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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.
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.
* To whom correspondence should be addressed. E-mail: f.e.jansen{at}umcutrecht.nl.
ABSTRACT
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.
This article has been cited by other articles:
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  C. J. Chu-Shore, P. Major, M. Montenegro, and E. Thiele Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex Neurology, March 31, 2009; 72(13): 1165 - 1169. [Abstract] [Full Text] [PDF]
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R. Nass and P. B. Crino Tuberous sclerosis complex: A tale of two genes Neurology, March 18, 2008; 70(12): 904 - 905. [Full Text] [PDF]
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