Holoprosencephaly: its nature and manifestation


An exploration into Holoprosencephaly, the genetic birth defect; we will observe how it presents itself in su erers- the physical and neurological symptoms, we will brie y try to identify the main candidates that can be linked to its etiology and nally taking the SHH pathway as an example we will explain how a genetic mutation could give rise to the associated symptoms of HPE.


Holoprosencephaly (HPE) is a congenital defect in the nervous system, whereby the developing prosencephalon (or forebrain) fails to bifurcate into left and right hemispheres- typically occurring ve to six weeks into pregnancy (Golden, 1999). It is the most common malformation of the brain- occurring in 1:250 developing embyros, with 1:8,000 live births due to a 3% chance of survival to delivery (Co-hen, 1989). The failure of the cleavage into two bilateral cerebral hemispheres gives rise to a continuum of motor and developmental malformations, the most prominent being craniofacial defects and damaged brain structure. There are four classes of HPE1, varying in the degree of cortical separation and associated severity of symptoms2 (Raam, 2011). The most severe form is Alobar HPE, this is characterised by a complete or near lack of interhemispheric separation and an absence of olfactory bulbs and corpus callosum. This makes up roughly two-thirds of HPE patients (OMIM, 2012), the most extreme grade in this class will have cyclopia: no separation along the midline of the brain, with no sense of chirality in their embryogenesis. In this case the foetus will develop a single, medial eye above the root of the nose- they will rarely survive the perinatal period. The next class is Semilobar HPE, which can be identi ed by a partial posterior cortical separation (but no anterior) with basal hemispheres, the olfac-tory bulbs and corpus callosum are either absent or hypoplastic. In this case the eyes are now slightly separated by proboscis, but the motor skills are still highly impaired. The next form is lobar HPE, this is a milder form of semilobar, di er-entiated by the latter by the presence of a frontal horn in the lateral ventricle. Lobar has an interhemispherical ssure, but there still incomplete separation of the prosencephalon; the corpus callosum is absent in the a ected region and the olfactory bulbs are hypoplastic. There is less severe motor malfunction, and the face can develop closely spaced eyes, at nose and cleft lip. The fourth and mildest form is the Middle Interhemispheric Variant (MIV), where the most a ected regions of nonseparation occur in the posterior frontal and pariental lobes; the corpus callosum is typically absent in the region or hypoplastic. This variant of HPE has mild craniofacial and neurological impairments. All of these deformities can be detected through neuroimaging, and can be discerned by the above phenotypes.

2 Causes

Current research into the causes of HPE is still developing; most sources can-not give exact causes, but there a number of factors that have been linked to the disorder. The most supported model is given by the Multiple Hit Hypothesis which states that HPE derives from a combination of environmental and genetic factors, i.e. it is an autosomal-dominant disease; it is believed that this would explain the heterogeneity of the phenotypes (OMIM, 2012). Teratogens are be-lieved to disturb the development of the normal phenotype: maternal diabetes has been linked to a 200% increased risk of HPE in the foetus( Croen, 2000; Raam, 2011). This along with hypocholesterolemia and the drug cyclopamine are linked to disturbances in cholesterol production, inhibiting the Sonic Hedge-hog (SHH) Signalling Pathway (Cohen, 1989). The fact that the defects occur early in pregnancy implies a gastrulation disorder supporting the theory that infections whilst pregnant and drug taking (alcohol, anti-epileptic medication

1 There is a mild associated form called Microform, with similar craniofacial characteristics, but no sign of nonseparation, as such typically not considered within HPE.

2 A common used term is that “the face predicts the brain”, this is a general correlation that exists between the degree of mental and physical retardation and mortality within the four classes and ethanol for example) are likely environmental causes. The genetic etiology are related to familial occurrences3, genetic syndromes of HPE and non ran-dom chromosomal aberrations- identi ed by high resolution karotype counts, or DNA microarrays. A relatively common cause of HPE-approximately 28%, (Geng, 2009)- has been found to be loss-of-function mutations in the genes: SHH, ZIC2, SIX3 and TGIF- whereby the particular gene product will be un-able to perform its original function. There are ve other genes identi ed with HPE, but these four mutations are the most prevalent and as such are the main roots for DNA sequencing. These genes are related to the Nodal and SHH pathways. De ciency in the Nodal protein results in a failure to form the PrCP gene; this e ects the formation of the primitive streak. The establishment of this structure is important in creating a longitudinal plane of symmetry along the embryonic disk that allows cell migration into the midline to create the mesoderm, the cells of which form a rod called the notochord. The SHH gene is a morphogen that regulates ventral midline structure in the forebrain (Roessler, 2003) and is crucial in formation of the eyes and face. It is a molecule that responds to variations in a concentration gradient within the neural tube by di using Sonic Hedgehog, produced by the signalling centre of the notochord (Placzek, 1999).

3 How the gene leads to the disorder

In order to understand how HPE4 manifests itself through the mutation in this gene we will consider its role in brain embryology (Marieb, 2003). By around the fth day after fertilisation, the blastocyst of the egg is released- this is a sphere composed of trophoblast cells and inner cell mass; this will undergo gastrulation whereby the inner cell mass is converted into the three primary germ layers and the embryonic disk. This disk attens and a primitive streak creates a midline depression along the median. Three weeks into pregnancy the ectoderm thick-ens along the dorsal midline axis of the embryo to form the neural plate, which when folds into the neural tube by the fourth week, the anterior of which expands rapidly to form the three brain ventricles of the prosencephalon along with the middle and the hindbrain; by this time eye rudiments are present. Normally, in the fth week the prosencephalon will bifurcate into the diencephalon and the telencephalon-from the dorsal plate and ventral plate, respectively- connected by the corpus callosum. The telencephalon then “swells” into the cerebral hemi-spheres and by the eighth week all brain exures are formed. The role of the SHH gene is to produce the Sonic Hedgehog protein that signals the activation of the ventral midline of the forebrain. In HPE, with a mutated SHH gene, there is a reduced or no production of this protein and as a result the fore-brain will not split into a left and right (Roessler, 2003). Along with this it secretes the molecule responsible for signalling the division of a single eye eld

3 There are a number of case studies in (OMIM, 2012) on families where HPE is an inherited condition

4 To be exact, this is Holoprosencephaly type 3 into two distinct eyes. Hence, a SHH mutation can lead to a lack of interhemi-spheric separation and merging of the eyes, which would a ect the development of the rest of the face. This shows the symptoms of HPE su erers, suggesting the disorder is a subclass related to the loss-of-function of the SHH signalling pathway. If there was a complete lack of SHH signalling there would be no separation in the telenchephalon, and as such no connecting corpus callosum, the primordial eye eld would not divide into two lateral eye elds, thereby resulting in an embyro with cyclopia from Alobar HPE. Similarly, inactivity of the Nodal signalling pathway causes failure in the formation of the mesendo-derm and axis-asymmetry. As stated before there are a number of genes that are linked to HPE that also regulate organogenesis but the spectrum of the disorder is entirely variable and there are 75% of HPE cases that do not have any of these gene mutations. The most satisfactory hypothesis is the Multi-hit model; there is no single exact cause that could trigger the defect in all of the presented cases and produce the four classes of severity, but it is possible that the pathogenesis must involve some event in the regulatory regions that induces the expression of the four identi ed genes in the forebrain, though the trigger might not necessarily be the same in every instance.

4 References

Cohen, M.M. Jr., Perspectives on holoprosencephaly: Part III. Spectra, distinc-tions, continuities, and discontinuities. Am J Med Genet. 1989; 34: 271-88. Cohen, M & Shiota, K, Teratogenesis of Holoprosencephaly. Amercian Journal of Medical Genetics. 2002; 109: 1-15.

Croen L.A, Shaw G.M & Lammer E.J, Risk factors for cytogenetically normal holoprosencephaly in California: A population-based case-control study. Am J Med Genet. 2000; 90: 320-325.

Geng, X & Oliver, G, Pathogenesis of holoprosencephaly. J Clin Invest. 2009;119(6):14031413 Golden, J.A, Towards a greater understanding of the pathogeneis of holoprosen-

cephaly. Brain & Dev. 1999; 21: 513-521.

Graham, J.M. Jr. & Shaw, G.M, Gene-Environment Interactions in Rare Dis-eases that Include Common Birth Defects. Birth Defects Research. 2005; 73: 865-867.

Marieb, E.N, Human Anatomy and Physiology. California: Benjamin Cum-mings, 1989.

Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Bal-timore, MD. MIM Number: 236100. [Accessed 28/11/2012] World Wide Web URL: http://omim.org/

Placzek, M, The role of the notochord andoor plate in inductive interactions.

Genetics and Development. 1997; 5(4): 499-506.

Raam, M.S, Soloman, B.D & Muenke, M, Holoprosencephaly: A Guide to Di-agnosis and Clinical Management. Indian Pediatrics. 2011; 48: 457-466.

Roessler, E & Muenke, M, How a Hedgehog might see holoprosencephaly. Hu-man Molecular Genetics. 2003; 12(1): R15-R25.

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