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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