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The molar tooth sign

A new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families

From the Clinical Genetics Department (M.S.Z., G.A.-S.), Medical Molecular Genetics Department (A.A.-A.), Human Genetics and Genome Research Division, National Research Centre, Neuromotor Institute, Cairo, Egypt; Neurogenetics Laboratory (S.E.M., J.L.S., J.G.G.), Department of Neurosciences, University of California, San Diego, La Jolla; Section of Neuroradiology (A.J.B.), Department of Radiology, University of California, San Francisco; Laboratory for Neurogenetics and Development (M.E.R.), Weill Medical College of Cornell University, New York, NY; Department of Radiology (S.N.S.), Cairo University, Cairo, Egypt; and Department of Human Genetics and Neurology (W.B.D.), University of Chicago, IL.

Address correspondence and reprint requests to Dr Gleeson, Leichtag 3A16, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0691 jogleeson{at}ucsd.edu or Dr. M.S. Zaki, National Research Centre, Clinical Genetics Department, El Tahrir St., Dokki, Cairo, Egypt mszaki60{at}internetegypt.com

Joubert syndrome and related cerebellar disorders (JSRD) are a group of recessive congenital ataxia conditions usually showing neonatal hypotonia, dysregulated breathing rhythms, oculomotor apraxia, and mental retardation. The pathognomonic finding in JSRD is the unique molar tooth sign (MTS) on brain imaging. There is a tremendously broad spectrum of signs and symptoms mainly including kidney, retina, and liver disease, along with polydactyly and facial dysmorphisms. Here we propose a new diagnostic classification within JSRD that includes four major subtypes. To test this classification, we performed a systematic recruitment and genetic evaluation from a single referral center in Egypt. Thirteen families were identified, four showed evidence of linkage to one of the four known genetic loci, three showed novel AHI1 mutations, and nine were excluded from known loci. Each family could be classified into one of the four subtypes. This classification may thus be useful in the evaluation of patients with JSRD.

GLOSSARY: BUN = blood urinary nitrogen; COACH = cerebellar vermis hypo/aplasia-oligophrenia-ataxia-ocular coloboma-hepatic fibrosis; CORS = cerebello-oculo-renal syndrome; CVH = cerebellar vermis hypoplasia; DAS = Dekaban-Arima syndrome; DWM = Dandy-Walker malformation; JSRD = Joubert syndrome and related cerebellar disorders; LCA = Leber congenital amaurosis; lod = logarithm of odds score; MKS = Meckel-Gruber syndrome; MTS = molar tooth sign; NPH = nephronophthisis; NRC = National Research Center; OFD-VI = oro-facio-digital syndrome type VI; PCH = pontocerebellar hypoplasia; RHO = rhombencephalosynapsis; SLS = Senior-Loken syndrome.

Supplemental data at www.neurology.org

Funded by grants from the NIH and the Burroughs Wellcome Fund in Translational Research.

Disclosure: The authors report no conflicts of interest.

Received October 2, 2006. Accepted in final form April 9, 2007.