Chapter 13 - Microcephaly

https://doi.org/10.1016/B978-0-444-52891-9.00013-0Get rights and content

Abstract

True microcephaly (head circumference ≤  3 SD), 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.

Introduction

Microcephaly is defined as an occipitofrontal head circumference (OFC)   2 standard deviations (SD) below the mean for sex, age, and ethnicity. The term “true” or “severe” microcephaly is used for an OFC   3 SD. The term microencephaly refers to a brain weight 2 SD below the mean. The incidence of true primary microcephaly worldwide varies from 1.3 to 150 per 100 000 live births.

Several developmental processes that are under control of genetic and environmental factors play a role in sculpting the brain size. Any condition that affects important processes of brain growth such as progenitor cell proliferation, cell differentiation, and cell death can thus induce microcephaly (Barkovich et al., 2005). Microcephaly may be evident at birth (primary microcephaly) or postnatally (secondary microcephaly). Anomalies leading to microcephaly may exclusively affect the cerebral development (non-syndromic microcephaly) or are associated with visceral, and/or skeletal malformations, and/or facial dysmorphism (syndromal microcephaly). These terms do not imply distinct etiologies and both syndromal and non-syndromal forms may coexist with some etiologies (as in Fanconi anemia). Microcephaly can be acquired (i.e., caused by environmental factors) (Abuelo, 2007) or genetic.

Section snippets

Acquired congenital microcephalies

Acquired congenital microcephaly can occur after various injuries to the developing brain such as intrauterine infection, irradiation, exposure to drugs/toxins including maternal alcohol consumption (fetal alcohol syndrome), fetal irradiation, maternal hyperphenylalaninemia, placental insufficiency, and/or severe maternal illness (Table 13.1). Prenatal brain damage is believed to be a multifactorial, multihit process that varies in severity between individuals, affects infants of different

Primary microcephalies

Primary microcephalies reflect an imbalance between progenitor cell production and cell death (Francis et al., 2006). Disruption of neural progenitor proliferation (defects in mitotic division or cell cycle regulation of progenitors) or of DNA damage response can lead to a reduced number of neuronal and glial cells within the brain.

Metabolic microcephalies

Two specific forms, commonly associated with primary microcephaly, deserve specific special comments.

Serine deficiency disorders are a group of neurometabolic diseases caused by defects in the biosynthesis of L-serine, a precursor of metabolites such as nucleotides, phospholipids, and the neurotransmitters glycine and D-serine. Clinical manifestations include congenital microcephaly, seizures, severe pyramidal syndrome, and severe psychomotor retardation. The diagnosis of serine deficiency is

Secondary microcephalies

Microcephaly that occurs postnatally within the first years of life (normal OFC at birth) often implies ongoing neurodegeneration and/or death of other cells. Most forms of secondary microcephaly such as those occurring in patients with Rett syndrome, Aicardi-Goutières disease, infantile neuronal ceroid lipofuscinoses, or other metabolic diseases are addressed in other chapters. Patients with secondary microcephaly often show progressive motor and cognitive deterioration and seizures, but their

Syndromic microcephalies

A large number of syndromes are associated with microcephaly, which can either be a major handle for suggesting or confirming the diagnosis, or a secondary, nonmandatory feature (Abuelo, 2007). More than 700 clinical syndromes are recorded with microcephaly in the London Dysmorphology Database and OMIM. Typically, most autosomal chromosomal anomalies are associated with small head size, as in classical 4p16 deletion (Wolff  Hirshhorn syndrome), but also in more recently delineated entities such

Management of microcephaly

Proper evaluation of a microcephalic child should be done by a pediatric neurologist and a dysmorphologist. A comprehensive anamnesis, including prenatal history, postnatal medical and developmental steps, and familial history with three-generational pedigree should be collected. Growth charts for height and OFC and a detailed physical examination should be recorded in all cases. They will sometimes suggest a specific diagnosis or deliver handles for further testings. Genetic etiologies have

References (44)

  • M.S. Al-Dosari et al.

    Novel CENPJ mutation causes Seckel syndrome

    J Med Genet

    (2010)
  • S. Ashwal et al.

    Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

    Neurology

    (2009)
  • L. Baala et al.

    Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis

    Nat Genet

    (2007)
  • A.J. Barkovich et al.

    A developmental and genetic classification for malformations of cortical development

    Neurology

    (2005)
  • A. Battaglia et al.

    Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation

    Pediatrics

    (2008)
  • C. Bendavid et al.

    Holoprosencephaly: an update on cytogenetic abnormalities

    Am J Med Genet C Semin Med Genet

    (2010)
  • K. Bilguvar et al.

    Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations

    Nature

    (2011)
  • N. Brunetti-Pierri et al.

    Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities

    Nat Genet

    (2008)
  • V.S. Caviness et al.

    Histogenetic processes leading to the laminated neocortex: migration is only a part of the story

    Dev Neurosci

    (2008)
  • M.M. Cohen

    Problems in the definition of holoprosencephaly

    Am J Med Genet

    (2001)
  • J. Desir et al.

    Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally

    Am J Med Genet A

    (2008)
  • P. Edery et al.

    Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA

    Science

    (2011)
  • Cited by (89)

    • Imaging of Microcephaly

      2022, Clinics in Perinatology
      Citation Excerpt :

      Similarly, severe microcephaly is defined as an OFC that is less than three standard deviations below the average.1,2 Microcephaly is not a diagnosis, but rather, a finding that is secondary to a multitude of etiologies that can be categorized as prenatal versus postnatal, genetic versus environmental, and congenital versus acquired.3 Depending on the exact definition used, and the population to which said definition is applied toward, the incidence of microcephaly varies.

    View all citing articles on Scopus
    View full text