Chapter 3: Microcephaly
Microcephaly: small head; also used to mean small brain regardless of head circumference.
- Cerebral hemispheres derived from the dorsal pallidum of the telencephalon
- Subpallidum (ventral telencephalon) forms the striatum and pallidum
- Dorsal pallidum = medial region (archicortex, hippocampus) + lateral region (olfactory cortex) + ventral region (claustroamygdaloid complex)
- progenitor cells from germinal ventricular zone of the lateral ventricles
- progenitor cells of ventral telencephalon from lateral and medial ganglionic eminences to generate the striatum and pallidum
Signals for cell proliferation and cell death are important in the sculpting of the size of the brain. Many genes involved in neuroblast differentiation, neuronal fate, axon guildance, dendritic polarization and growth, and synaptic development.
Head circumference >3 standard deviations below age and sex related mean, without any associated malformations or triggers.
Micro(en)cephaly vera and microcephaly with simplified gyral pattern
Micro(en)cephaly vera: small brains with no gross abnormalities. Depletion of germinal periventricular cells and neurons in cortical layers II and III. Could be due to premature exhaustion of neuronal progenitors in the germinal layer.
Micro(en)cephaly with abnormal or simplified gyral pattern: oligogyric microcephaly, micro-lissencephaly. Abnormal allocortical architechture, cmmon periventricular heterotopia.
Primary autosomal recessive microcephaly (MCPH)
- Single clinical phenotype, multiple genetic causes
- Mild to moderate mental retardation
- No structural anomalies or abnormal neural migration
- lacking in cell population numbers
- Five genetic loci identified for this condition, with roles in cell proliferation
Primary autosomal dominant microcephaly
Several families with normal intelligence reported.
- families with mental retardation syndromes
- associated with mental retardation and short stature
Microcephaly in chromosomal syndromes
- Down syndrome (trisomy 21)
- Edwards syndrome (trisomy 18)
- cri-du-chat syndrome (5p)
- Wolf-Hirschhorn syndrome (4p)
Other syndromes with congenital microcephaly
A number of autosomal recessive conditions have microcephaly. Some examples:
- Amish microcephaly - 2-ketoglutaric aciduria
- Nijmegen breakage syndrome (NBS) - microcephaly, immunodeficiency, chromosomal instability, hypersensitivity to ionizing radiation, growth retardation, facioskeletal abnormalities and susceptibility to malignancies (B-cell lymphoma)
- A syndrome with microcephaly, microphthalmia, ectrodactyly and prognatism
- Microcephjalic osteodysplastic primordial dwarfism (MOPD) - bone dysplasia and short limbs. Microcephaly, agenesis of corpus callosum, abnormalities in gyration and neuroglial ectopias occur
- Smith-Lemli-Optiz - autosomal recessive linked to gene for delta7-sterol reductase in cholesterol biosynthesis.
- Rubinstein-Taybi syndrome
Genetic disorders with post-natal progressive microcephaly
Normal at birth, develop neurological symptoms and progressive microcephaly. Includes a number of metabolic disorders.
- Rett syndrome - X-linked
- Infantile neuronal ceroid lipofuscinosis with granular osmiophilic deposits (GROD) - accumulation of ceroid in neurons leading to neuronal cell death
- Alpers syndrome - complex seizures, progressive mental deterioration, ataxia, dystonia, visual loss, tetraparesis, liver failure, severe microcephaly "walnut brain". Complex IV of respiratory chain involved (from nuclear DNA)
Secondary (non-genetic) microcephaly
- From exposure to physical agents and toxins resulting in mental retardation and small brains, e.g, ionizing radiation from atomic bombs and nuclear power plant accidents.
- Fetal alcohol syndrome - characteristic facies, microcephaly, mental retardation, impaired cortical neuronal organization, dendritic spine dysgenesis
- congenital infections, e.g., rubella, CMV, toxoplasmosis, AIDS
- other putative elements: hyperthermia, malnutrition, antiepileptic drugs, other drugs
Lissencephaly, holoprosencephaly, and other cerebral malformations usually result in microcephaly.
Variable, from normal intelligence to profound mental retardation. Need to look for consanguinity, risk factors during pregnancy and postnatally.