Genetics and Neurobiology of Down Syndrome

500 Pages·2022·9.933 MB·English

by  Bani Bandana Ganguly

GENETICS AND NEUROBIOLOGY
OF DOWN SYNDROME
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GENETICS AND
NEUROBIOLOGY
OF DOWN
SYNDROME
B B G
ANI ANDANA ANGULY
MGMNewBombayHospital,Vashi,NaviMumbai,India
MGMInstituteofHealthSciences,Kamothe,NaviMumbai,India
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Contents
An overview of this book ix 5. Prevention of Down syndrome: genetic
Preface xxiii counseling, prenatal screening, testing,
awareness, attitude, and socio-cultural and
1. Down syndrome: history and overview public health aspects
1. History 1 1. Introduction 71
2. Incidence 4 2. Geneticcounseling 72
3. Sexratio 7 3. Preconceptionscreeningandprenatal
4. Recurrence 7 diagnosis 76
5. WhatothernamesdopeopleuseforDown 4. Theattitudeandawarenessoftheparents 79
syndrome? 8 5. Ethicalaspects 83
6. CanDownsyndromebeinherited? 8 6. Policiesandguidelines 84
7. Seculartrendsandracialandethnicvariation 10 7. PublichealthpointofviewtowardDown
References 11 syndrome 85
8. Socio-culturalaspectsofDownsyndrome 88
2. Implications of trisomy 21 on congenital References 90
features and health aspects
6. Gene-dosage imbalance due to trisomic
1. Introduction 13
2. Phenotypicfeaturesandsystemiccomplicationsof HSA21andgenotypeephenotypeassociationin
Downsyndrome 17 Down syndrome
3. Life-spanofindividualswithDownsyndrome 30 1. Introduction 93
4. AttentiontobepaidforhealthmonitoringofDown 2. Gene-dosageimbalance 96
syndrome 31 3. Genotypeephenotypecorrelation 100
5. FertilityofDownsyndrome 35 4. Transcriptomesoftrisomy21 112
References 36 5. Proteomesoftrisomy21 113
References 128
3. Chromosomal etiology of Down syndrome:
genesis of trisomy 21
7. Development of specific phenotypes and
1. Introduction 41
genetic consequences in Down syndrome:
2. Chromosome21 42
malformations in craniofacial and cardiac
3. GenesofHSA21 51
References 55 anatomy and development of leukemia and
cognitive and learning deficits
4. Possiblefactorscontributingtochromosomal
1. Introduction 135
nondisjunction and formation of trisomic
2. Genesofdevelopmentalstages 136
HSA21 3. Trisomicsegmentsinmousemodels:genotypingofDS
1. Introduction 59 phenotypes 138
2. Factorsthatcancausenondisjunctionof 4. CraniofacialalterationsinDown
chromosomes 60 syndrome 140
References 66 5. CardiacdefectsinDownsyndrome 148
v
vi
Contents
6. Cognitivedevelopmentandlearningandmemory 11. Imbalance in glutamatergic and
deficits 157 GABAergic transmission in Down syndrome
7. GeneticsofleukemiainDownsyndrome 163
and therapeutic targets
8. LessofsolidtumorsinDownsyndrome 167
1. Introduction 275
9. Genesofmotorcontrolandhypotonia 168
2. NeurotransmissioninDSbrain 277
10. TrisomicHSA21genesandhypocomplementia 169
3. TheGABAergicreceptorsandontogenic
11. Concludingremarks 170
changes 281
References 171
4. GlutamatergicandGABAergicsystemsduring
development 285
8. Triplicated HSA21 genes and mtDNA on 5. GABAsignalingintrisomiccondition 292
mitochondrial dysfunction: consequential 6. AlterationsofGABAergiccircuitsinDSmodeland
changes in mitochondrial dynamics, biogenesis, neurodevelopmentaldisorders 295
7. PerspectivesontherapeuticsofGABAergic
bioenergetics, redox potential and
transmission 298
Ca-homeostasis
8. Concludingremarks 310
1. Introduction 181
References 311
2. Mitochondrialdynamicsandgenome 184
3. AlterationsinmitochondrialdynamicsinDS 188
12. Alzheimer disease and neuroinflammation
4. Regulationofmitochondrialbioenergeticsin
in Down syndrome: Effects of gene dosage and
DS 190
therapeutics
5. MitochrondrialdysfunctioninDS:increasedoxidative
stressandinflammation 191 1. Introduction 321
6. TriplicatedHSA21genes:implicationon 2. Preclinicalchangesofcognitiveperformance 323
mitochondrialbiogenesisandfunction 195 3. DementiainAD 324
References 210 4. Bio-markersofAD 326
5. Age-relatedconsequencesofADpathogenesis 336
6. Genesinvolvedinneuropathologiceventsin
9. Disarrayed mitochondrial function on
DSAD 336
pathobiology in Down syndrome and targeted
7. UbiquitinylationandproteasomesystemofAD
therapeutics
development 340
1. Introduction 219 8. PerspectivesofneuroinflammationinDSAD 341
2. Diseasescausedbymitochondrialdysfunction 220 9. GenesofneuroinflammationinDownsyndrome 350
3. Oxidativestress:anindicationofadaptiveresponsein 10. TherapeuticsofADmanagementinDS 353
DS 228 11. Conclusionandfuturedirection 358
4. Clearanceofdeadcells:autophagyandmitophagyin References 359
DS 229
5. Targetedtherapiesforrestorationofmitochondrial 13. MicroRNAs and epigenetic signatures in
networkinDS 231
Down syndrome
6. Concludingremarks 238
1. Introduction 369
References 239
2. MicroRNAsandbiogenesis 373
3. HSA21-MicroRNAsinDownsyndrome 376
10. Gene-dosage imbalance and altered
4. DiseaseconsequencesofHSA21-miRNAs 380
neurogenesis in Down syndrome
5. Associationofothernon-HSA21miRNAswith
1. Introduction 245 HSA21-miRNAs 384
2. DevelopmentalconsequencesofbraininDS 246 6. DrugtargetsofmiRNAs 385
3. Geneticimplicationofneurologicalterationsin 7. PerspectivesofmicroRNAsinprenataldiagnosisof
DS 250 DS 388
4. Mitochondrialcontrolofneuralprogenitorcells 266 8. SpectrumofepigeneticexpressioninDS 389
5. Concludingremarks 269 9. DSphenotypesassociatedwithepigenetic
References 269 modulation 393
vii
Contents
10. Therapeutictargetsofepigeneticexpression 396 5. Organoids(iPSC-based)aschimericmodelstostudy
11. Concludingremarks 397 neurogenesisinDS 440
References 398 6. TechnicalchallengesofDSmodelingandengineering
ofgenesofinterest 442
14. In vivo and in vitro models for research on 7. HSA21syntenystudiedonothermodels 449
Down syndrome 8. ModelsforpharmaceuticaldevelopmentsforDS 454
9. Conclusionandperspectives 457
1. Introduction 405
References 458
2. ModelsofDSresearch 407
3. MousemodelsinDSresearch 408
Index 465
4. iPSCswithHSA21asmodelinDSresearch 438
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An overview of this book
Down syndrome (DS), the most common translocationbetween“D”groupandHSA21are
chromosomal disorder, was first characterized at greater risk of reproducing a child with DS,
clinically in 1862 by John Haydon Langdon- while parents carrying one such translocation
^
Down, and genetically in 1959 by Jérome betweentwoHSA21swilldeliver100%children
Lejeune. The epidemiological incidence is esti- withDS.AlbeitconceptionswithDShaveahigh
mated at one in 600 to 700 newborns; however, rateofpregnancylossorearlydeathinpostnatal
this ratio is heavily influenced by age of the life, this autosomal aneuploidy has exhibited
mother.DSisawell-exemplifiedaneuploidalge- extended lifespan due to early intervention of
netic disorder manifested with the syndrome- medical therapeutics and increasing parental
specific but variable facial and clinical features awareness.
andearlyonsetofAlzheimerdisease(AD)-asso- Thechaptershavebeenarrangedbasedonthe
ciateddementia.Thelonghistoryofunderstand- orderofdevelopmentalsequencesoftheknowl-
ing the syndrome in different geo-political edgebankonthesyndrome,whichstartedwith
boundaries has been narrated in Chapter 1 of identificationoftrisomy21asgeneticetiologyto
this book. One must know the journey of these expressionoftrisomicHSA21genesandinterac-
individuals from institutionalized homes, tionwithnon-HSA21disomicgenesleadingtoa
care-givers’ centers to living with parents, and complex scenario. Indeed, the DS patients with
their acceptance by the general public. They the trisomy of the smallest chromosome have
require schooling with special arrangements for not yet been fully understood for clinical man-
facilitating improvement of their learning skill. agement of their cognitive performance, facial
Besides typical syndromic craniofacial appear- correction,orameliorationofADatpre-orpost-
ance, their intellectual disability and delayed natal age, even with the advent of the current
motormilestonessegregatetheminperformance geneeditingCRISPRtechnologiesortherapeutic
fromtheirage-matchedpeers.Indeed,oneextra targets.Theimpact ofgene-dosage imbalanceis
copy (trisomy) of the human chromosome 21 highly critical for DS pathobiology, albeit varia-
(HSA21), which harbors w500 genes, arises de tions in phenotypic manifestations observed
novo during prefertilization gametogenesis amongtheDSpopulation.Notably,over80phe-
(meiotic nondisjunction) of the parents (most notypeshavebeendemonstratedinDS,ofwhich
with full trisomy, w95%) or postfertilization theuniquecraniofacialfeatures,musclehypoto-
mitotic nondisjunction (most of mosaic DS). nia,halluxvarus,intellectualdisability,andrisk
This trisomic HSA21 confers an altogether ofADcausingearlyaginganddementiaarecon-
different facial configuration, cognitive impair- stant features for all individuals with DS, while
ment, congenital heart disease (CHD, in w50 of remaining are variable, but affecting majority
DS) early onset of AD, and many other clinical of the DS individuals (illustrated in Chapter 2).
complications throughout their life. One must Among the variable characters, atlantoaxial
knowtheriskofparentscarryingaRobertsonian instability, reduced neural density, CHD,
ix