Valeria Capra1, Michele Iacomino1,2, Andrea Accogli1, Marco Pavanello1, Federico Zara2, Armando Cama1, Patrizia De Marco3. 1. UOC Neurochirurgia, IRCCS Istituto Giannina Gaslini, v. G. Gaslini 5, 16147, Genoa, Italy. 2. UOSD Laboratorio Neurogenetica e Neuroscienze, IRCCS Istituto Giannina Gaslini, v. G. Gaslini 5, 16147, Genoa, Italy. 3. UOSD Laboratorio Neurogenetica e Neuroscienze, IRCCS Istituto Giannina Gaslini, v. G. Gaslini 5, 16147, Genoa, Italy. patriziademarco@gaslini.org.
Abstract
PURPOSE: Chiari malformation type I (CMI), a rare disorder of the craniocerebral junction with an estimated incidence of 1 in 1280, is characterized by the downward herniation of the cerebellar tonsils of at least 5 mm through the foramen magnum, resulting in significant neurologic morbidity. Classical CMI is thought to be caused by an underdeveloped occipital bone, resulting in a posterior cranial fossa which is too small to accommodate the normal-sized cerebellum. In this review, we dissect the lines of evidence supporting a genetic contribution for this disorder. METHODS: We present the results of two types of approaches: animal models and human studies encompassing different study designs such as whole genome linkage analysis, case-control association studies, and expression studies. The update of the literature also includes the most recent findings emerged by whole exome sequencing strategy. RESULTS: Despite evidence for a genetic component, no major genes have been identified and the genetics of CMI is still very much unknown. One major challenge is the variability of clinical presentation within CMI patient population that reflects an underlying genetic heterogeneity. CONCLUSIONS: The identification of the genes that contribute to the etiology of CMI will provide an important step to the understanding of the underlying pathology. The finding of a predisposing gene may lead to the development of simple and accurate diagnostic tests for better prognosis, counseling, and clinical management of patients and their relatives.
PURPOSE:Chiari malformation type I (CMI), a rare disorder of the craniocerebral junction with an estimated incidence of 1 in 1280, is characterized by the downward herniation of the cerebellar tonsils of at least 5 mm through the foramen magnum, resulting in significant neurologic morbidity. Classical CMI is thought to be caused by an underdeveloped occipital bone, resulting in a posterior cranial fossa which is too small to accommodate the normal-sized cerebellum. In this review, we dissect the lines of evidence supporting a genetic contribution for this disorder. METHODS: We present the results of two types of approaches: animal models and human studies encompassing different study designs such as whole genome linkage analysis, case-control association studies, and expression studies. The update of the literature also includes the most recent findings emerged by whole exome sequencing strategy. RESULTS: Despite evidence for a genetic component, no major genes have been identified and the genetics of CMI is still very much unknown. One major challenge is the variability of clinical presentation within CMI patient population that reflects an underlying genetic heterogeneity. CONCLUSIONS: The identification of the genes that contribute to the etiology of CMI will provide an important step to the understanding of the underlying pathology. The finding of a predisposing gene may lead to the development of simple and accurate diagnostic tests for better prognosis, counseling, and clinical management of patients and their relatives.
Authors: M Mukhopadhyay; S Shtrom; C Rodriguez-Esteban; L Chen; T Tsukui; L Gomer; D W Dorward; A Glinka; A Grinberg; S P Huang; C Niehrs; J C Izpisúa Belmonte; H Westphal Journal: Dev Cell Date: 2001-09 Impact factor: 12.270