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YSEIZ-2321; No. of Pages 3 Seizure xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Clinical letter
A novel TSC2 mutation causing tuberless tuberous sclerosis Nadia Mariagrazia Giannantoni a,*, Domenico Restuccia a, Giacomo Della Marca a, Rosa Maria Alfano b, Catello Vollono a a b
Institute of Neurology, Unit of Neurophysiology and Sleep Medicine, Catholic University, Rome, Italy Unit of Human Pathology, Department of Health Science San Paolo Hospital, Milan, Italy
A R T I C L E I N F O
Article history: Received 22 January 2014 Received in revised form 3 March 2014 Accepted 1 April 2014
1. Introduction Tuberous Sclerosis Complex (TSC) is a neurocutaneous, nonstatic, multisystemic disorder that affects 1:6000 live births. It is a dominantly inherited disease with a high sporadic mutation rate (66%), caused by inactivating mutations in one of the tumor suppressor genes, TSC1 or TSC2. This disease leads to
hamartomas most commonly in the brain, skin, kidney and eye, that cause disabling neuro-pschyatric manifestations. It’s clinical manifestations and penetrance are highly variable and the classical triad of presentation occurs in just 29% of patients. Locus heterogeneity may account for some of the extensive phenotypical variability of TSC but it is not viable for observed variability in kindred. TSC2 mutations usually lead to a more severe clinical phenotype and their clinical variability is commonly attributed to the burden of cortical tubers that are considered the substrate for epileptogenicity, together with the perituberal cortex.1 We describe two cases of genetically proven TCS2, sharing the same genotype, the first suffering from intractable epilepsy and mental delay but with no tubers, cortical dysplasia nor alterations of the white matter during 25-year neuroradiological follow-up, and the second with a typical neuroradiological picture but with no clinical impairment.
Fig. 1. Ten seconds of inter-ictal EEG. Epileptic activity in the left fronto-temporal derivations with a clear left prevalence.
* Corresponding author at: Institute of Neurology, Unit of Neurophysiology and Sleep Medicine, Catholic University, Policlinico Universitario ‘‘A. Gemelli’’ L.go A. Gemelli, 8, 00168 Rome, Italy. Tel.: +39 06 30154276; fax: +39 06 35501909. E-mail address: [email protected] (N.M. Giannantoni). http://dx.doi.org/10.1016/j.seizure.2014.04.001 1059-1311/ß 2014 Published by Elsevier Ltd on behalf of British Epilepsy Association.
Please cite this article in press as: Giannantoni NM, et al. A novel TSC2 mutation causing tuberless tuberous sclerosis. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.001
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YSEIZ-2321; No. of Pages 3 N.M. Giannantoni et al. / Seizure xxx (2014) xxx–xxx
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2. Case report A 28-year-old man came to our observation for a focal and poorly controlled epilepsy. A diagnosis of Tuberous Sclerosis was
clinically made at 3 years of age. The patient was born from unrelated parents, normal pregnancy and natural delivery, without perinatal complications. Mild psycho-motor delay was reported. At age 3 the patient started to suffer from infantile spasms, treated
Fig. 2. Magnetic Resonance Imaging of proband and his mother. (A, D, and E) T2-weighted axial (panel A), coronal (panel D), and sagittal (panel E) images of the proband; these images show no abnormalities. (B, C) T1-weighted axial FLAIR sequences (panels B and C) of the proband; these images are unremarkable for the presence of cortical tubers. (F) Coronal inversion recovery image of the proband; these image is not significant for the presence of cortical dysplasias. (G–N) T1-weighted axial FLAIR sequences of the proband’s mother displaying the presence of various cortical tubers.
Please cite this article in press as: Giannantoni NM, et al. A novel TSC2 mutation causing tuberless tuberous sclerosis. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.001
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YSEIZ-2321; No. of Pages 3 N.M. Giannantoni et al. / Seizure xxx (2014) xxx–xxx
successfully with carbamazepine, and manifested the first dermatological features of the disease. At age 10, partial seizures replaced infantile spasms and then gradually became medically intractable. Since then he presented brief episodes, lasting few seconds and occurring weekly, characterized by right eyelid myoclonus associated with parhasthesias, described as a migrating right occipito-temporal electrical discharge, and followed by a fainting feeling. Several cerebral CT scans and various brain MRI scans were performed in the following 25 years, always being irrelevant. A large variety of anticonvulsant medications, including phenobarbital, vigabatrin, clobazam, nitrazepam, lamotrigine, lacosamide were administered throughout the years without complete control of seizures. Clinical examination of the patient yielded facial angiofibroma over his nose and cheeks and a small number of hypopigmented skin lesions, consistent with hypomelanotic macules (ash-leaf spots), on his arms and legs. Neurological examination showed mild cognitive impairment (IQ 65) and behavioral disturbances, without sensory-motor impairment. Psychiatric evaluation assessed the presence of autistic tracts and of psychotic features. Electroencephalography revealed some bouffe´s of polymorph theta activity and brief sequences of spikes and poly-spikes-waves bilaterally over the fronto-temporal derivations with a clear left prevalence (Fig. 1). Given the lack of any typical neuropathological hallmarks of TSC in previous neuroradiological studies, an MR epilepsy-protocol was performed and interpreted by an expert neuroradiologist, showing no signs of malformation of cortical development (Fig. 2). A full-body CT scanning displayed no other pathological sign of the disease. A genetic analysis was conducted with DHPLC methods and detected a novel, small and in frame deletion/insertion TSC2 mutation on exon 30 (c.3664_3665delinsTT-p.Asp1222Phe), described according to HGVS nomenclature (accession number NM_000548.3), thus confirming the diagnosis of tuberous sclerosis complex (supplementary materials-1 and 2) He was put on carbamazepine at the dosage of 1200 mg per day with no substantial benefit. On the basis of the genetic results obtained in the proband, his mother, an asymptomatic 53-year-old woman with a past history of infantile spasms and complex partial seizures, underwent a genetic and neuroradiological assessment that confirmed the mutation identified in the proband and showed several calcified cortical tubers (Fig. 2).
3
detecting cortical tubers in infancy, probably due to the immature myelination of the brain. Moreover, there is no information available with regard to the neuroradiological follow-up of this child.2 Even though pathophysiologically tubers are considered to be responsible for seizures and indeed their resection contribute greatly to their control in selected cases, tubers might not be necessary for epileptogenesis in TSC. In effect, it has been suggested that plasticity and seizure susceptibility, that ultimately lead to cognitive impairment and epilepsy, are altered even with no structural damage in human TSC, analogously with the data in Eker rats. In our patient we hypothesize that the effect of the oncosuppressor dysfunction over cortical excitability, due to TSC2 mutation, is crucial for epileptogenesis. This speculation is consistent with the evidence of a progressive functional disruption of cortico-cortical and subcortico-cortical networks that has predispose to an increased intrinsic neuronal excitability, which ultimately explain the full clinical spectrum of the disease.3 Although the absence of tubers in the animal models of TSC is considered the main limitation with relation to humans’ disease, our patient confirms that epilepsy can occur also in human Tuberous Sclerosis even in the absence of structural lesions. Hence various tuber free rat models of TSC corroborate the theory of a role of cortical hyperexcitability and of functional abnormalities in epileptogenesis, directly secondary to the TSC’s molecular mutation.4 In conclusion, our findings confirm the pathogenic relevance of both cortical hyperexcitability, directly due to TSC’s molecular mutation, and of multifactorial influences on TSC’s extremely wide phenotypic expression. Overall, we argue that the pathogenesis of this disease is not merely linked to the structural cortical lesions characteristic of the disease as traditionally acknowledged. Ethics The work described is consistent with the Journal’s guidelines for ethical publication. Conflict of interest None of the authors has any conflict of interest to disclose.
3. Discussion Appendix A. Supplementary data We report two cases of the same TSC2 mutation responsible for two opposite phenotypes: the proband’s mother, asymptomatic and with a ‘de novo’ mutation despite an important tuber’s burden, and the proband, severely affected but showing no brain structural abnormalities. To our knowledge, we describe the first case of tuberless TSC occurring in an adult with the full clinical scenario of the disease but without evidence of TSC’s neuropathological characterizing features identifiable by means of MRI. In fact, the only described case in literature was a 2 year old child in which no cortical tubers were detected on MRI/CT scans. However, as acknowledged by the same Authors, just a single neuroradiological examination was performed, which most likely indicates imaging limitations in
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.seizure.2014.04.001. References 1. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345–56. 2. Kaufmann R, Kornreich L, Goldberg-Stern H. Unusual clinical presentation of tuberless tuberous sclerosis complex. J Child Neurol 2009;24:361–4. 3. Napolioni V, Moavero R, Curatolo P. Recent advances in neurobiology of Tuberous Sclerosis Complex. Brain Dev 2009;31:104–13. 4. Wang Y, Greenwood JS, Calcagnotto ME, Kirsch HE, Barbaro NM, Baraban SC. Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Ann Neurol 2007;61:139–52.
Please cite this article in press as: Giannantoni NM, et al. A novel TSC2 mutation causing tuberless tuberous sclerosis. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.001
YSEIZ-2321; No. of Pages 3 Seizure xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Clinical letter
A novel TSC2 mutation causing tuberless tuberous sclerosis Nadia Mariagrazia Giannantoni a,*, Domenico Restuccia a, Giacomo Della Marca a, Rosa Maria Alfano b, Catello Vollono a a b
Institute of Neurology, Unit of Neurophysiology and Sleep Medicine, Catholic University, Rome, Italy Unit of Human Pathology, Department of Health Science San Paolo Hospital, Milan, Italy
A R T I C L E I N F O
Article history: Received 22 January 2014 Received in revised form 3 March 2014 Accepted 1 April 2014
1. Introduction Tuberous Sclerosis Complex (TSC) is a neurocutaneous, nonstatic, multisystemic disorder that affects 1:6000 live births. It is a dominantly inherited disease with a high sporadic mutation rate (66%), caused by inactivating mutations in one of the tumor suppressor genes, TSC1 or TSC2. This disease leads to
hamartomas most commonly in the brain, skin, kidney and eye, that cause disabling neuro-pschyatric manifestations. It’s clinical manifestations and penetrance are highly variable and the classical triad of presentation occurs in just 29% of patients. Locus heterogeneity may account for some of the extensive phenotypical variability of TSC but it is not viable for observed variability in kindred. TSC2 mutations usually lead to a more severe clinical phenotype and their clinical variability is commonly attributed to the burden of cortical tubers that are considered the substrate for epileptogenicity, together with the perituberal cortex.1 We describe two cases of genetically proven TCS2, sharing the same genotype, the first suffering from intractable epilepsy and mental delay but with no tubers, cortical dysplasia nor alterations of the white matter during 25-year neuroradiological follow-up, and the second with a typical neuroradiological picture but with no clinical impairment.
Fig. 1. Ten seconds of inter-ictal EEG. Epileptic activity in the left fronto-temporal derivations with a clear left prevalence.
* Corresponding author at: Institute of Neurology, Unit of Neurophysiology and Sleep Medicine, Catholic University, Policlinico Universitario ‘‘A. Gemelli’’ L.go A. Gemelli, 8, 00168 Rome, Italy. Tel.: +39 06 30154276; fax: +39 06 35501909. E-mail address: [email protected] (N.M. Giannantoni). http://dx.doi.org/10.1016/j.seizure.2014.04.001 1059-1311/ß 2014 Published by Elsevier Ltd on behalf of British Epilepsy Association.
Please cite this article in press as: Giannantoni NM, et al. A novel TSC2 mutation causing tuberless tuberous sclerosis. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.001
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YSEIZ-2321; No. of Pages 3 N.M. Giannantoni et al. / Seizure xxx (2014) xxx–xxx
2
2. Case report A 28-year-old man came to our observation for a focal and poorly controlled epilepsy. A diagnosis of Tuberous Sclerosis was
clinically made at 3 years of age. The patient was born from unrelated parents, normal pregnancy and natural delivery, without perinatal complications. Mild psycho-motor delay was reported. At age 3 the patient started to suffer from infantile spasms, treated
Fig. 2. Magnetic Resonance Imaging of proband and his mother. (A, D, and E) T2-weighted axial (panel A), coronal (panel D), and sagittal (panel E) images of the proband; these images show no abnormalities. (B, C) T1-weighted axial FLAIR sequences (panels B and C) of the proband; these images are unremarkable for the presence of cortical tubers. (F) Coronal inversion recovery image of the proband; these image is not significant for the presence of cortical dysplasias. (G–N) T1-weighted axial FLAIR sequences of the proband’s mother displaying the presence of various cortical tubers.
Please cite this article in press as: Giannantoni NM, et al. A novel TSC2 mutation causing tuberless tuberous sclerosis. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.001
G Model
YSEIZ-2321; No. of Pages 3 N.M. Giannantoni et al. / Seizure xxx (2014) xxx–xxx
successfully with carbamazepine, and manifested the first dermatological features of the disease. At age 10, partial seizures replaced infantile spasms and then gradually became medically intractable. Since then he presented brief episodes, lasting few seconds and occurring weekly, characterized by right eyelid myoclonus associated with parhasthesias, described as a migrating right occipito-temporal electrical discharge, and followed by a fainting feeling. Several cerebral CT scans and various brain MRI scans were performed in the following 25 years, always being irrelevant. A large variety of anticonvulsant medications, including phenobarbital, vigabatrin, clobazam, nitrazepam, lamotrigine, lacosamide were administered throughout the years without complete control of seizures. Clinical examination of the patient yielded facial angiofibroma over his nose and cheeks and a small number of hypopigmented skin lesions, consistent with hypomelanotic macules (ash-leaf spots), on his arms and legs. Neurological examination showed mild cognitive impairment (IQ 65) and behavioral disturbances, without sensory-motor impairment. Psychiatric evaluation assessed the presence of autistic tracts and of psychotic features. Electroencephalography revealed some bouffe´s of polymorph theta activity and brief sequences of spikes and poly-spikes-waves bilaterally over the fronto-temporal derivations with a clear left prevalence (Fig. 1). Given the lack of any typical neuropathological hallmarks of TSC in previous neuroradiological studies, an MR epilepsy-protocol was performed and interpreted by an expert neuroradiologist, showing no signs of malformation of cortical development (Fig. 2). A full-body CT scanning displayed no other pathological sign of the disease. A genetic analysis was conducted with DHPLC methods and detected a novel, small and in frame deletion/insertion TSC2 mutation on exon 30 (c.3664_3665delinsTT-p.Asp1222Phe), described according to HGVS nomenclature (accession number NM_000548.3), thus confirming the diagnosis of tuberous sclerosis complex (supplementary materials-1 and 2) He was put on carbamazepine at the dosage of 1200 mg per day with no substantial benefit. On the basis of the genetic results obtained in the proband, his mother, an asymptomatic 53-year-old woman with a past history of infantile spasms and complex partial seizures, underwent a genetic and neuroradiological assessment that confirmed the mutation identified in the proband and showed several calcified cortical tubers (Fig. 2).
3
detecting cortical tubers in infancy, probably due to the immature myelination of the brain. Moreover, there is no information available with regard to the neuroradiological follow-up of this child.2 Even though pathophysiologically tubers are considered to be responsible for seizures and indeed their resection contribute greatly to their control in selected cases, tubers might not be necessary for epileptogenesis in TSC. In effect, it has been suggested that plasticity and seizure susceptibility, that ultimately lead to cognitive impairment and epilepsy, are altered even with no structural damage in human TSC, analogously with the data in Eker rats. In our patient we hypothesize that the effect of the oncosuppressor dysfunction over cortical excitability, due to TSC2 mutation, is crucial for epileptogenesis. This speculation is consistent with the evidence of a progressive functional disruption of cortico-cortical and subcortico-cortical networks that has predispose to an increased intrinsic neuronal excitability, which ultimately explain the full clinical spectrum of the disease.3 Although the absence of tubers in the animal models of TSC is considered the main limitation with relation to humans’ disease, our patient confirms that epilepsy can occur also in human Tuberous Sclerosis even in the absence of structural lesions. Hence various tuber free rat models of TSC corroborate the theory of a role of cortical hyperexcitability and of functional abnormalities in epileptogenesis, directly secondary to the TSC’s molecular mutation.4 In conclusion, our findings confirm the pathogenic relevance of both cortical hyperexcitability, directly due to TSC’s molecular mutation, and of multifactorial influences on TSC’s extremely wide phenotypic expression. Overall, we argue that the pathogenesis of this disease is not merely linked to the structural cortical lesions characteristic of the disease as traditionally acknowledged. Ethics The work described is consistent with the Journal’s guidelines for ethical publication. Conflict of interest None of the authors has any conflict of interest to disclose.
3. Discussion Appendix A. Supplementary data We report two cases of the same TSC2 mutation responsible for two opposite phenotypes: the proband’s mother, asymptomatic and with a ‘de novo’ mutation despite an important tuber’s burden, and the proband, severely affected but showing no brain structural abnormalities. To our knowledge, we describe the first case of tuberless TSC occurring in an adult with the full clinical scenario of the disease but without evidence of TSC’s neuropathological characterizing features identifiable by means of MRI. In fact, the only described case in literature was a 2 year old child in which no cortical tubers were detected on MRI/CT scans. However, as acknowledged by the same Authors, just a single neuroradiological examination was performed, which most likely indicates imaging limitations in
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.seizure.2014.04.001. References 1. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345–56. 2. Kaufmann R, Kornreich L, Goldberg-Stern H. Unusual clinical presentation of tuberless tuberous sclerosis complex. J Child Neurol 2009;24:361–4. 3. Napolioni V, Moavero R, Curatolo P. Recent advances in neurobiology of Tuberous Sclerosis Complex. Brain Dev 2009;31:104–13. 4. Wang Y, Greenwood JS, Calcagnotto ME, Kirsch HE, Barbaro NM, Baraban SC. Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Ann Neurol 2007;61:139–52.
Please cite this article in press as: Giannantoni NM, et al. A novel TSC2 mutation causing tuberless tuberous sclerosis. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.001
