Normal and Abnormal Brain Development

Normal development of the human central nervous system (CNS) encompasses several steps, including neuroectoderm induction, neurulation, cell proliferation and migration, programmed cell death, neurogenesis and elimination of excess neurons, synaptogenesis, stabilization and elimination of synapses, gliogenesis, and myelination ( Table 51.1 ).

TABLE 51.1

Schematic Chronology of the Major Events During Human Neocortical Development

Neuroectoderm induction	3rd GW
Neurulation	3rd to end of 4th GW
Prosencephalic and hemispheric formation	5th to 10th GW
Neuronal proliferation	10th to 20th GW (?10th to end of gestation for interneurons)
Neuronal migration	12th to 24th GW (?10th to 41st GW for interneurons)
Programmed neuronal cell death	28th to 41st GW
Synaptogenesis	20th GW to puberty
Gliogenesis	20th to 24th GW to ?postnatal years
Myelination	36th to 38th GW to 2 to 3 postnatal years
Angiogenesis	5th to 10th GW to ?postnatal years

GW, Gestational week.

These different steps of brain development and maturation are controlled by the interaction between genes and the environment. Numerous genes involved in brain development have been identified: genes controlling neurulation, neuronal proliferation, neuronal size and shape, programmed cell death, neuronal–glial interactions, and synaptic stabilization. However, it seems unlikely that the 30,000 genes in humans can totally control the organization of 100 billion neurons and trillions of synapses. A normal pattern of expression of these genes requires an adequate environment. Interactions with the intrauterine milieu (factors coming from the mother, placenta, or amniotic fluid) and with the postnatal environment critically modulate gene expression through reciprocal action with neurotransmitters, trophic factors, and hormones and their machinery. Accordingly, brain malformations can be due to environmental factors, genetic factors, or an interaction of both ( Boxes 51.1 through 51.4 ).

Box 51.1

Environmental Factors and Maternal Conditions With Potential Impact on the Developing Brain

Therapeutic Drugs

Retinoic acid
Antithyroid drugs
Estroprogestative hormones, testosterone, and derivatives
Antimitotic drugs
Lithium and psychotropic drugs
Benzodiazepines and antiepileptic drugs

Addiction Drugs

Tobacco
Caffeine
Ethanol
Cocaine
Opiates
Cannabis

Physical and Chemical Agents

Dioxins and heavy metals
Organic solvents
Ionizing radiation
Head trauma
Repeated shaking

Maternal Factors and Status

Sex hormones
Catecholamines
Thyroid hormones
Diabetes mellitus
Peptides (vasoactive intestinal peptide)
Placenta and decidual hormones
Oxygen and hypoxia–ischemia
Hyperthermia

Infectious Agents

Herpes simplex virus I and II
Herpes zoster virus
Cytomegalovirus
Rubella virus
Parvovirus B19
Coxsackie virus, B group
Human immunodeficiency virus
Influenza virus
Benign lymphocytic meningitis virus
Toxoplasma gondii
Listeria monocytogenes
Treponema pallidum

Box 51.2

Major Etiologies of Human Holoprosencephaly

Chromosomal Holoprosencephaly

Chromosome 13: trisomy, deletion or duplication of 13q, ring
Deletion 2p, duplication 3p, deletion 7q, deletion 21q
Triploidy

Syndromal Holoprosencephaly

Meckel syndrome
Varadi-Papp syndrome
Pallister-Hall syndrome
Smith-Lemli-Opitz syndrome
Velo-cardio-facial syndrome

Nonsyndromal Genetic Holoprosencephaly (Sporadic or Mendelian Inheritance)

SIX3: HPE2 locus on chromosome 2p21
SHH: HPE3 locus on chromosome 7q36
TGIF: HPE4 locus on chromosome 18p11.3
ZIC2: HPE5 locus on chromosome 13q32

Environmental Holoprosencephaly

Hypocholesterolemia
Retinoic acid exposure
Ethanol exposure

Box 51.3

Classification of Human Congenital Microcephaly

Primary Genetic Microcephaly

Microcephaly Primary Hereditary (MCPH): Autosomal Recessive Inheritance, Except for MCPH18

MCPH1 (Microcephaly) , WDR62 (MCPH2) , CDK5RAP2 (MCPH3), CASC5 (MCPH4) , ASPM (MCPH5), CENPJ (MCPH6), STIL (MCPH7), CEP135 (MCPH8), CEP152 (MCPH9), ZNF335 (MCPH10), PHC1 (MCPH11), CDK6 (MCPH12), CENPE (MCPH13) , SASS6 (MCPH14) , MFSD2A (MCPH15), ANKLE2 (MCPH16), CIT (MCPH17), WDFY3 (MCPH18).

Primary Microcephaly With Dwarfism (Autosomal Recessive)

Seckel syndrome: ATR (SCKL1), RBBP8 (SCKL2), CENPJ (SCKL4), CEP152 (SCKL5), CEP63 (SCKL6), NIN (SCKL7), DNA2 (SCKL8), TRAIP (SCKL9), NSMCE2 (SCKL10),
Microcephalic osteodysplastic primordial dwarfism: PCNT
Meier Gorlin syndrome: ORC1 (MGORS1), ORC4 (MGORS2), ORC6 (MGORS3), CDT1 (MGORS4), CDC6 (MGORS5), GMNN (MGORS6), CDC45L (MGORS7), MCM5 (MGORS8).

Microcephaly With Simplified Gyral Pattern (Autosomal Recessive)

Normal or thin corpus callosum
Agenesis of the corpus callosum

Microlissencephaly, MLIS (Autosomal Recessive)

With thin cortex: RELN (MILIS1 or Norman Roberts syndrome)
With thin cortex, brainstem and cerebellar hypoplasia (MLIS2 or Barth syndrome)
With intermediate cortex (MLIS3)
With mildly to moderately thin cortex (MLIS4)

Microcephaly Associated With Other Brain Malformations

Microcephaly as Part of a Syndrome

Neu-Laxova syndrome (autosomal recessive)
PHGDH (NLS1), PSAT1 (NLS2)
Rubinstein-Taybi syndrome (autosomal dominant)
CREBBP (RSTS1), EP300 (RSTS2)
Cornelia de Lange syndrome (autosomal dominant except for CDLS X-linked)
NIPBL (CDLS1), SMC1A (CDLS2), SMC3 (CDLS3), RAD21 (CDLS4), HDAC8 (CDLS5).

Microcephaly Associated With Biochemical Disorders

Microcephaly Secondary to Environmental Factors

Hypoxia–ischemia
Severe malnutrition
Maternal hyperphenylalaninemia and phenylketonuria
Ionizing radiation
Ethanol exposure
Infections (cytomegalovirus, benign lymphocytic meningitis virus, Toxoplasma gondii , Rubella virus, Zika virus)

Box 51.4

Genes and Environmental Factors Identified in Human Neuronal Migration Disorders

Periventricular Heterotopia

FLNA (X-linked)
With microcephaly: ARFGEF2 (autosomal recessive)

Classic Lissencephalies

LIS1 (autosomal dominant)
DCX (X-linked)
TUBA3 (autosomal dominant)
ARX (X-linked)

Cobblestone Lissencephalies (Autosomal Recessive)

POMT1
POMT2
FCMD (FKTN)
FKRP
POMGNT1
POMGNT2
DAG1
ISPD
LAMB1
POMK
RXYLT1

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