Recent Advances in Joubert Syndrome: Genetic Insights, Clinical Management, and Emerging Therapeutic Strategies

Abstract

Joubert syndrome (JS) is a rare, genetically heterogeneous autosomal recessive ciliopathy characterized by the pathognomonic molar tooth sign (MTS) on brain magnetic resonance imaging, resulting from cerebellar vermis hypoplasia or aplasia and abnormal superior cerebellar peduncles. Since its first description by Marie Joubert in 1969, substantial advances in molecular genetics have transformed the understanding of JS, with more than 40 disease-causing genes identified to date. These genes encode proteins that are essential for the structure and function of the primary cilium, a highly specialized sensory organelle involved in embryonic development and multiple intracellular signaling pathways. Consequently, JS is now recognized as part of the broader spectrum of ciliopathies, with multisystem involvement including retinal dystrophy, nephronophthisis, congenital hepatic fibrosis, and skeletal abnormalities, collectively referred to as Joubert syndrome and related disorders (JSRD). This review provides a comprehensive overview of recent advances in the molecular genetics, ciliary biology, pathophysiological mechanisms, clinical manifestations, diagnostic strategies, and current multidisciplinary management of JS. Particular emphasis is placed on emerging therapeutic approaches, including adenoassociated virus-mediated gene replacement, antisense oligonucleotide therapy, CRISPR-Cas9 genome editing, pharmacological modulation of Sonic Hedgehog (SHH) and mTOR signaling pathways, and novel smallmolecule therapies targeting ciliary dysfunction. This review emphasizes the evolving landscape of Joubert syndrome research and provides a comprehensive framework for understanding its molecular basis, clinical management, and emerging therapeutic strategies, thereby supporting future research and the translation of precision medicine into clinical practice.