Introducing the cerebellum. Mid-hindbrain morphogenesis. Famous paper towel model - CBL 1/19/2017

Transcription

1 Introducing the cerebellum Canary in the coal mine: the cerebellum as a sentinel for developmental brain disorders Highly conserved structure and function Foliation conserved across evolution Structure is simple Only 9 principle types of neurons All morphologically distinct Layers and circuitry are stereotyped Contains more neurons than rest of brain In mouse, 59/71 million neurons (83%) In human, 69/86 billion neurons (80%) Malformations in mice and in humans Window into developmental neurogenetics Canary in the coal mine for rest of brain Mid-hindbrain morphogenesis Famous paper towel model - CBL Mouse 9 days 9.5 days 10 days 10.5 days Human 25 days 30 days 36 days 39 days V H V H H V H Rostro-caudal medio-lateral 1

2 Isthmic organizer CBL from dorsal anterior hindbrain Glutaminergic GABAergic Late development of cerebellum Late development GW37 CBL In mice GW7.5 GW9 and man 2mm GW17 2mm 2mm GW23 GW26 2mm 2mm Bayer and Altman 2004: Human CNS Development atlas 2mm 2

3 Foxc1 is a mesenchymal TF Mesenchymal signaling in the PF e12.5 +/- cbl 4V cbl Foxc1 transcription factor is expressed in overlying mesenchyme NOT cerebellum directly regulates mesenchyme development (posterior fossa) indirectly regulates cerebellar development via transcriptional control of secreted factors Loss of function causes major midline rhombic lip problem WT Foxc1 -/- Foxc1 SDF1α Glu Foxc1 SDF1α +/+ -/- Foxc1 / GABAergic e14.5 RL Normal CBL CBVH CBVH/MCM - DWM Normal mid-hindbrain structure in humans Mid-hindbrain malformations Incidence Relatively common ~1/5000 live births Outcome Most cause DEV delay ± ID ± motor abnormalities Represent tip of the iceberg for DEV disorders ID and ID syndromes, autism, early life epilepsy Causes Can occur in isolation or part of syndrome Genes identified for only a few rare forms Ciliopathies (JS/MGS), CDG, PCH, and a few others Prenatal issues Most (not all) are visible by GW20 but Difficult to distinguish by fetal ultrasound/mri 3

4 Mid-hindbrain Early patterning defects CBL agenesis Altered segmentation (GTAV) Rhombencephalosynapsis Common imaging patterns CBLHdiffuse CBVH isolated DWM-MCM-CBVH spectrum Special classes of MHM Cobblestone malformations Molar tooth malformation (JS) Pontocerebellar hypoplasia Cerebellar hypoplasia (CBLH) is a common finding associated with a highly heterogeneous group of disorders. Causes include prenatal infections and exposure to teratogens, chromosomal anomalies, metabolic disorders, genetic syndromes, and more. Dandy-Walker malformation DWM and intellectual disability The 800-pound gorilla in the room..... Diagnostic criteria cerebellar vermis hypoplasia and upward rotation Cystic enlargement 4V (wide outflow tract) Enlarged posterior fossa with elevated torcula Common associated malformations Cerebellar hemisphere hypoplasia Brainstem hypoplasia autism Hydrocephalus 20-80% Phenotype Ataxia Intellectual disability 40% Motor, visual problems Epilepsy DWM LR LR IQ percent > <55 Data from 104 DWM patients 6 references Mortality 24% Most from Neurosurgery clinics 4

5 CBLH subtypes and outcome In the MFM literature DWM is bad DW variant is not so bad Where did this come from? In Lisdb database and DEV literature CBLH and PCH are bad CBVH is bad when it is real DWM is bad only half the time So DW variant has proven to be a terrible name 1978 (MCM) LR (MCM) LR LR

6 Dup 6p25.3 including FOXC1 LR06-253a1 unknownajb LR LR

7 CASK LR LR DP99-044a2 LR clefts LR LR

8 Figure 1. Patterns of cerebellar malformations in Venn diagram LR08-085a1 CBAG, cerebellar agenesis (total) MIC-CBLH, severe congenital microcephaly with disproportionate cerebellar hypoplasia CBLH, cerebellar hypoplasia {diffuse) PCH, pontocerebellar hypoplasia ICCA, infantile cerebral and cerebellar atrophy SCA, spinocerebellar ataxia {degeneration) RES, rhombencephalosynapsis CBVH, cerebellar vermis hypoplasia MTM, molar tooth malformation (Joubert) DWM, Dandy-Walker malformation MCM, mega-cisterna magna Causes of cerebellar hypoplasia Causes of DWM and CBLH Extrinsic (non-genetic) Prenatal hemorrhage Cerebellar Posterior fossa Prenatal HIE Prenatal infections CMV Zika Teratogens Anticonvulsants (Dil, VP) Retinoic acid Alcohol, cocaine Genetic syndromes Copy number variants (CNV) Chromosome abnormalities Small CNV Genetic syndromes with CBLH Metabolic disorders Brain malformations Recognizable syndromes Epileptic encephalopathies and similar DEV disorders Complex NDEV disorders Autism, schizophrenia and psychosis, bipolar disorder MFM estimates Other CNV SEQ MFM CNV SEQ Other 8

9 Mechanisms MFM CNV SEQ Other Extrinsic causes of CBLH Prenatal hemorrhage PF and CBL Prenatal infections CMV Zika virus Teratogens Antiepileptic drugs Phenytoin, valproate Alcohol; cocaine Retinoic acid Retinoic acid exposure at 6 weeks gestation; no cardiac defects LR CBL bleeds premies Limperopoulos et al in PEDIATRICS 35 of 1242 infants <1500 g CBL bleed and DWM Prenatal 19 wkg 9

10 CBL bleed and DWM CBL bleed and DWM 26 weeks 32 weeks 5 days 1 year Prenatal 27 wkg AV canal, diffuse CBLH Prenatal 31 wkg CBLH, enlarged 4V but normal PF, hemosiderin on CBL Postnatal 5 days CBLH, enlarged 4V but normal PF, hemosiderin on CBL Postnatal 1 year CBLH DWM, enlarged 4V and enlarged PF, no hemosiderin 26 weeks 5 days 1 year Mechanisms MFM CNV SEQ Other Copy number variants (CMV) N DX CYTO Copy Genome position hg19 Genes ~10 DWM 3q24 1 chr3: ZIC1, ZIC4 ~20 DWM 6p chr6: FOXC1, FOXF2 ~02 DWM 7p chr7:10,818,761-11,268,476 ~02 DWM 7p chr7:10,358,477-11,060,11 ~01 DWM 8p21.2p chr8: FGF17 (?) ~15 DWM 9p24.2p chr9: ~17 DWM 13q32.2q chr13: ZIC2 (?) ~07 CBVH 17p chr17: HIC1 (?) N DWM Trisomy13 3 N DWM Trisomy18 3 N DWM Trisomy

11 DWM and FOXC1 CNV are rare CNV are rare in CBLH-DWM Compare Agenesis corpus callosum CBLH N=220 Polymicrogyria 11

12 Mechanisms CBVH and OPHN1 MFM CNV SEQ Other OPHN1 /Y LR02-469a1 OPHN1 /Y LR02-469a2 OPHN1 /Y LR02-469a3 OPHN1 /Y LR02-469a4 CBLH and CASK CBLH and CASK CASK +/ or CASK /Y LR LR LR LR LR LR NORMAL LR LP LR LR LP

13 WES in 71 families with CBLH CBLH all types including DWM N=13/71 (18%) solved probable N=21/71 (30%) solved probable or possible CBLH excluding DWM N=10/42 (24%) solved probable N=16/42 (38%) solved probable or possible WES in 71 families with CBLH DEV disorder known genes BCL11A (x2), DDX3X (x2) AHDC1, AUTS2, CASK, FOXP1, SETD2, STXBP1 DEV disorder brain malformation genes FGFR1, TUBA1A DWM classic N=3/29 (10%) solved probable N=5/29 (17%) solved probable or possible p= DEV disorder candidate genes ADCY1, BRAF, BRAT1, KCTD1, KLHL17, TRIO, WDR37 CBLH and AUTS2 CBLH and AUTS2 LR

14 DWM and SETD2 LR CBLH with AD or XL inheritance Developmental encephalopathies AHDC1, AUTS2, BCL11A, FOXP1, PITX2, SETD2 Developmental epilepsies KPNA7, STXBP1 Cerebellar hypoplasia (relatively pure) FGFR1, FOXC1-6p25.3, ZIC1-ZIC4, NID1, LAMC1 Malformations of cortical development TUBA1A, TUBB2B, TUBB, TUBB3, DYNC1H1 CBLH with X-linked inheritance AP1S2, CASK, DDX3X, OFD1, OPHN CBLH with AR inheritance Transcription factors PTF1A, WNT1 Ciliopathies and MTM AHI1, CEP290, RPGRIP1L and ~30 others Dystroglycanopathies and lamininopathies POMT1, POMT2, POMGnT1, ~15 others, LAMA2, LAMB1 Pontocerebellar hypoplasia (trna splicing) TSEN54, AMPD2, CHMP1A, RARS2, TSEN2, TSEN34, EXOSC3, VRK1 Congenital disorders of glycosylation B3GALTL, B4GALT1, PMM2 and others CBLH and WNT1 14

15 Mechanisms MFM CNV SEQ Other DWM in BWS Is DWM due to an imprinting defect? DWM in BWS Patient Mutation Bui 2009LOM at IC2 Patient_1 Patient_2 Patient_3 Patient_4 Patient_5 Patient_6 Patient_7 LR LR LOM at IC2 LOM at IC2 LOM at IC2 CDKN1C p.gly261fsx CDKN1C p.gln58x LOM at IC2, del 11p15.4 LOM at IC2 CDKN1C p.ala211glyfsx26 DWM in BWS (11p15.4 imprint) BWS and DWM Loss of methylation IC2 6 Mutations CDKN1C 3 Unknown 1 Gardiner pt1 Gardiner pt2 LR

16 DWM in MZ twin DWM in MZ twins MZ twins Complicated monochorionic twin pregnancies DWM in 10/660 (1.5%) But NONE had confirmed DWM! LR LR Growth abnormalities are common Non-DWM twins 217/650 (33.4%) p = 0.03 significant DWM twins 7/10 (70%) Either DONOR twin or just IUGR Twin-twin transfusion syndrome (TTTS) N=4 Intrauterine growth retardation (IUGR) N=5 LR H and H from MN DWM Summary from Kontopoulos et al Incidence of DWM in complicated monochorionic twins is 200 times expected for singletons DWM more likely in smallertwin Mechanism could be related to either TTTS oriugr 16