Joubert Syndrome

Joubert syndrome is a rare autosomal recessive genetic disorder (*) that affects the cerebellum, an area of the brain that controls balance and coordination. Joubert syndrome is one of the many genetic syndromes associated with syndromic retinitis pigmentosa.[1] The syndrome was first identified in 1969 by pediatric neurologist Marie Joubert in Montreal, Quebec, Canada, while working at the Montreal Neurological Institute and McGill University.[2]

Most of the signs and symptoms of the Joubert syndrome appear very early in infancy with most children showing delays in gross motor milestones.[3] Although other signs and symptoms vary widely from individual to individual, they generally fall under the hallmark of cerebellum involvement or in this case, lack thereof. Consequently, the most common features include ataxia (lack of muscle control), hyperpnea (abnormal breathing patterns), sleep apnea, abnormal eye and tongue movements, and hypotonia in early childhood. Other malformations such as polydactyly(extra fingers and toes), cleft lip or palate, tongue abnormalities, and seizures may also occur. Developmental delays, including cognitive, are always present to some degree.[4]

Those suffering from this syndrome often exhibit specific facial features such as a broad forehead, arched eyebrows, ptosis (droopy eyelids), hypertelorism (widely spaced eyes), low-set ears and a triangle shaped mouth.

Additionally, this disease can include a broad range of other abnormalities to other organ systems such as retinal dystrophy, kidney diseases, liver diseases, skeletal deformities and endocrine (hormonal) problems and more, see NIH’s take below.[5]

NIH Characterizations

“Joubert syndrome is a disorder that affects many parts of the body. The signs and symptoms of this condition vary among affected individuals, even among members of the same family. The hallmark feature of Joubert syndrome is a combination of brain abnormalities that together are known as the molar tooth sign, which can be seen on brain imaging studies such as magnetic resonance imaging (MRI). This sign results from the abnormal development of structures near the back of the brain, including the cerebellar vermis and the brainstem. The molar tooth sign got its name because the characteristic brain abnormalities resemble the cross-section of a molar tooth when seen on an MRI. Most infants with Joubert syndrome have low muscle tone (hypotonia) in infancy, which contributes to difficulty coordinating movements (ataxia) in early childhood. Other characteristic features of the condition include episodes of unusually fast (hyperpnea) or slow (apnea) breathing in infancy, and abnormal eye movements (ocular motor apraxia). Most affected individuals have delayed development and intellectual disability, which can range from mild to severe. Distinctive facial features can also occur in Joubert syndrome; these include a broad forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes (hypertelorism), low-set ears, and a triangle-shaped mouth. Joubert syndrome can include a broad range of additional signs and symptoms. The condition is sometimes associated with other eye abnormalities (such as retinal dystrophy, which can cause vision loss, and coloboma, which is a gap or split in a structure of the eye), kidney disease (including polycystic kidney disease and nephronophthisis), liver disease, skeletal abnormalities (such as the presence of extra fingers and toes), or hormone (endocrine) problems. A combination of the characteristic features of Joubert syndrome and one or more of these additional signs and symptoms once characterized several separate disorders. Together, those disorders were referred to as Joubert syndrome and related disorders (JSRD). Now, however, any instances that involve the molar tooth sign, including those with these additional signs and symptoms, are usually considered Joubert syndrome. (Source)

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Picture: Univ of Washington Med School ((Source)

Genetic Configurations

A number of mutations have been identified in individuals with Joubert syndrome (JBTS) which allowed for classification of the disorder into subtypes.

This disorder can be caused by mutations in more than 30 genes within genetic makeup. The primary cilia play an important role in the structure and function of cells. When primary cilia are mutated and defected, it can cause various genetic disorders among individuals. This mutation of primary cilia can disrupt significant signaling pathways during the development of the fetus.

Mutations in these various genes are known for causing around 60-90% of Joubert Syndrome cases. The remaining cases, the cause is unknown if isn’t linked to a mutation of known genes.[6]

The disorder is characterized by absence or underdevelopment of the cerebellar vermis and a malformed brain stem (molar tooth sign), both of which can be visualized on a MRI scan.[10] Together with this sign, the diagnosis is based on the physical symptoms and genetic testing for mutations. If the gene mutations have been identified in a family member, prenatal or carrier diagnosis can be pursued.[3]

Joubert Syndrome is known to affect 1 in 80,000-100,000 newborns. Due to the variety of genes this disorder is affected by, it is likely to be under-diagnosed. It is commonly found in Ashkenazi Jewish, French-Canadians, and Hutterite ethnic populations. Most cases of Joubert syndrome are autosomal recessive – in these cases, both parents are either carriers or affected. Rarely, Joubert syndrome is inherited in an X-linked recessive pattern. In these cases, males are more commonly affected because affected males must have one X chromosome mutated, while affected females must have mutated genes on both X chromosomes.[6]

According to the University of Washington in Seattle, the following is a good summary of this health challenge.

“Joubert syndrome is a neurogenetic disorder characterized by hypotonia, developmental disability, abnormal breathing pattern, abnormal eye movements, and a distinctive brain malformation giving the appearance of “the molar tooth sign” on axial brain MRI. In addition to developmental disability and the brain malformation, subsets of patients have coloboma (a gap in the retina of the eye), polydactyly (extra fingers or toes), and other malformations, and some patients also develop retinal dystrophy, cystic kidney disease, and/or liver fibrosis. The neurologic symptoms (hypotonia, impaired coordination, abnormal eye movements, poor speech articulation, and abnormal breathing pattern) reflect the parts of the brain most affected in patients with Joubert: the cerebellar vermis and brainstem. Joubert syndrome is inherited in a recessive manner, so once a couple has had a child with Joubert syndrome, they have a 25% chance of having another affected child each time they get pregnant. Identifying the genes responsible for Joubert syndrome has helped define a new category of diseases called the “ciliopathies” because all of the Joubert syndrome genes seem to be involved with an important cellular structure called the primary cilium. The primary cilium acts as an antenna for most cells in the body, allowing the cells to detect the environment outside the cell and react to it” (Source)

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Picture: Univ of Washington Med School (Source)

Treatment

Allopathic mainstream treatment for Joubert syndrome is symptomatic and supportive.[4] Infant stimulation and physical, occupational, speech and hearing therapy may benefit some patients. Infants with abnormal breathing patterns should be monitored.

 The syndrome is associated with progressive worsening for kidneys, the liver and the eyes and thus require regular monitoring.[4]

In a sample of 19 children, a 1997 study found that 3 died before the age of 3, and 2 never learned to walk. The children had various levels of delayed development with developmental quotients from 60 to 85.[11]

Research has revealed that a number of genetic disorders, not previously thought to be related, may indeed be related as to their root cause. Joubert syndrome is one such disease. It is a member of an emerging class of diseases called ciliopathies.

Root Causes

The underlying cause of the ciliopathies may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect “numerous critical developmental signaling pathways” essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases.

Ciliopathies

Currently recognized ciliopathies include Joubert syndrome, primary ciliary dyskinesia (also known as Kartagener Syndrome), Bardet-Biedl syndrome, polycystic kidney disease and polycystic liver disease, nephronophthisis, Alström syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration.[12] Joubert syndrome type 2 is disproportionately frequent among people of Jewish descent.[13]

 Prognosis

The prognosis for children with Joubert’s Syndrome is a function of the degree of development of the cerebellar vermis and the brainstem. In case of children who develop complications due to breathing problems due to Joubert’s Syndrome then the prognosis is not all that good but if hat aspect of the disease is controlled then the prognosis is quite a bit better. Children with mild forms of this disorder will have minimal motor disability and good mental development while children with severe form may have severe motor disability, impaired mental development and other problems regarding other organs.

Illustrations

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Top: Arched eyebrows, a common Joubert syndrom sign
 
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Top: Severe case of ptosis
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Picture: Fr pain assist Source

Holistic Medicine and Research

Recent research has identified Biallelic pathogenic variants in PIBF1  as one of the genetic etiologies of Joubert syndrome. (Source) In Holistic and innovative medicine, the focus is on root cause search, in particular that which has a potential to fix the Genetic disorder via bioelectric signaling, gene thereapy, embryology and holistic RNA expression. But to the Institute’s knowledge, there have been no breakthroughs as of yet.

 References

  1. ^ Saraiva, JM; Baraitser, M (1992). “Joubert syndrome: a review”. American Journal of Medical Genetics. 43 (4): 726–731. doi:10.1002/ajmg.1320430415. PMID 1341417.
  2. ^ Joubert M, Eisenring JJ, Robb JP, Andermann F (September 1969). “Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation”. Neurology. 19 (9): 813–25. doi:10.1212/wnl.19.9.813. PMID 5816874.
  3. Joubert Syndrome – NORD (National Organization for Rare Disorders)”. NORD (National Organization for Rare Disorders). Retrieved 2016-12-19.
  4. Parisi, Melissa A.; Doherty, Dan; Chance, Phillip F.; Glass, Ian A. (2007-03-21). “Joubert syndrome (and related disorders) (OMIM 213300)”. European Journal of Human Genetics. 15 (5): 511–521. doi:10.1038/sj.ejhg.5201648. ISSN 1018-4813.
  5. ^ Reference, Genetics Home. “Joubert syndrome”. Genetics Home Reference. Retrieved 2016-12-19.
  6. Reference, Genetics Home. “Joubert syndrome”. Genetics Home Reference. Retrieved 2017-09-13.
  7. ^ Shaheen, R.; Shamseldin, H. E.; Loucks, C. M.; Seidahmed, M. Z.; Ansari, S.; Ibrahim Khalil, M.; Al-Yacoub, N.; Davis, E. E.; Mola, N. A.; Szymanska, K.; Herridge, W.; Chudley, A. E.; Chodirker, B. N.; Schwartzentruber, J.; Majewski, J.; Katsanis, N.; Poizat, C.; Johnson, C. A.; Parboosingh, J.; Boycott, K. M.; Innes, A. M.; Alkuraya, F. S. (2013). “Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans”. The American Journal of Human Genetics. 94 (1): 73–9. doi:10.1016/j.ajhg.2013.11.010. PMC 3882732. PMID 24360803.
  8. ^ Akizu, N.; Silhavy, J. L.; Rosti, R. O.; Scott, E.; Fenstermaker, A. G.; Schroth, J.; Zaki, M. S.; Sanchez, H.; Gupta, N.; Kabra, M.; Kara, M.; Ben-Omran, T.; Rosti, B.; Guemez-Gamboa, A.; Spencer, E.; Pan, R.; Cai, N.; Abdellateef, M.; Gabriel, S.; Halbritter, J.; Hildebrandt, F.; Van Bokhoven, H.; Gunel, M.; Gleeson, J. G. (2013). “Mutations in CSPP1 Lead to Classical Joubert Syndrome”. The American Journal of Human Genetics. 94 (1): 80–6. doi:10.1016/j.ajhg.2013.11.015. PMC 3882909. PMID 24360807.
  9. ^ Tuz, K.; Bachmann-Gagescu, R.; o’Day, D. R.; Hua, K.; Isabella, C. R.; Phelps, I. G.; Stolarski, A. E.; o’Roak, B. J.; Dempsey, J. C.; Lourenco, C.; Alswaid, A.; Bönnemann, C. G.; Medne, L.; Nampoothiri, S.; Stark, Z.; Leventer, R. J.; Topçu, M.; Cansu, A.; Jagadeesh, S.; Done, S.; Ishak, G. E.; Glass, I. A.; Shendure, J.; Neuhauss, S. C. F.; Haldeman-Englert, C. R.; Doherty, D.; Ferland, R. J. (2013). “Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy”. The American Journal of Human Genetics. 94 (1): 62–72. doi:10.1016/j.ajhg.2013.11.019. PMC 3882733. PMID 24360808.
  10. ^ Brancati F, Dallapiccola B, Valente EM (2010). “Joubert Syndrome and related disorders”. Orphanet J Rare Dis. 5: 20. doi:10.1186/1750-1172-5-20. PMC 2913941. PMID 20615230.
  11. ^ Steinlin, M.; Schmid, M.; Landau, K.; Boltshauser, E. (1997-08-01). “Follow-Up in Children with Joubert Syndrome”. Neuropediatrics. 28 (04): 204–211. doi:10.1055/s-2007-973701. ISSN 0174-304X. PMID 9309710.
  12. ^ Badano, Jose L.; Norimasa Mitsuma; Phil L. Beales; Nicholas Katsanis (September 2006). “The Ciliopathies : An Emerging Class of Human Genetic Disorders”. Annual Review of Genomics and Human Genetics. 7: 125–148. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. Retrieved 2008-06-15.
  13. ^ Gutkind, Lee; Kennedy, Pagan (10 October 2013). An Immense New Power to Heal: The Promise of Personalized Medicine. Underland Press. p. 36. ISBN 978-1-937163-07-5.
(*).  A gene is the basic physical and functional unit of heredity. Genes are made up of DNA. Some genes act as instructions to make molecules called proteins. However, many genes do not code for proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features. In this context, a gene disorder or mutation is a quasi permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people. Mutations range in size; they can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes. They can be inherited or acquired.

External Source & Education Video

NINDS Joubert Syndrome Information PageResearchers Identify Joubert Syndrome GenesGeneReviews: Joubert syndromeUniversity of Washington Joubert Research ProgramNCBI Joubert SyndromeJoubert Research Program – Seattle Research Hospital Children’s Foundation

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