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Microcephaly
Sandrine Passemard1, Angela M Kaindl, Alain Verloes
1Department of Genetics, Hôpital Robert Debré, Paris, France; Inserm U676 and Medical School, Denis Diderot-Paris VII University, Paris, France.
Abstract:
True microcephaly (head circumference ≤-3SD), either primary (present at birth) or secondary (of postnatal onset) results from an imbalance between progenitor cell production and cell death that lead to a reduced number of neuronal and glial cells within the brain, resulting in reduced brain growth. Primary non-syndromal microcephalies are recessive disorders resulting from abnormal control of mitotic spindle and cell cycle kinetics in progenitor cells. Microcephaly is also a frequent sign of defects in DNA double- and/or single-strand break repair and in nucleotide excision repair, in which it often is associated with general growth impairment. In these etiologies, cognitive functions are reasonably well preserved despite severe reduction in brain volume. Neuronal migration defects are often associated with secondary microcephaly, as are anomalies of telencephalic cleavage. Secondary microcephalies are often associated with increased neuronal death, and can be associated with metabolic disorders such as serine deficiency or thiamine pyrophosphate transporter deficiency. Microcephaly can be associated with hundreds of syndromal congenital anomalies, including many chromosomal disorders. Genetic etiologies of developmental microcephalies are reviewed.
Insights
True microcephaly, a condition of reduced brain growth, stems from an imbalance in brain cell production and death. Genetic factors, DNA repair defects, and metabolic disorders contribute to this developmental condition.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Microcephaly is characterized by a reduced brain size, impacting neuronal and glial cell numbers.
- It can be primary (congenital) or secondary (postnatal onset), stemming from various cellular and genetic disruptions.
- Cognitive functions may be preserved in some microcephaly etiologies despite reduced brain volume.
Purpose of the Study:
- To review the genetic etiologies of developmental microcephalies.
- To elucidate the cellular mechanisms underlying microcephaly, including progenitor cell dynamics and DNA repair.
- To discuss the association of microcephaly with syndromic anomalies and metabolic disorders.
Main Methods:
- Review of genetic etiologies for developmental microcephaly.
- Analysis of cellular mechanisms: progenitor cell production, cell death, mitotic spindle control, cell cycle kinetics.
- Examination of DNA repair pathways (double-strand break, single-strand break, nucleotide excision repair) and their link to microcephaly.
- Investigation of neuronal migration and telencephalic cleavage defects.
- Assessment of associations with metabolic disorders and chromosomal abnormalities.
Main Results:
- Primary microcephalies are often recessive disorders linked to abnormal mitotic spindle and cell cycle control.
- Microcephaly frequently indicates defects in DNA repair mechanisms, sometimes with general growth impairment.
- Secondary microcephalies involve neuronal migration defects, telencephalic cleavage anomalies, increased neuronal death, and can be linked to metabolic issues.
- Microcephaly is a common feature in numerous syndromic congenital anomalies and chromosomal disorders.
Conclusions:
- Developmental microcephalies arise from a complex interplay of genetic, cellular, and molecular factors.
- Understanding these diverse etiologies is crucial for diagnosis and potential therapeutic strategies.
- The review highlights the significant role of progenitor cell regulation and DNA integrity in brain development.
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