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The Molecular Basis of Joubert Syndrome and Related Disorders 

The Molecular Basis of Joubert Syndrome and Related Disorders
The Molecular Basis of Joubert Syndrome and Related Disorders

Jeong Ho Lee

and Joseph G. Gleeson

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date: 16 January 2021

Joubert syndrome and related disorders (JSRD) are autosomal recessive conditions that are characterized by cerebellar vermis hypoplasia (CVH), diffuse hypotonia, developmental delay, abnormal respiratory patterns in the neonatal period, and oculomotor apraxia. The key neuroradiological finding in JSRD is the presence of a complex malformation of the hindbrain-midbrain junction, CVH, thick and maloriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa. On axial magnetic resonance imaging at the level of the junction of the cerebellum and midbrain, the malformation is associated with an unusual appearance resembling a molar tooth, the so-called molar tooth sign (MTS). Along with these typical features, the eyes, kidneys, liver, and other organs may be affected. Other noted features have included postaxial polydactyly, soft tissue tumors of the tongue, encephalocele, and behavioral abnormalities suggestive of autism. The genetic basis of JSRD is highly heterogeneous. To date, 18 causative genes have been identified in ~50% of individual with JSRD. All these genes encode proteins regulating the function or structure of the primary cilium, which is a microtubule-based membrane protrusion and plays a role as a signaling antenna of the cell. JSRD are now classified into “ciliopathies”, a group of genetic disorders caused by malfunction of primary cilia. The genotype-phenotype correlations are known for selected genes. The CEP290 gene is known to be associated with cerebellar, ocular, and renal involvment. The TMEM67 gene is associated with hepatic and retinal involvement. The long-term outcome of patients with JSRD is varied, but generally involves marked impairment of intelligence, speech deficit, and ataxia of gait, but mild improvements in oculomotor and breathing abnormalities with time. Genetic counseling for JSRD relies upon recognizing the autosomal recessive inheritance pattern and the natural variability of disease with a rare exception of X-linked recessive inheritance. Prenatal diagnosis in at-risk pregnancies is possible with prenatal imaging. Currently, management involves supportive measures along with individualized neuropsychologic assessment and screening for other organ involvement. Recent advance in sequencing technologies and future efforts will accelerate the identification of JSRD causative genetic variations and revolutionize genetic testing strategies.

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