A Developmental and Genetic Classification for Malformations of Cortical Development

Authors and Disclosures

A. James Barkovich,¹ Renzo Guerrini,^2,3 Ruben I. Kuzniecky,⁴ Graeme D. Jackson^5,6 and William B. Dobyns^7,8

1 Departments of Radiology and Biomedical Imaging, Neurology, Paediatrics and Neurosurgery, The University of California at San Francisco and the Benioff Children's Hospital at UCSF, San Francisco, CA 94143-0628, USA
2 Child Neurology Unit, A. Meyer Children's Hospital, University of Florence, Florence 50100, Italy
3 IRCCS Stella Maris, Pisa 56108, Italy
4 Department of Neurology and NYU Comprehensive Epilepsy Center, New York University, New York, NY 10016, USA
5 Florey Neuroscience Institutes, Austin Hospital, Heidelberg, 3084 Victoria, Australia
6 Department of Medicine, University of Melbourne, Melbourne Brain Centre, Heidelberg, 3084 Victoria, Australia
7 Departments of Paediatrics and Neurology, University of Washington, Seattle, WA 98195, USA
8 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA

Correspondence to
A. James Barkovich, MD, Neuroradiology, Room L371, University of California at San Francisco, 505 Parnassus Avenue, San Francisco, CA 94913-0628, USA E-mail: james.barkovich@ucsf.edu

Appendix 1 Full Classification Scheme

(I) MALFORMATIONS SECONDARY TO ABNORMAL NEURONAL AND GLIAL PROLIFERATION OR APOPTOSIS

(A) SEVERE CONGENITAL MICROCEPHALY (MIC), pre-migrational reduced proliferation or excess apoptosis

1. MIC with severe IUGR deficiency and short stature Clinically defined with AR inheritance

   1. Seckel syndrome with unknown cause (Shanske et al., 1997)

   2. MOPD syndromes with unknown cause

   3. Other MIC-IUGR syndromes

   4. Seckel syndrome with mutations in ATR at 3q22–q24 (O'Driscoll et al., 2003)

   5. MOPD type 2 with mutations in PCNT at 21q22.3 (Rauch et al., 2008)

   6. MOPD type 1 with mutations in ORC1 at 1p32 (Bicknell et al., 2011)

   7. MOPD type 1 with mutations in ORC4 at 2q22-q23 (Guernsey et al., 2011)

   8. MOPD type 1 with mutations in ORC6 at 16q12 (Bernal and Venkitaraman, 2011)

   9. MOPD type 1 with mutations in CDT1 at 16q24.3 (Bicknell et al., 2011b)

   10. MOPD type 1 with mutations in CDC6 at 17q21.2 (Bicknell et al., 2011a)

2. MIC with variable short stature (severe IUGR to mildly short), moderate to severe DD/ID, normal to thin cortex, SIMP, with/without callosal hypogenesis
   Genetically defined with AR inheritance

   1. Seckel syndrome or AR primary microcephaly (MCPH) with mutations in CENPJ at 13q12.12 (Al-Dosari et al., 2010)

   2. Seckel syndrome or MCPH with mutations in CEP152 at 15q21.1 (Kalay et al., 2011)

3. MIC with mildly short stature or normal growth, mild-moderate DD/ID, normal to thin cortex, with/without SIMP, with/without callosal hypogenesis and with/without focal PNH
   Clinically defined with AR inheritance

   1. AR primary microcephaly (MCPH) (Woods et al., 2005)
      Genetically defined with AR inheritance

   2. MCPH with mutations in ASPM at 1q31.3 (Bond et al., 2003; Shen et al., 2005; Desir et al., 2008)

   3. MCPH with mutations in MCPH1 at 8p23.1 (Trimborn et al., 2004; Darvish et al., 2010)

   4. MCPH with mutations in CDKRAP5 (Bond et al., 2005; W.B.D., in preparation)

   5. MCPH with mutations in STIL at 1p33 (Kumar et al., 2009)

4. MIC with mildly short stature or normal growth, severe DD/ID, variable cortical development with SIMP or cortical dysgenesis and with/without ACC (includes genes with spectrum from SIMP to dysgenetic cortex or PMG)
   Clinically defined with AR or XL inheritance

   1. MIC with diffuse PMG

   2. MIC with asymmetric PMG

   3. MIC with atypical cortical dysgenesis
      Genetically defined with AR inheritance

   4. MCPH with mutations in PNKP at 19q13.33 (Shen et al., 2010)

   5. MCPH, MIC with diffuse PMG (MDP) or MIC with asymmetric PMG (MAP) with mutations in WDR62 at 19q13.12 (Bilgüvar et al., 2010; Yu et al., 2010)

   6. MCPH, MDP (other cortical malformation) with mutations in NDE1 at 16p13.11 (Alkuraya et al., 2011; Bakircioglu et al., 2011)

   7. MDP–MAP and ACC with mutations of TBR2 (EOMES) at 3p24.1 (Baala et al., 2007)

5. MIC with variable anomalies and less well characterized syndromes; with/without SIMP; with/without PNH, with/without CBLH
   Clinically defined with probable AR inheritance

   1. MIC with diffuse periventricular nodular heterotopia

   2. MIC with disproportionate cerebellar hypoplasia

   3. MIC (extreme) with jejunal atresia (Stromme et al., 1993)
      Genetically defined with AR inheritance

   4. MIC–PNH associated with mutations in ARFGEF2 at 20q13.13 (Sheen et al., 2004; de Wit et al., 2009)

6. MIC with severe DD/ID and evidence of degeneration, with/without mildly short stature, with/without enlarged extraaxial spaces, with/without ACC, with/without atypical cortical dysgenesis
   Clinically defined with AR inheritance

   1. MIC with enlarged extra-axial space

   2. MIC with enlarged extra-axial spaces and disproportionate cerebellar hypoplasia

   3. MIC due to foetal brain disruption with unknown cause
      Genetically defined with AR inheritance

   4. Amish lethal microcephaly associated with mutations in SLC25A19 at 17q25.1 (Rosenberg et al., 2002)

   5. MIC-capillary malformation syndrome (mutations in pending report)

7. MIC with LIS (MLIS)—cortex thick or relatively thick, smooth white–grey border
   Clinically defined with AR inheritance

   1. Barth MLIS syndrome

   2. Norman–Roberts MLIS syndrome

   3. MOPD1 variant with three-layer lissencephaly (Juric-Sekhar et al., 2011)

   4. MIC with lissencephaly, CBLH and Hirschsprung disease

8. MIC with tissue loss and enlarged ventricles (hydrocephalus ex vacuo or hydranencephaly), with/without cortical dysplasia and with/without ACC Clinically defined with presumed extrinsic (non-genetic) cause

   1. Foetal brain disruption sequence (Corona-Rivera et al., 2001)

   2. Clinically defined with AR inheritance

   3. Familial foetal brain disruption-like syndrome with unknown cause

   4. Familial 'microhydranencephaly' with unknown cause (Behunova et al., 2010)
      Genetically defined with AR inheritance

   5. Familial 'microhydranencephaly' associated with mutations of MHAC at 16p13.13–p12.2 (Kavaslar et al., 2000)

(B) MEGALENCEPHALY (MEG) including both congenital and early postnatal

1. MEG with normal cortex (or presumably normal cortex)
   Clinically defined with polygenic or AD inheritance

   1. Familial MEG
      Genetically defined with AD inheritance

   2. Bannayan–Riley–Ruvalcaba syndrome, Cowden disease and MEG–autism with mutations in PTEN at 10q23.31 (Marsh et al., 1997; Marsh et al., 1999; Pilarski et al., 2011)

   3. Sotos syndrome with mutations in NSD1 at 5q35.2–q35.3 (Türkmen et al., 2003)

   4. DD/ID, autism with HEPACAM mutations at 11q24.2 (AD, homozygous mutations cause AR megalencephaly with leukoencephalopathy and cysts) (López-Hernández et al., 2011)

   5. MEG, thumb anomalies and Weaver-like dysmorphism with dup 2p24.3 (includes MYCN)
      Genetically defined with AR inheritance

   6. MACS syndrome with mutations in RIN2 at 20p11.23 (Basel-Vanagaite et al., 2009)
      Genetically defined with XL inheritance

   7. Simpson–Golabi–Behmel syndrome 1 with mutations in GPC3 at Xq26.2 (Pilia et al., 1996)

   8. Simpson–Golabi–Behmel syndrome 2 with mutations in OFD1 at Xp22.2 (Budny et al., 2006)

   9. MEG with DD/ID and seizures with mutations in RAB39B at Xq28 (Giannandrea et al., 2010)
      Genetically defined with somatic mosaicism

   10. Proteus syndrome caused by somatic activating mutation in AKT1 at 14q32.33 (Lindhurst et al., 2011)

2. MEG with PNH—plus other anomalies
   Clinically defined with AD or unknown inheritance

   1. MEG–PNH phenotype (Jan, 1999)

3. MEG with PMG and other cortical dysgenesis Clinically defined with unknown cause

   1. MCAP syndrome, includes MPPH (Mirzaa et al., 2004; Conway et al., 2007)

   2. Thanatophoric dysplasia or Apert syndrome with mutation of FGFR3 at 4p16.3 (six-layered PMG-like cortex) (Hevner, 2005)

(C) CORTICAL DYSGENESIS WITH ABNORMAL CELL PROLIFERATION BUT WITHOUT NEOPLASIA

1. Diffuse cortical dysgenesis
   Genetically defined with AR inheritance

   1. PMSE syndrome with MEG, cortical dysgenesis including leptomeningeal glioneuronal heterotopia and cortical dyslamination with mutations in STRADA (LYK5) (Puffenberger et al., 2007)

2. Focal and multifocal cortical and subcortical dysgenesis
   Clinically defined with putative postzygotic mosaicism

   1. HMEG isolated (Flores-Sarnat, 2002; Salamon et al., 2006; Mathern et al., 2007)

   2. HMEG with neurocutaneous syndromes (Flores-Sarnat, 2002)

   3. FCD Type II with large, dysmorphic neurons (FCDIIa) (Blümcke et al., 2011)

   4. FCD Type II with large, dysmorphic neurons and balloon cells (FCDIIb), including transmantle dysplasia and bottom of sulcus dysplasia (Blümcke et al., 2011)
      Genetically defined with AD inheritance

   5. Tuberous sclerosis with cortical hamartomas and mutations of TSC1 at 9q34.13 (Jones et al., 1999; Crino et al., 2006)

   6. Tuberous sclerosis with cortical hamartomas and mutations of TSC2 at 16p13.3 (Jones et al., 1999; Crino et al., 2006)

   7. Tuberous sclerosis with HMEG (Galluzzi et al., 2002)

(D) CORTICAL DYSPLASIAS WITH ABNORMAL CELL PROLIFERATION AND NEOPLASIA

1. Neoplastic dysgenesis with primitive cells

   1. DNET

2. Neoplastic dysgenesis with mature cells

   1. Ganglioglioma

   2. Gangliocytoma

(II) MALFORMATIONS DUE TO ABNORMAL NEURONAL MIGRATION

(A) MALFORMATIONS WITH NEUROEPENDYMAL ABNORMALITIES: PERIVENTRICULAR HETEROTOPIA

1. Anterior predominate and diffuse PNH Clinically defined with unknown cause

   1. Diffuse PNH with/without sparing of temporal horns

   2. Diffuse PNH composed of micronodules

   3. Diffuse PNH with frontonasal dysplasia (Guerrini and Dobyns, 1998)

   4. Anterior predominant PNH

   5. Anterior predominant PNH with fronto-perisylvian PMG (Wieck et al., 2005)

   6. Unilateral or bilateral isolated PNH Genetically defined with AD inheritance (new mutations)

   7. Anterior PNH with duplication 5p15.1 (Sheen et al., 2003)

   8. Anterior or diffuse PNH with duplication 5p15.33 (Sheen et al., 2003)

   9. Diffuse (but variable) PNH with del 6q27 (W.B.D, in preparation)

   10. PNH and Williams syndrome with del 7q11.23, including HIP1 and YWHAG (Ferland et al., 2006; Ramocki et al., 2010)

   11. PNH with del 4p15 (gene not identified) (Gawlik-Kuklinska et al., 2008)

   12. PNH with deletion 5q14.3–q15 (Cardoso et al., 2009)

   13. PNH and agenesis of the corpus callosum with del 1p36.22-pter (Neal et al., 2006)
       Genetically defined with XL inheritance

   14. Bilateral PNH due to mutations of FLNA, with/without Ehlers–Danlos (Sheen et al., 2001; Parrini et al., 2006)

   15. PNH and Fragile X syndrome (Moro et al., 2006)

2. Posterior predominant (temporal-trigonal) PNH
   Clinically defined with unknown cause

   1. Posterior PNH only

   2. Posterior PNH with hippocampal dysgenesis, colpocephaly, anomalies of midbrain tectum or cerebellar hypoplasia

   3. Posterior PNH with posterior PMG (Wieck et al., 2005)

3. Periventricular heterotopia, not nodular (unilateral or bilateral)
   Clinically defined with unknown cause

   1. Diffuse PLH

   2. Frontal predominant PLH

   3. Posterior predominant PLH

4. Ribbon-like heterotopia, bilateral undulating heterotopic band Clinically defined with unknown cause

   1. Posterior predominant ribbon-like heterotopia

   2. Diffuse ribbon-like heterotopia

(B) MALFORMATIONS DUE TO GENERALIZED ABNORMAL TRANSMANTLE MIGRATION (radial and non-radial)

1. Anterior predominant or diffuse classic (four-layered) LIS and SBH
   Clinically defined with unknown cause

   1. Anterior predominant LIS with abrupt transition and cerebellar hypoplasia (previously LCHe)

   2. Anterior predominant or diffuse LIS (ILS)

   3. Clinically defined with AR inheritance

   4. Anterior predominant LIS (ILS) with AR inheritance

   5. Winter–Tsukahara syndrome (Levin et al., 1993)
      Clinically defined with AD (new mutation) inheritance

   6. Baraitser–Winter syndrome with anterior or diffuse LIS–SBH (Rossi et al., 2003)

   7. Anterior predominant LIS (ILS) or SBH with DCX mutation at Xq22.3–q23 (Dobyns et al., 1999)

2. Posterior predominant or diffuse classic (four-layered) and two-layered (without cell-sparse zone) LIS and SBH
   Clinically defined with unknown cause

   1. Posterior predominant or diffuse LIS with brainstem and cerebellar hypoplasia, with/without ACC (includes former LCHa, LCHc, LCHd, LCHf (Ross et al., 2001))

   2. Posterior predominant or diffuse LIS (ILS) (Pilz et al., 1998, Dobyns et al., 1999)

   3. Diffuse LIS with hair and nail anomalies (Celentano et al., 2006)

   4. Perisylvian (central) pachygyria (ILS)

   5. Ribbon like deep white matter heterotopia with/without ACC, thin overlying cortex
      Clinically defined with AD inheritance

   6. Posterior predominant SBH (Deconinck et al., 2003)
      Genetically defined with AD inheritance (new mutation)

   7. Posterior or diffuse LIS with cerebellar hypoplasia or LIS (ILS) with TUBA1A mutations at 12q12-q14 (Poirier et al., 2007; Kumar et al., 2010)

   8. Miller-Dieker syndrome (four-layered) with deletion 17p13.3 (YWHAE to LIS1) (Dobyns et al., 1991)

   9. Posterior or diffuse LIS (ILS, four-layered) or posterior SBH with LIS1 deletions or mutations at 17p13.3 (Dobyns et al., 1993; Pilz et al., 1999)

3. X-linked lissencephaly (three-layered, without cell-sparse zone) with callosal agenesis, ambiguous genitalia (XLAG) Clinically defined with unknown cause

   1. XLAG-like syndrome with temporal-posterior predominant LIS, ACC, microphthalmia and midline cleft lip and palate

   2. XLAG with temporal-posterior predominant LIS and ACC with mutations in ARX at Xp22.13 (Bonneau et al., 2002)

4. Reelin-type LIS (inverted cortical lamination, without cell-sparse zone)
   Clinically defined with AR inheritance

   1. Frontal predominant mild LIS with severe hippocampal and CBLH (Kato et al., 1999)
      Genetically defined with AR inheritance

   2. Frontal predominant mild LIS with severe hippocampal and CBLH with RELN mutation at 7q22 (Hong et al., 2000)

   3. Frontal predominant mild LIS with severe hippocampal and CBLH with VLDLR mutation at 9p24 (Boycott et al., 2005)

   4. Variant LIS (other rare types exist but are poorly characterized)

(C) MALFORMATIONS PRESUMABLY DUE TO LOCALIZED ABNORMAL LATE RADIAL OR TANGENTIAL TRANSMANTLE MIGRATION

1. Subcortical heterotopia (other than band heterotopia or cortical infolding), all clinically defined with unknown cause

   1. Curvilinear transmantle heterotopia, with thinning of overlying cortex, decreased volume of affected hemisphere, with/without ACC, with/without basal ganglia anomalies (Barkovich, 1996)

   2. Multinodular subcortical heterotopia with thin overlying cortex, with/without PMG (Barkovich, 2000)

   3. Transmantle columnar heterotopia with/without PNH

2. Sublobar Dysplasia, clinically defined with unknown cause (Tuxhorn et al., 2009)

(D) MALFORMATIONS DUE TO ABNORMAL TERMINAL MIGRATION AND DEFECTS IN PIAL LIMITING MEMBRANE

1. Dystroglycan–laminin complex abnormalities with cobblestone malformation complex (COB), with or without congenital muscular dystrophy Clinically defined with AR inheritance but causative gene unknown

   1. Walker–Warburg syndrome (Dobyns et al., 1985, 1997)

   2. Muscle–eye–brain syndrome (Santavuori et al., 1989; Haltia et al., 1997)

   3. Congenital muscular dystrophy with CBLH (Italian MEB)

   4. Genetically defined with frontal predominant COB and AR inheritance

   5. WWS or MEB with POMT1 mutation at 9q34.1 (Beltran-Valero de Bernabe et al., 2002; van Reeuwijk et al., 2006)

   6. WWS or MEB with POMT2 mutation at 14q24.3 (van Reeuwijk et al., 2005; Mercuri et al., 2006)

   7. MEB with POMGnT1 mutation at 1p34–p33 (Manya et al., 2003)

   8. WWS, FCMD or FCMD with retinal abnormality (MEB-like) with FKTN mutation at 9q31 (Beltran-Valero de Bernabe et al., 2003, Manzini et al., 2008, Yoshioka, 2009, Yis et al., 2011)

   9. WWS or MEB with FKRP mutation at 19q13.3 (Beltran-Valero de Bernabe et al., 2004)

   10. WWS or MEB with LARGE mutation at 22q12.3-q13.1 (van Reeuwijk et al., 2007) Genetically defined with posterior predominate COB and AR inheritance

   11. Posterior predominant COB and CMD with LAMA1A mutation at 18p11.31

   12. Posterior predominant COB with LAMC3 mutation at 9q33–q34 (lacks CMD) (Barak et al., 2011)

2. Cobblestone malformations in CDG
   Genetically defined with AR inheritance

   1. CHIME-like syndrome with frontal predominant COB with SRD5A3 mutation at 4q12 (Al-Gazali et al., 2008; Cantagrel et al., 2010)

   2. Debré-type cutis laxa with frontal predominant COB and ATP6V0A2 mutation at 12q24.3 (Kornak et al., 2008; Van Maldergem et al., 2008)

3. Cobblestone malformation with no known glycosylation defect

   1. Frontal predominant COB with GPR56 mutations at 16q13 ('bilateral frontoparietal polymicrogyria') (Piao et al., 2002, 2005)

   2. Walker-Warburg syndrome secondary to COL4A1 mutations at 13q34 (Labelle-Dumais et al., 2011)

4. Other syndromes with cortical dysgenesis and marginal glioneuronal heterotopia, but with normal cell types Clinically defined with extrinsic or unknown cause

   1. Foetal alcohol syndrome
      Clinically defined with AR inheritance

   2. Galloway–Mowat syndrome

(III) MALFORMATIONS DUE TO ABNORMAL POSTMIGRATIONAL DEVELOPMENT

(A) MALFORMATIONS WITH PMG OR CORTICAL MALFORMATIONS RESEMBLING PMG

1. PMG (classic) with transmantle clefts (schizencephaly) or calcification
   Clinically defined with clefts suggesting vascular pathogenesis or unknown cause

   1. Schizencephaly (Barkovich and Kjos, 1992)

   2. Septo-optic dysplasia with schizencephaly (Barkovich et al., 1989)
      Clinically defined with prenatal viral exposure (especially CMV)

   3. chizencephaly with positive neonatal CMV testing (Iannetti et al., 1998)

   4. Diffuse or patchy PMG with periventricular calcifications and positive neonatal CMV testing

   5. Diffuse, patchy or perisylvian PMG with hearing loss and positive neonatal CMV testing
      Clinically defined with AR inheritance

   6. Familial schizencephaly with single unilateral or bilateral clefts (Haverkamp et al., 1995

   7. Familial schizencephaly with multiple bilateral clefts

   8. Band-like calcifications with PMG (pseudo-TORCH) (Briggs et al., 2008)
      Genetically defined with AR inheritance

   9. Band-like calcifications with PMG (pseudo-TORCH) with mutations of OCLN1 at 5q13.2 (O'Driscoll et al., 2010)

2. Polymicrogyria without clefts or calcifications classified by location
   Clinically defined bilateral PMG without clefts of unknown cause

   1. Generalized PMG (Chang et al., 2004)

   2. Frontal PMG (Guerrini et al., 2000)

   3. Perisylvian PMG (Kuzniecky et al., 1993)

   4. Posterior PMG (lateral parieto-occipital) (Barkovich et al., 1999)

   5. Parasagittal PMG

   6. Parasagittal mesial occipital PMG (Guerrini et al., 1997)
      Clinically defined unilateral PMG without clefts of unknown cause

   7. Hemispheric PMG (Chang et al., 2006)

   8. Perisylvian PMG (Chang et al., 2006)

   9. Focal PMG (Barkovich, 2010a)

3. Syndromes with PMG (neuropathology may differ from classic PMG)
   Clinically defined syndromes with AD inheritance

   1. Adams–Oliver syndrome AD form (Snape et al., 2009)
      Clinically defined syndromes with AR inheritance

   2. Adams–Oliver syndrome AR form (Snape et al., 2009)

   3. Joubert syndrome and related disorders with PMG, includes Meckel–Gruber, Arima (cerebro-oculo-renal) and Joubert syndromes with causative genes unknown (Gleeson et al., 2004)
      Clinically defined syndromes with XL inheritance (probable)

   4. Aicardi syndrome (Aicardi, 2005)

   5. Oculocerebrocutaneous (Delleman) syndrome (Moog et al., 2005)
      Genetically defined with AD inheritance (new mutations)

   6. Fronto-parietal PMG, variable ACC and delayed myelination of anterior limb internal capsule with TUBB2B mutations at 6p25.2 (Jaglin et al., 2009)

   7. Fronto-parietal PMG, variable with TUBB3 mutations at 16q24.3 (Poirier et al., 2010)

   8. Knobloch syndrome with high myopia, vitreoretinal degeneration, retinal detachment, occipital cephalocele and variable PMG with COL18A1 mutations at 21q22.3 (Sertiéet al., 2000)

   9. Aniridia, variable temporal PMG, absent anterior commissure and pineal gland, and variable CBLH with PAX6 mutations at 11p13 (Mitchell et al., 2003; Graziano et al., 2007)

   10. Perisylvian PMG with deletion 1p36.3 (gene not identified) (Dobyns et al., 2008)

   11. Perisylvian PMG with deletion 22q11.2 (gene not identified) (Cramer et al., 1996)
       Genetically defined with AR inheritance

   12. Goldberg–Shprintzen (megacolon) syndrome with mutations of KIAA1279 at 10q22.1 (Brooks et al., 2005)

   13. Joubert syndrome with variable (low penetrance) PMG and AHI1 mutations at 6q23.3 (Dixon-Salazar et al., 2004; Valente et al., 2006)

   14. Meckel–Gruber syndrome with variable (low penetrance) PMG and TMEM216 mutations at 11q12.2 (Valente et al., 2010)

   15. Generalized (versus perisylvian) PMG, ACC and optic nerve hypoplasia with TUBA8 mutations at 22q11.21 (Abdollahi et al., 2009)

   16. Perisylvian PMG, ACC, delayed myelination of anterior limb internal capsule and cerebellar vermian hypoplasia with mutation of TBR2 (EOMES) at 3p24.1 (Baala et al., 2007)

   17. Warburg Micro syndrome with mutations of RAB3GAP1 at 2q21.3 (Morris-Rosendahl et al., 2010)

   18. Warburg Micro syndrome with mutations of RAB3GAP2 at 1q41 (Borck et al., 2011)

   19. Warburg Micro syndrome with mutations of RAB18 at 10p12.1 (Bem et al., 2011)
       Genetically defined with XL inheritance

   20. Perisylvian PMG, rolandic seizures and speech-language dyspraxia with SRPX2 at Xq22.1 mutations (Roll et al., 2006, 2010)

   21. Perisylvian PMG, mild MIC and thin body habitus with NSDHL mutation at Xq28 (McLarren et al., 2010)

   22. Perisylvian PMG with Xq27 locus (gene not identified) (Santos et al., 2008)

   23. Perisylvian PMG with Xq28 locus (gene not identified) (Villard et al., 2002)

(B) CORTICAL DYSGENESIS SECONDARY TO INBORN ERRORS OF METABOLISM (neuropathology differs from classic PMG) Genetically and biochemically defined with AR inheritance

1. Mitochondrial and pyruvate metabolic disorders

   1. Non-ketotic hyperglycinaemia with mutations of GLDC at 9p24.1, GCSH at 16q23.2 or AMT at 3p21.31

   2. Multiple Acyl-CoA dehydrogenase deficiency (Glutaric aciduria type II) with mutations of ETFA at 15q24.2-q24.3, ETFB at 19q13.41 or ETFDH at 4q32.1 (Govaert et al., 2004)

2. Peroxisomal disorders

   1. Zellweger syndrome with mutation of many genes involved in peroxisomal biogenesis (Volpe and Adams, 1972; Steinberg et al., 2006)

   2. Neonatal adrenoleukodystrophy with mutation of many genes involved in peroxisomal biogenesis (Kamei et al., 1993)

   3. D-Bifunctional protein deficiency with HSD17B4 mutation at 5q2 (Grønborg et al., 2010)

(C) FOCAL CORTICAL DYSPLASIAS (WITHOUT DYSMORPHIC NEURONS) DUE TO LATE DEVELOPMENTAL DISTURBANCES
Clinically/histologically defined and sporadic

1. Minor malformations of Cortical Development (mMCD)

2. Type I FCD

   1. Abnormal radial cortical lamination (Blümcke et al., 2011)

   2. Abnormal tangential cortical lamination (Blümcke et al., 2011)

   3. Abnormal radial and tangential lamination (Blümcke et al., 2011)

3. Type III FCD

4. Associated with hippocampal sclerosis (Blümcke et al., 2011)

5. Associated with tumors (Blümcke et al., 2011)

6. Associated with vascular malformations (Blümcke et al., 2011)

7. Associated with other principal lesions during early life (Blümcke et al., 2011)

(D) POSTMIGRATIONAL DEVELOPMENTAL MICROCEPHALY (PREVIOUSLY POSTNATAL MIC) WITH BIRTH OFC –3 SD OR LARGER, LATER OFC BELOW –4 SD AND NO EVIDENCE OF BRAIN INJURY

1. Postmigrational MIC with limited functional deficits
   Clinically defined

   1. Postmigrational MIC with no cause or syndrome identified
      Genetically defined with AD inheritance (sporadic new mutations)

   2. MIC and mild ID with SHH mutation (Ginocchio et al

   3. MIC and variable ACC with deletion 1q43q44 (includes AKT3) (Hill et al., 2007)

2. Postmigrational MIC with broad functional deficits consistent with a 'developmental encephalopathy' (Angelman-like, Rettlike class of disorders)
   Clinically defined with AR inheritance

   1. PEHO syndrome (Salonen et al., 1991; Vanhatalo et al., 2002)
      Genetically defined with AD inheritance (sporadic new mutations)

   2. Pitt–Hopkins syndrome with mutations of TCF4 at 18q21.1 (Zweier et al., 2007)

   3. FOXG1 syndrome with deletions or mutations of FOXG1 at 14q13 (Kortüm et al., 2011)

   4. Duplication of FOXG1 at 14q13 (Brunetti-Pierri et al., 2011)
      Genetically defined with AD inheritance (or pathogenic de novo copy number variant) and imprinting effects

   5. Maternal duplication 15q11.2 (Kitsiou-Tzeli et al., 2010)

   6. Angelman syndrome with maternally deletion 15q11.2 or mutation of UBE3A at 15q11.2 (Matsuura et al., 1997)
      Genetically defined with AR inheritance

   7. Pitt–Hopkins like syndrome with mutations of NRXN1 at 2p16.3 (Zweier et al., 2009)

   8. Pitt–Hopkins-like syndrome with mutations of CNTNAP2 at 7q35-q36 (Zweier et al., 2009)

   9. Pontocerebellar hypoplasia with mutations of TSEN54 at 17q25.1, TSEN2 at 3p25.1, TSEN34 at 19q13.4, RARS2 at 6q16.1 (Namavar et al., 2011)
      Genetically defined with XL inheritance

   10. Rett syndrome with mutations of MECP2 at Xq28 (Amir et al., 1999)

   11. Angelman-like syndrome with mutations of SLC9A6 at Xq26.3 (Gilfillan et al., 2008)

   12. X-linked mental retardation and autistic features with mutations of JARID1C at xp11.22–p11.21 (Jensen et al., 2005; Abidi et al., 2008)

   13. X-linked MIC with disproportionate cerebellar hypoplasia with mutations of CASK at Xp11.4 (in females) (Najm et al.,2008)

ACC = agenesis of corpus callosum; AD = autosomal dominant inheritance; AR = autosomal recessive inheritance; CBLH = cerebellar hypoplasia; CDG = congenital disorders of glycosylation; CHIME = coloboma, heart defect, ichthyosiform dermatosis, mental retardation, ear anomalies; CMD = congential muscular dystrophy; CMV = cytomegalovirus; COB = cobblestone complex; DD/ID = developmental delay/intellectual disability; DNET = dysembryoplastic neuroepithelial tumour; FCMD = Fukuyama congenital muscular dystrophy; HMEG = hemimegalencephaly; ILS = isolated lissencephaly syndrome; IUGR = intrauterine growth retardation; LCH = lissencephaly with cerebellar hypoplasia; LIS = lissencephaly; MACS = macrocephaly, alopecia, cutis laxa, scoliosis; MAP = microcephaly with asymmetric polymicrogyria; MCPH = autosomal recessive primary microcephaly; MDP = microcephaly with diffuse polymicrogyria; MEB = muscle-eye-brain syndrome; MEG = megalencephaly; MIC = microcephaly; MLIS = microcephaly with lissencephaly; MOPD = microcephalic osteodysplastic primordial dwarfism syndrome; MPPH = megalencephaly with polymicrogyria, polydactyly and hydrocephalus; PEHO = progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy; PLH = periventricular laminar heterotopia; PMG = polymicrogyria; PMSE = polyhydramnios, megalencephaly and symptomatic epilepsy; PNH = periventricular nodular heterotopia; SBH = subcortical band heterotopia; SIMP = simplified gyral pattern; WWS = Walker-Warburg syndrome; XL = X-linked inheritance; XLAG = X-linked lissencephaly with agenesis of corpus callosum and ambiguous genitalia.