of Medicine, 2011).
The prevalence of Joubert syndrome has been estimated in approximately 1 / 80,000 to 1 / 100,0000 cases of children born alive. Worldwide, more than 200 clinical cases have been registered (Angemi and Zuccoti, 2012).
Many experts consider these figures to be underestimated, since Joubert syndrome has a wide range of affectations and is largely underdiagnosed (US National Library of Medicine, 2011).
Much of the clinical symptoms of Joubert syndrome are more than evident at the infancy stage, many affected children have significant motor delays (National Organization for Rare Disease, 2011).
The most common features of the clinical course are: lack of muscle control (ataxia), altered breathing patterns (hypercapnia), sleep apnea , abnormal eye movements (nystagmus) and low muscle tone (National Organization for Rare Disease, 2011).
On the other hand, some of the alterations that may be associated with Joubert’s syndrome include altered retinal development, iris abnormalities, strabismus, renal and / or hepatic alterations, protrusion of membranes lining the brain, among others ( National Organization for Rare Disease, 2011).
All the alterations derived from this syndrome, are included in several areas: neurological, ocular, renal, and musculoskeletal alterations (Bracanti et al., 2010).
Neurological disorders ( Bracanti et al., 2010)
The most characteristic neurological alterations of Joubert syndrome are Bracanti et al., 2010): hypotonia, ataxia, generalized developmental delay, intellectual alterations, altered respiratory patterns and abnormal eye movements.
- Hypotonia: Muscle weakness is one of the symptoms that may be observed earlier, during the neonatal period or during early childhood. Although muscular weakness is a clinical finding that a wide variety of pathologies are present, the joint presentation with other alterations allows the diagnosis of Joubert’s syndrome.
- Ataxia : Initial muscle weakness usually evolves into ataxia or significant motor coordination. A major imbalance and instability often occurs during the early years of the independent march.
- Respiratory disorders : Respiratory anomalies are present shortly after birth and usually improve with development, even disappearing at approximately six months of age. The most characteristic alteration is the occurrence of brief episodes of apnea (interruption of respiration) followed by episodes of hyperpnea (acceleration of respiration).
- Abnormal ocular movements : oculomotor ataxia is one of the most frequent features, it presents as a difficulty to follow objects visually accompanied by compensatory movements of the head, decreased slow eye tracking, among others. In addition, observation of nystagmus in these patients is also frequent. All these alterations are independent of the specific ocular abnormalities that exist at physical level.
- Delay in development: In all cases, there is a variable level of delay in maturation development, in particular, language and motor skills are the most affected. On the other hand, it is also common the presence of intellectual alterations, however, is not an essential characteristic, in many cases can appear a normal intelligence and in other limits.
- CNS malformations: in addition to the clinical alterations described above, there are several alterations of the central nervous system that are usually associated with the occurrence of Joubert’s syndrome: hydrocephalus, widening of the posterior fossa, alterations of the corpus callosum , cysts in the white matter, hypothalamic hematomas, absence of pituitary gland , abnormalities in neuronal migration, alterations and defects in cortical organization, among others.
Ocular alterations (Bracanti et al., 2010)
At the physical level, the retina is one of the organs affected by Joubert syndrome. The alterations in this organ present in form of retinal dystrophy , due to a progressive degeneration of the cells in charge of the photo reception.
At the clinical level, ocular alterations can range from congenital retinal blindness to progressive degeneration of the retina.
On the other hand, it is also possible to observe the presence of the coloboma. This ocular alteration is a congenital defect that affects the ocular iris and presents as an orifice or cleft.
Renal Alterations ( Bracanti et al., 2010)
Pathologies related to renal function affect more than 25% of those affected by Joubert’s syndrome.
In many cases, renal alterations may remain asymptomatic for several years or begin to manifest with nonspecific signs, until it presents as an acute or chronic renal failure.
Mucoskeletal alterations (Bracanti et al., 2010)
From the earliest descriptions of this pathology, a common clinical finding is polydactialia (a genetic disorder that increases the number of fingers or toes).
In addition it is also common to observe orofacial or structural anomalies at the level of the spine.
Experimental studies have classified Joubert’s syndrome as an autosomal recessive disorder (National Organization for Rare Disease, 2011).
An autosomal recessive genetic disorder means that two copies of an abnormal gene must be present for the trait or disease to occur (National Institutes of Healh, 2014).
Thus, a genetic recessive disorder occurs when a person inherits the same abnormal gene for the same trait of each parent. If an individual only receives a copy of the gene related to the pathology, it will be a carrier but will not show symptoms (National Organization for Rare Disease, 2011).
In addition, at least ten genes have been identified as one of the possible causes of Joubert syndrome (National Organization for Rare Disease, 2011).
A mutation in the AHI1 gene is responsible for this pathological condition in approximately 11% of affected families. In people with this genetic alteration, vision changes are often present due to the development of a retinal dystrophy (National Organization for Rare Disease, 2011).
The mutation of the nphp1 gene is the cause of approximately 1-2% of the cases of Joubert syndrome. In individuals presenting with this genetic alteration, renal alterations are frequent (National Organization for Rare Disease, 2011).
On the other hand, a mutation of the CEP290 gene is the cause of 4-10% of cases of Joubert syndrome (National Organization for Rare Disease, 2011).
In addition, mutations in the TME67 , JBTS1 , JBTS2 , JBTS7 , JBTS8 and JBTS9 genes are also related to the development of Joubert syndrome (National Organization for Rare Disease, 2011).
The diagnosis of Joubert’s syndrome is based on the physical symptomatology. It is necessary to perform a detailed physical examination, as well as the use of different diagnostic tests, especially magnetic resonance imaging (Ophatnet, 2009).
Molecular genetics tests are also often used to identify genetic alterations that have been demonstrated in 40% of Joubert syndrome cases (National Organization for Rare Disease, 2011).
On the other hand, it is also possible to perform a prenatal diagnosis of this pathology through fetal ultrasound and molecular analysis, especially in families with a genetic history of Joubert syndrome (Ophatnet, 2009).
When the most characteristic features of Joubert syndrome occur in combination with one or more additional physical pathologies, it is possible that a diagnosis of ” Joubert Syndrome and Related Disorders (JSRD) ?? (US National Library of Medicine, 2011).
Therefore, depending on the type of pathology involved is associated with the presence of Joubert syndrome, we can find subtypes of this. However, the classification system of Joubert syndrome is still in a phase of evolution due to the discovery of the genetic contributions and the greater knowledge of the phenotypic correlations.
We can therefore find (Bracanti et al., 2010):
- Pure Joubert Syndrome (SJ): In addition to the abnormalities related to the ?? molar sign ?? , patients show neurological symptoms characterized by ataxia, developmental delay and alterations in respiration and ocular coordination. It is not associated with other alterations at the physical level.
- Joubert syndrome with ocular defects (JS-O): In addition to the neurological characteristics, there are physical alterations related to retinal dystrophy.
- Joubert syndrome with renal defects (JS-R) : In addition to the neurological characteristics, there are physical alterations related to the renal pathologies.
- Joubert syndrome with oculo-renal defects ( JS-OR ): In addition to the neurological characteristics, there are physical alterations related to retinal dystrophy and renal pathologies.
- Joubert Syndrome with Hepatic Defects ( JS-H ): The characteristic symptoms of Joubert Syndrome are related to the presence of hepatic, chorioretinanane or cloboma alterations in the optic nerve.
- Joubert Syndrome with digital-facial-defect (JS-OFD): neurological symptoms are accompanied by physical alterations such as lobular or bifid, oral frenulum, polydactyly, among others.
The treatment used in Joubert syndrome is symptomatic and supports the underlying pathologies. In addition to pharmacological interventions, early stimulation at the physical and cognitive levels is often used (National Institute of Neurological Disorders and Stoke, 2016).
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When respiratory changes are significant, especially in the early stages of life, respiratory function needs to be monitored (National Institute of Neurological Disorders and Stoke, 2016).
On the other hand, the identification and control of ocular degeneration, renal complications, and all other complications related to Joubert’s syndrome should be performed as early as possible to adjust therapeutic measures (National Institute of Neurological Disorders and Stoke, 2016) .