Human microcephaly
Introduction
It is two years since Mochida and Walsh [1] first reviewed human microcephaly and there have been exciting developments in this field in the time that has elapsed. Microcephaly is the clinical finding of a reduced occipital-frontal head circumference (OFC) of less than −3 SD (given as a standard deviation score compared to age and sex matched controls) [2]. This measurement gives an approximation of brain size as the human foetal and postnatal skull bones enlarge because of outward pressure exerted by the growing brain (a child’s brain doubles in size in the first year of life). As 55% of the human brain consists of the cerebral cortex microcephalic individuals have a small cerebral cortex and the majority are mentally retarded.
It is helpful to consider microcephaly as being divided into primary, occurring by 32 weeks of gestation and secondary, occurring after birth. The vast majority of neurones are generated by week 21 of foetal life, but dendritic connection and myelination predominantly occur after birth. Primary microcephaly is therefore likely to be due to a reduced production of neurones, whereas secondary microcephaly is probably caused by decreased dendritic connection/activity of a (near) normal number of neurones.
Although I place emphasis on genetic disorders in this review, other significant but predominantly non-genetic causes of primary microcephaly should not be forgotten, such as maternal alcohol consumption during pregnancy, maternal syphilis infection, inadequate gestational weight gain or poor prenatal care and ‘non-accidental head injury’ 3., 4.. Of these, risk factors for neurone loss after foetal alcohol exposure may have a significant genetic component involving neural nitric oxide synthase activity [5•]. The potential ability to identify women whose pregnancies are at significant risk of foetal alcohol syndrome, with the resultant mental retardation and microcephaly, would have significant public health implications. Other interesting work that I cover in this review includes; the autosomal recessive primary microcephaly A gene; extending the neurological phenotype of mitochondrial disorders to include congenital microcephaly, the X-linked lissencephaly with absent corpus callosum and ambiguous genitalia gene; the first human gene identified to cause a reduction of inhibitory inter-neurones, and the 14-3-3epsilon; a second gene in the Miller-Dieker critical region causing lissencephaly.
Section snippets
Investigating and understanding the specialised mitosis of neurogenesis
All foetal neurones of the central nervous system are produced from neuronal precursor cells within the pseudo-stratified neuroepithelium of the developing brain (Figure 1). The newly generated neurones move out of the neuroepithelium to a position where they can begin to form functional synapses. The neuronal precursors undergo two specialised forms of mitosis. In the first, the neuronal progenitor pool is increased by ‘symmetric’ cell divisions. Each precursor divides to produce two
Autosomal recessive primary microcephaly
Individuals with autosomal recessive primary microcephaly (MCPH) are born with a significantly small head circumference (-4 to -12 SD) and are mentally retarded, but have no other abnormal findings or neurological features (Figure 2; [11•]). Brain scans show that the whole brain is reduced in size, but it is the cerebral cortex that is most severely affected 11.•, 12.••. Two of the genes that cause MCPH have recently been discovered, Microcephalin and abnormal spindle in microcephaly (ASPM)
Chromosome breakage syndromes
The chromosome breakage syndromes are a diverse group of genetic disorders in which DNA repair is faulty and damage to chromosomes can be visualised by microscopy after the addition of various DNA ‘poisons’. Primary microcephaly occurs in some chromosome breakage syndromes such as Bloom syndrome (due to mutation in a recombination protein Q [RecQ] helicase) and Nijmegen breakage syndrome 1., 26.. Seckel syndrome is another example, in which the affected child is born with a birth weight of <1.5
Metabolic disease causing microcephaly
Many inborn errors of metabolism are associated with secondary microcephaly, but few with primary microcephaly. A large multi-affected Amish family has been reported with an autosomal recessive disease called MCPHA, which is characterized by a progressive primary microcephaly, a raised urinary alpha-ketoglutarate and a severely shortened life expectancy. The causative gene is SLC25A19, a mitochondrial deoxynucleotide carrier capable of transporting deoxynucleotides into mitochondria in exchange
Syndromic secondary microcephaly
Any clinical disorder in which secondary microcephaly is a feature will (eventually) give us insights into normal dendritic and synaptic functioning. Rett syndrome is one of the most common and best known of the secondary microcephalies. Brain size and neurological function are apparently normal until the onset of the disease at 6-18 months [30••]. Thereafter, developmental regression occurs coincident with a reduction in brain growth, which results in severe mental retardation and frequent
Neuronal migration disorders
In neuronal migration disorders neurones are produced normally in the neuroepithelium but subsequently a proportion fail to migrate to their correct position within the central nervous system [34•]. Discovery of the causative genes and their function has taught us much about normal neuronal migration. Microcephaly occurs in some neuronal migration disorders, for instance primary microcephaly in reelin mutations and secondary microcephaly in Miller-Dieker syndrome, although the mechanism(s) that
Evolutionary considerations
The MCPH brain is comparable in size to that of our nearest higher primate relatives, the gorilla and chimpanzee, and therefore MCPH has been hypothesised to be a disease in which an evolutionary development that distinguishes us from these species has failed to occur [42]. Comparison of human MCPH genes to their primate orthologues and to other mammals with a smaller relative brain size could help to reveal the evolutionary changes that have lead to the current human brain size. It is
Conclusions
New neurological disorders continue to be defined and described [44•]. Each of these phenotypes will be due to malfunction of a limited number of genes. Increasingly, identification of these genes and neuro-developmental processes in which they participate is allowing us to understand how a human brain forms and begins to function.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
I would like to thank S Lindsay, Centre for Life, University of Newcastle-upon-Tyne, UK and J Bond, same address as author, for use of Figure 1. The family are thanked for allowing the use of Figure 2 and J Bond for producing Figure 3.
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