The Genetic Factors of Human Holoprosencephaly
Holoprosencephaly (HPE) is a ‘less known’ but common disease that cause incomplete cleavage of prosencephalon (forebrain) into two lobes of cerebral hemispheres (telencephalon). This review will explain about genetic abnormalities in HPE caused by mutation of specific major genes or even the minor genes and how HPE is identified in new patients. Despite being a minor HPE causation (25 to 50% of HPE cases), studies in genetic factor will help in gaining updated information about HPE and the discovery of new HPE candidate genes.
HPE affects 1 fetus in 200-250 pregnancies and 1 in 16 000 live-born infants in the world(Roessler et al., 1996). HPE can be classified into 4 types which are alobar, semi lobar, lobar and middle interhemispheric variant (MIHV). The most severe is alobar HPE, which can be characterized by incomplete cleavage of brain into hemisphere due to the absence of interhemispheric fissure.
The moderate HPE is semi lobar that can be detected by partially divided brain when it is fused in the front but separated in the rear. The mild lobar HPE’s patients have well disjoined brain but some fusions on the ventral telencephalon do exist. The patients diagnosed with MIHV HPE will have incomplete division of the middle brain in between parietal lobes and posterior frontal in the telencephalon.
Symptoms that can be observed in the patient are as severe as cyclopia, having a single central eye and proboscis, which the nose is located on the forehead to the mild type, of having single inaxillary central incisor that refers to an upper central tooth (Dubourg et al., 2007). Epilepsy, mental retardation and endocrine abnormalities are common diseases affecting the patients with HPE (Dubourg et al., 2007).
Besides genetic factors that contribute to 20 to 50% of HPE (based on number of patients taking part in previous research), most HPE cases were caused by maternal factors. Mother suffering from diabetes mellitus, infection occurring during pregnancy such as herpes, rubella and syphilis or even pregnancy loss and bleeding in the first trimester, all can lead to HPE (Johnson and Rasmussen, 2010).Teratogen consumption, for example, retinoic acid and alcohol can affect the embryo development too (Johnson and Rasmussen, 2010).
Figure 1. The 4 types of HPE with the brain structure and facial deformities formed. A. Undivided brain of alobar HPE and patient with cyclopia and proboscis. B. Partially divided brain of semi lobar HPE and patient with cleft lip. C. Well disjoined brain of lobar HPE and patient with normal facial appearance. D. Undivided middle brain of MIHV HPE and patient with normal face appearance. Pictures obtained from Muenke and Gropman, 2000.
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