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Introducing the Cerebellum Mid-Hindbrain Morphogenesis

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Introducing the Cerebellum Mid-Hindbrain Morphogenesis 1/19/2017 Introducing the cerebellum • 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: the cerebellum as a –“Canary in the coal mine” for rest of brain sentinel for developmental brain disorders 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 V H H Rostro-caudal medio-lateral 1 1/19/2017 Isthmic organizer CBL from dorsal anterior hindbrain Glutaminergic GABAergic Late development of cerebellum Late development GW37 CBL GW7.5 In mice GW9 and man 2mm 2mm GW17 2mm GW23 GW26 2mm 2mm 2mm Bayer and Altman 2004: Human CNS Development atlas 2 1/19/2017 Foxc1 is a mesenchymal TF Mesenchymal signaling in the PF +/- • Foxc1 transcription factor is expressed in overlying mesenchyme NOT cerebellum WT Foxc1 -/- ▫ directly regulates mesenchyme development (posterior fossa) Foxc1 ▫ indirectly regulates cerebellar development via Foxc1 cbl cbl transcriptional control of secreted factors SDF1α e12.5 ▫ Loss of function causes major midline rhombic SDF1α lip problem Glu 4V +/+ -/- Foxc1–/– GABAergic e14.5 RL Normal CBL CBVH – CBVH/MCM - DWM Normal mid-hindbrain structure in Mid-hindbrain malformations humans • 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 1/19/2017 Cerebellar hypoplasia (CBLH) is a common finding associated with a highly heterogeneous group of disorders. Causes include prenatal infections and Mid-hindbrain … exposure to teratogens, chromosomal anomalies, metabolic disorders, genetic syndromes, and more. • 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” Dandy-Walker malformation DWM and intellectual disability 50 • The 800-pound gorilla in the room . 45 percent • Diagnostic criteria • Data from 104 DWM – cerebellar vermis hypoplasia and upward rotation 40 patients – Cystic enlargement 4V (wide outflow tract) 35 – 6 references – Enlarged posterior fossa with elevated torcula • Common associated malformations 30 – 1981 – 1995 – Cerebellar hemisphere hypoplasia 25 – Mortality 24% – Brainstem hypoplasia autism 20 – Hydrocephalus 20-80% • Most from Neurosurgery • Phenotype 15 clinics –Ataxia 10 – Intellectual disability 40% 5 – Motor, visual problems – Epilepsy 0 IQ DWM LR09-094 LR09-094 >80 56-79 <55 4 1/19/2017 CBLH subtypes and outcome Cerebellar hypoplasia variations • In the MFM literature • Dandy-Walker malformation (DWM) – Classic DWM with tail – DWM is “bad” – Classic DWM no tail – CBVH – vermis – DW “variant” is not so bad 1978 – CBVH with mega-cisterna magna (MCM) • Where did this come from? • Posterior fossa cysts – Blake’s pouch cyst • In Lisdb database and DEV – Mega-cisterna magna only literature – Arachnoid cysts – CBLH and PCH are bad • Cerebellar hypoplasia (CBLH) – Cerebellar agenesis (CBAG) – CBVH is bad when it is real – CBLH – diffuse – CBVH – vermis – DWM is bad only half the time – CBLH unilateral-asymmetric • So DW “variant” has proven to • CBLH other specific types be a terrible name – Molar tooth malformation (Joubert) – Pontocerebellar hypoplasia (PCH) LR01-276 Cerebellar hypoplasia variations Cerebellar hypoplasia variations • Dandy-Walker malformation (DWM) • Dandy-Walker malformation (DWM) – Classic DWM with tail – Classic DWM with tail – Classic DWM no tail – Classic DWM no tail – CBVH – vermis – CBVH – vermis – CBVH with mega-cisterna magna (MCM) – CBVH with mega-cisterna magna • Posterior fossa cysts • Posterior fossa cysts – Blake’s pouch cyst – Blake’s pouch cyst – Mega-cisterna magna only – Mega-cisterna magna only – Arachnoid cysts – Arachnoid cysts • Cerebellar hypoplasia (CBLH) • Cerebellar hypoplasia (CBLH) – Cerebellar agenesis (CBAG) – Cerebellar agenesis (CBAG) – CBLH – diffuse – CBLH – diffuse – CBVH – vermis – CBLH unilateral-asymmetric – CBLH unilateral-asymmetric – CBVH – vermis • CBLH other specific types • CBLH other specific types – Molar tooth malformation (Joubert) – Molar tooth malformation (Joubert) – Pontocerebellar hypoplasia (PCH) – Pontocerebellar hypoplasia (PCH) LR02-196 LR13-199 5 1/19/2017 Cerebellar hypoplasia variations Cerebellar hypoplasia variations • Dandy-Walker malformation (DWM) • Dandy-Walker malformation (DWM) – Classic DWM with tail – Classic DWM with tail – Classic DWM no tail – Classic DWM no tail – CBVH – vermis Dup 6p25.3 including FOXC1 – CBVH with mega-cisterna magna – CBVH with mega-cisterna magna – CBVH – vermis • Posterior fossa cysts • Posterior fossa cysts – Blake’s pouch cyst – Blake’s pouch cyst – Mega-cisterna magna only – Mega-cisterna magna only – Arachnoid cysts – Arachnoid cysts • Cerebellar hypoplasia (CBLH) • Cerebellar hypoplasia (CBLH) – Cerebellar agenesis (CBAG) – Cerebellar agenesis (CBAG) – CBLH – diffuse – CBLH – diffuse – CBLH unilateral-asymmetric – CBLH unilateral-asymmetric – CBVH – vermis – CBVH – vermis • CBLH other specific types • CBLH other specific types – Molar tooth malformation (Joubert) – Molar tooth malformation (Joubert) – Pontocerebellar hypoplasia (PCH) – Pontocerebellar hypoplasia (PCH) LR06-253a1 unknownAJB Cerebellar hypoplasia variations Cerebellar hypoplasia variations • Dandy-Walker malformation (DWM) • Dandy-Walker malformation (DWM) – Classic DWM with tail – Classic DWM with tail – Classic DWM no tail – Classic DWM no tail – CBVH with mega-cisterna magna – CBVH with mega-cisterna magna – CBVH – vermis – CBVH – vermis • Posterior fossa cysts • Posterior fossa cysts – Blake’s pouch cyst – Blake’s pouch cyst – Mega-cisterna magna only – Mega-cisterna magna only – Arachnoid cysts – Arachnoid cysts • Cerebellar hypoplasia (CBLH) • Cerebellar hypoplasia (CBLH) – Cerebellar agenesis (CBAG) – Cerebellar agenesis (CBAG) – CBLH – diffuse – CBLH – diffuse – CBLH unilateral-asymmetric – CBLH unilateral-asymmetric – CBVH – vermis – CBVH – vermis • CBLH other specific types • CBLH other specific types – Molar tooth malformation (Joubert) – Molar tooth malformation (Joubert) – Pontocerebellar hypoplasia (PCH) – Pontocerebellar hypoplasia (PCH) LR13-153 LR06-201 6 1/19/2017 Cerebellar hypoplasia variations Cerebellar hypoplasia variations • Dandy-Walker malformation (DWM) • Dandy-Walker malformation (DWM) – Classic DWM with tail – Classic DWM with tail – Classic DWM no tail – Classic DWM no tail – CBVH with mega-cisterna magna – CBVH with mega-cisterna magna CASK – CBVH – vermis – CBVH – vermis • Posterior fossa cysts • Posterior fossa cysts – Blake’s pouch cyst – Blake’s pouch cyst – Mega-cisterna magna only – Mega-cisterna magna only – Arachnoid cysts – Arachnoid cysts • Cerebellar hypoplasia (CBLH) • Cerebellar hypoplasia (CBLH) – Cerebellar agenesis (CBAG) – Cerebellar agenesis (CBAG) – CBLH – diffuse – CBLH – diffuse – CBLH unilateral-asymmetric – CBLH unilateral-asymmetric – CBVH – vermis – CBVH – vermis • CBLH other specific types • CBLH other specific types – Molar tooth malformation (Joubert) – Molar tooth malformation (Joubert) – Pontocerebellar hypoplasia (PCH) – Pontocerebellar hypoplasia (PCH) LR09-114 LR03-279 Cerebellar hypoplasia variations Cerebellar hypoplasia variations • Dandy-Walker malformation (DWM) • Dandy-Walker malformation (DWM) – Classic DWM with tail – Classic DWM with tail – Classic DWM no tail – Classic DWM no tail – CBVH with mega-cisterna magna – CBVH with mega-cisterna magna – CBVH – vermis – CBVH – vermis • Posterior fossa cysts • Posterior fossa cysts – Blake’s pouch cyst – Blake’s pouch cyst DP99-044a2 LR01-303 – Mega-cisterna magna only – Mega-cisterna magna only – Arachnoid cysts – Arachnoid cysts • Cerebellar hypoplasia (CBLH) • Cerebellar hypoplasia (CBLH) – Cerebellar agenesis (CBAG) – Cerebellar agenesis (CBAG) – CBLH – diffuse – CBLH – diffuse – CBLH unilateral-asymmetric-clefts – CBLH unilateral-asymmetric – CBVH – vermis – CBVH – vermis • CBLH other specific types • CBLH other specific types – Molar tooth malformation (Joubert) – Molar tooth malformation (Joubert) – Pontocerebellar hypoplasia (PCH) – Pontocerebellar hypoplasia (PCH) LR14-232 LR01-340 7 1/19/2017 Figure 1. Patterns of cerebellar malformations in Venn diagram Cerebellar hypoplasia variations • Dandy-Walker malformation (DWM) – Classic DWM with tail – Classic DWM no tail – CBVH with mega-cisterna magna – CBVH – vermis • Posterior fossa cysts – Blake’s pouch cyst – Mega-cisterna magna only – Arachnoid cysts • Cerebellar hypoplasia (CBLH) – Cerebellar agenesis (CBAG) – CBLH – diffuse – CBLH unilateral-asymmetric – CBVH – vermis • CBAG, cerebellar agenesis (total) • SCA, spinocerebellar ataxia {degeneration) • CBLH other specific types • MIC-CBLH, severe congenital microcephaly
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