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Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations

From the Rudolf Magnus Institute of Neuroscience, Departments of Child Neurology (F.E.J., O.v.N), Neurology (F.E.J., A.A.), Neuropsychology (O.B., A.J.S.), and Image Sciences Institute (K.L.V., P.A.), Department of Clinical Epidemiology (A.A.), Julius Centre for Health Sciences and Primary Care, Departments of Internal Medicine (B.A.Z.), TSC Clinic and Clinical Neurophysiology (A.C.v.H.), University Medical Centre, Utrecht, Department of Clinical Genetics (A.v.d.O., D.H., M.N.), Erasmus Medical Centre, Rotterdam, the Netherlands.

Address correspondence and reprint requests to Dr Jansen, Department of Neurology, C03236, University Medical Centre, P.O. Box 85500, 3508 GA Utrecht, the Netherlands f.e.jansen{at}umcutrecht.nl

Objective: The purpose of this study was to systematically analyze the associations between different TSC1 and TSC2 mutations and the neurologic and cognitive phenotype in patients with tuberous sclerosis complex (TSC).

Methods: Mutation analysis was performed in 58 patients with TSC. Epilepsy variables, including EEG, were classified. A cognition index was determined based on a comprehensive neuropsychological assessment. On three-dimensional fluid-attenuated inversion recovery MR images, an automated tuber segmentation program detected and calculated the number of tubers and the proportion of total brain volume occupied by tubers (tuber/brain proportion [TBP]).

Results: As a group, patients with a TSC2 mutation had earlier age at seizure onset, lower cognition index, more tubers, and a greater TBP than those with a TSC1 mutation, but the ranges overlapped considerably. Familial cases were older at seizure onset and had a higher cognition index than nonfamilial cases. Patients with a mutation deleting or directly inactivating the tuberin GTPase activating protein (GAP) domain had more tubers and a greater TBP than those with an intact GAP domain. Patients with a truncating TSC1 or TSC2 mutation differed from those with nontruncating mutations in seizure types only.

Conclusions: Although patients with a TSC1 mutation are more likely to have a less severe neurologic and cognitive phenotype than those with a TSC2 mutation, the considerable overlap between both aspects of the phenotype implies that prediction of the neurologic and cognitive phenotypes in individuals with tuberous sclerosis complex should not be based on their particular TSC1 or TSC2 mutation.

Abbreviations: GAP = GTPase activating protein; IE = intelligence equivalent; IS = infantile spasms; mTOR = mammalian target of rapamycin; sGTCS = secondary generalized tonic clonic seizure; TBP = tuber/brain proportion; TSC = tuberous sclerosis complex.

Supplemental data at www.neurology.org

Editorial, page 904

See also page 916

e-Pub ahead of print on November 21, 2007, at www.neurology.org.

Floor Jansen was supported by the Epilepsy Fund of the Netherlands (project no. 02-13). Floor Jansen and Olga Braams were supported by the EPOCH Foundation. Financial support for Mark Nellist was provided by the Stichting Michelle and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).

Disclosure: The authors report no conflicts of interest.

Received November 20, 2006. Accepted in final form July 5, 2007.

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