Is focal cortical dysplasia sporadic? Family evidence for genetic susceptibility

Authors

  • Richard J. Leventer,

    Corresponding author
    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
    3. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia
    • Address correspondence to Richard J. Leventer, Department of Neurology, Royal Children's Hospital, Flemington Road, Parkville, Vic. 3052, Australia. E-mail: richard.leventer@rch.org.au

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    • These authors contributed equally to this work.
  • Floor E. Jansen,

    1. Department of Pediatric Neurology, Rudolf Magnus Institute of Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands
    2. Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
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    • These authors contributed equally to this work.
  • Simone A. Mandelstam,

    1. The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
    2. Department of Radiology, University of Melbourne, Melbourne, Victoria, Australia
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  • Alice Ho,

    1. Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
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  • Ismail Mohamed,

    1. Department of Pediatrics, IWK Health Center, Dalhousie University, Halifax, Nova Scotia, Canada
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  • Harvey B. Sarnat,

    1. Department of Pediatrics, Pathology, (Neuropathology) and Clinical Neurosciences, University of Calgary Faculty of Medicine, Alberta Children's Hospital, Calgary, Alberta, Canada
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  • Mitsuhiro Kato,

    1. Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan
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  • Tatsuya Fukasawa,

    1. Department of Pediatrics, Anjo Kosei Hospital, Aichi, Japan
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  • Hirotomo Saitsu,

    1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Naomichi Matsumoto,

    1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Masayuki Itoh,

    1. Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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  • Renate M. Kalnins,

    1. Department of Anatomical Pathology, Austin Hospital, Melbourne, Victoria, Australia
    2. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
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  • Chung W. Chow,

    1. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia
    2. Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • A. Simon Harvey,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
    3. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia
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  • Graeme D. Jackson,

    1. Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
    2. Department of Radiology, University of Melbourne, Melbourne, Victoria, Australia
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  • Peter B. Crino,

    1. Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, Pennsylvania, U.S.A
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  • Samuel F. Berkovic,

    1. Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
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  • Ingrid E. Scheffer

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia
    3. Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
    4. Department of Radiology, University of Melbourne, Melbourne, Victoria, Australia
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Summary

Focal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co-occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants.

A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

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Dr Richard Leventer is a consultant pediatric neurologist at the Royal Children's Hospital.

Focal cortical dysplasia (FCD) encompasses a spectrum of cortical abnormalities characterized by dyslamination with or without abnormal cell types. FCDs are among the most common malformations of cortical development (MCDs) and are frequently associated with intractable epilepsy. FCD is often the only congenital abnormality present in the brain or elsewhere, with seizures usually being the sole clinical manifestation. The classification of FCD is based on the presence or absence of features in addition to cortical dyslamination: type I (no abnormal cell types), type II (dysmorphic neurons with or without balloon cells), and type III (type I with another lesion).[1] FCD may accompany hippocampal sclerosis and the “developmental” glioneuronal tumors, ganglioglioma and dysembryoplastic neuroepithelial tumors (DNETs), refining the classification to type IIIa and type IIIb, respectively.[1] A broad developmental classification of MCDs classifies the tubers of tuberous sclerosis complex (TSC), FCD type II, ganglioglioma, hemimegalencephaly, and DNET as all being malformations due to abnormal neuronal and glial proliferation with abnormal cell types.[2]

The etiology of FCD is largely unknown. Although the lesions of FCD (particularly FCD type II) share many imaging and histologic features with cortical tubers of TSC, FCD is usually sporadic, without clinical evidence to support a simple genetic etiology. Mutations in CNTNAP2 have been reported in children with FCD from Old Order Amish pedigrees.[3] These children differed from most patients with FCD because of mental retardation and macrocephaly, and the imaging findings and histology were not typical of either FCD type I or FCD type II. There have been no other reports of familial FCD. Apart from a single report of a father-son pair with DNET,[4] clinical evidence is lacking to suggest a familial basis for ganglioglioma, DNET, or nonsyndromic hemimegalencephaly, or familial co-occurrence of FCD with hemimegalencephaly, ganglioglioma, or DNET. A role for human papilloma virus (HPV)16 infection in the etiology of FCD type IIb has recently been suggested from studies of resected tissue and a mouse model.[5]

Recent studies of resected tissue from patients with hemimegalencephaly identified de novo somatic mosaic mutations in the genes of the PI3K-AKT3-mTOR (mammalian target of rapamycin) pathway in 9 of 28 patients.[6, 7] Evidence from molecular analysis of FCD specimens has led to the hypothesis that these malformations may have a shared pathogenesis, due to abnormalities of mTOR or other cellular pathways that regulate neuronal and glial proliferation.[8] However, until now, there has been no evidence to suggest a link between these disorders from family studies. Here, we report six families, each with two individuals with FCD, ganglioglioma, hemimegalencephaly, or DNET, adding clinical evidence that suggests a shared genetic susceptibility underlying these disorders, and showing for the first time that typical FCD can be familial.

Methods

Families were ascertained by referral to pediatric and adult epilepsy services. Clinical details were obtained from patient interview and medical records. Each institution's human research ethics committee approved the study. Informed consent was obtained from patients or their parents in the case of minors.

Brain magnetic resonance imaging (MRI) was obtained using age-specific epilepsy protocols on 1.5 T or 3 T scanners. Neurologists and neuroradiologists skilled in the detection of MCDs reviewed the MRI scans. Resected tissue was classified by a neuropathologist, according to the proposed system of the International League Against Epilepsy (ILAE) Diagnostic Methods Commission.[1] TSC1 and TSC2 mutation screening was performed using DNA extracted from resected brain tissue or whole blood using polymerase chain reaction (PCR) with exon-specific primers for TSC1 and TSC2 or by whole exome sequencing techniques.

Results

Six families, each with two affected individuals with seizures and at least one having FCD, were ascertained (pedigrees and selected MRI and neuropathology images: Fig. 1, clinical and imaging details: Table 1, additional MRI and neuropathology images: Fig. S1). All but one patient has undergone epilepsy surgery. None of the patients had clinical features suggestive of TSC, and all patients except family 5 were screened for TSC1 and TSC2 mutations. No mutations were identified.

Table 1. Clinical data for the six families
PatientAgeSz onsetSz typesIctal onsetLesion localizationAge at surgeryType of surgeryPathologyCurrent AEDsOutcome
  1. ND, not done; VPA, sodium valproate; LEV, levetiracetam; LTG, lamotrigine; CBZ, carbamazepine; PHT, phenytoin; ZNS, zonisamide; FCD, focal cortical dysplasia; GG, ganglioglioma; DNET, dysembryoplastic neuroepithelial tumor; HME, hemimegalencephaly; HS, hippocampal sclerosis; Sz, seizure; y, year; m, months; L, left; R, right; d, days, w, weeks.

1A16 year1 dTonic, L focal motorMultifocal R hemisphereMultifocal R hemisphere6 mHemispherectomyFCDIIaNILSz – free
1B10 y2 wL focal motorR posterior quadrantR posterior quadrant10 w and 5 mCorticectomy + temporo-parietooccipital resectionFCDIIaNILSz – free
2A37 y7 yR focal motorL centralL precentral gyrus27 yL central corticectomyFCDIaLEV>50% Sz reduction
2B23 y8 yFocal dyscognitive with dysphasiaL temporalL superior temporal gyrus14 yLesionectomyGGNILSz – free
3A24 y9 yFocal dyscognitive with L arm dystoniaR anterior quadrantR anterior temporal pole14 yLesionectomyFCDIIbNILSz – free
3B28 y12 yAphasia, R facial sensorimotor with generalizationL frontalL middle frontal gyrus17 yPartial lesionectomyDNETLEV>50% Sz reduction
4A35 y6 yVisual aura then L arm dystonia with generalizationR occipitalR occipital24 yLesionectomyFCDIIbNILSz – free
4B12 y3 yFocal dyscognitive with vomitingNDL posterior parietalNDNDVPASz – free
5A14 y3 yArousal and bipedal hyperkinetic movementsL frontalL medial superior frontal gyrus12 yLesionectomyFCDIIbCBZ, VPASz – free
5B12 y4 yFocal dyscognitive with bilateral hand automatisms +/− generalizationL temporooccipitalL hippocampus and parahippocampal gyrus5 yLesionectomy and anterior temporal lobectomyHSCBZSz – free
6A5 y1 mEpileptic spasms and focal motorL parietalL posterior quadrant8 m and 5 yFocal corticectomy then L posterior quadrantectomyFCDIIaLTG, CBZ, PHTOngoing Sz
6B4 m1 dEpileptic spasms and multifocal clonicL frontalR hemisphere2 mFunctional hemispherectomyFCDIIa (HME)PHT, ZNSSz – free
Figure 1.

Pedigrees of the six families and selected brain MRI and neuropathology images of families 1 and 6. (A) (top): The proband is marked with an arrow and is assigned “A” and their affected relative is assigned “B.” Blue, focal cortical dysplasia; green, ganglioglioma; yellow, DNET; red, hemimegalencephaly. (B) (bottom): All MR images are T2 axial and all pathology images are stained with hematoxylin and eosin (H&E). Family 1 is on the left panel and family 6 is on the right panel. MRI of patient 1A aged 6 weeks (A) shows multifocal areas of irregular and thickened cortex, irregular sulcation, and abnormal subcortical signal in the right hemisphere (arrows). MRI of patient 1B aged 14 weeks (C) shows an extensive area of irregular and thickened cortex with abnormal signal in the right posterior quadrant (arrows). Histopathology of both patient 1A (B) and patient 1B (D) showed cortical dyslamination with dense clusters of large dysmorphic neurons (arrows), irregular in orientation, often with prominent Nissl substance and bundles of pinkish fibrillary material in the cytoplasm. Balloon cells were not seen, consistent with FCD type IIa. MRI of patient 6A aged 8 weeks (E) shows loss of gray–white matter differentiation, abnormal sulcation, and low signal in the underlying white matter in the posterior left hemisphere (arrows). MRI of patient 6B aged 2 weeks (G) shows an enlarged left hemisphere with abnormal sulcation, poor gray–white matter differentiation, and abnormal signal throughout, most prominent in the frontal lobe suggestive of hemimegalencephaly. Histopathology from patient 6A (F) showed severe dyslamination and occasional dysmorphic neurons (arrows) consistent with FCD type IIa. Histopathology from patient 6B (H) showed abnormal lamination and dysmorphic neurons (arrow) with heterotopic neurons and microcalcification in the white matter. Balloon cells were not seen, consistent with FCD type IIa (within hemimegalencephaly).

Family 1 comprises brothers with neonatal seizures secondary to right hemisphere FCD type IIa, multifocal in patient 1A and restricted to the right posterior quadrant in patient 1B. The father and paternal uncle of these brothers have each had rare nocturnal seizures without focal features on interictal electroencephalography (EEG). Review of their recent brain MRI studies performed at 3 T revealed no abnormalities. Family 2 includes female 2A with FCD type Ia at the depth of an abnormal branch of the left central sulcus. Her female first cousin 2B had a ganglioglioma in the left superior temporal gyrus. Family 3 includes a female 3A with FCD type IIb in the right anterior temporal pole. Her male cousin 3B had a left middle frontal gyrus DNET. Family 4 includes female 4A with right occipital lobe FCD type IIb. Her nephew 4B had well-controlled focal seizures with a left posterior parietal region lesion on MRI, highly suggestive of FCD that was not removed (see Fig. S1). Family 5 includes a male 5A with an area of FCD type IIb at the depth of an abnormally deep left medial frontal lobe sulcus. His sister 5B had left temporal lobe imaging consistent with both hippocampal sclerosis and FCD in the posteromedial left temporal region, with cortical thickening, blurring of the gray-white matter junction, and high signal on T2 and fluid-attenuated inversion recovery (FLAIR) images. Histopathology showed hippocampal sclerosis. It was not surprising that no histologic features of FCD were found as there was limited surgical tissue obtained from the abnormal posterior region. Family 6 includes a female 6A with a large area of FCD type IIa in the left posterior quadrant. Her brother 6B had left hemimegalencephaly, containing areas of severe dyslamination and dysmorphic neurons as seen in FCD type IIa.

Discussion

Despite its prevalence, and histopathologic similarity to the tubers in TSC, the molecular causes of FCD remain unknown, and there are no familial cases of typical FCD reported. This suggests that either FCD does not have a genetic basis, or that it does have a genetic basis but occurs sporadically, possibly due to somatic mutations in affected tissue. Evidence to support a relationship between FCD, DNET, hemimegalencephaly, and ganglioglioma has come from a number of sources. First, there are numerous reports of both FCD type I and FCD type II occurring with DNET and ganglioglioma,[9, 10] and a report of DNET, ganglioglioma, and FCD coexisting in a “composite lesion” in one patient.[11] Second, an association of FCD, hemimegalencephaly, and ganglioglioma has been suggested from molecular and genetic studies of surgical specimens. These studies show that cytomegaly, seen not only in tubers of TSC but also in hemimegalencephaly, FCD, and ganglioglioma, may reflect aberrant activation of the mTOR and β-catenin signaling cascades, known regulators of cell growth, consequently causing defective control of neuronal and glial proliferation.[12-14] As found in our series, attempts to detect germ line or somatic mutations in TSC1 and TSC2 in patients with FCD and related lesions have largely been unsuccessful,[15] suggesting that abnormalities in other genes in the mTOR cascade or related pathways of neuronal proliferation and differentiation may play a role. If we assume that some forms of FCD, DNET, hemimegalencephaly, and ganglioglioma may have a shared etiologic mechanism and timing, then it is reasonable to consider that the occurrence of these lesions in closely related family members may be more than a coincidence and reflective of a shared mechanism and genetic etiology.

If the lesions in our families are caused by genetic mutations giving rise to increased susceptibility, then the question remains as to how different family members may have different lesions, especially in families 2, 3, 4, and 6 in which the proband has FCD but their relative has a developmental tumor or hemimegalencephaly. In TSC, there is significant phenotypic pleiotropy with variation of lesions in family members with the same mutation. More so, within an individual patient with TSC, a mutation can result in both a dysplastic cortical lesion (cortical tubers) and a benign neoplastic lesion (giant cell astrocytoma). Alternatively, lesions in these families could result from “two hits,” one causing a nonpathogenic germ line mutation in a cortical development gene carried within the family, and the other causing a somatic mutation of the other allele of that gene within the FCD or other MCD. This hypothesis may explain the sparing of other family members. One may speculate that the nature of the “second hit” may explain the differences in phenotypes within families, with the second mutation either affecting different cellular precursors (i.e., glial vs. neuronal) or affecting precursors at different developmental time points (i.e., early vs. late progenitors).

Identifying the etiology of FCD and related lesions has remained elusive, despite FCD being a relatively common entity. The six families presented herein provide suggestive clinical evidence of a genetic link between FCD, ganglioglioma, hemimegalencephaly, and DNET. It must be acknowledged that FCD and related lesions may occur within the same pedigree as a chance association. Although accurate data on the prevalence of FCD are lacking, we estimate from our own experience that FCD and related lesions are the cause of epilepsy in at most 1 in 100 patients, so the occurrence in multiple families by chance alone would be quite unlikely. Families 1 and 6 in our study, each with siblings with pathologic features of FCD type IIa, are therefore the most convincing pedigrees supporting our hypothesis of a shared genetic susceptibility. Whether this susceptibility extends to other pedigrees that include a family member with FCD and others with MRI-negative epilepsy requires further study, but it is important that in such families the MRI studies of patients with MRI-negative epilepsy be closely scrutinized for subtle lesions. Exploring these relationships further will require molecular exploration of germline mutations in families of interest, in combination with the study of tissue resected at epilepsy surgery for somatic mutations.

Acknowledgments

We would like to thank the patients and their families for participating in this study, Jacinta McMahon for the preparation of pedigree data in Figure 1, and Kate Pope and Rosie Burgess for helping to obtain patient data and DNA samples. This work has been supported by the Victorian Government's Operational Infrastructure Support Program. Funding was provided by the National Health and Medical Research Council of Australia and the Murdoch Childrens Research Institute.

Disclosures or Conflicts of Interest

None of the authors have any conflicts of interest to disclose. We confirm that we have read the Journal's position in issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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