Editorial pubs.acs.org/chemneuro
Cite This: ACS Chem. Neurosci. 2018, 9, 626−627
Genetic and Rare Disease of the CNS. Part II: Holoprosencephaly (HPE)
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ur journey through genetic and rare diseases of the CNS1−3 continues this month. Following the first feature on fatal familial insomnia (FFI),4 which occurs in a patient’s mid-to-late 40s, we now focus on a birth defect that occurs within the first weeks of pregnancy, holoprosencephaly (HPE).5−8 While I am far from an expert on HPE, this series of editorials is designed to provide a general overview of a genetic and rare disease with the aim to raise awareness and hopefully encourage experts in the field to draft the definitive manuscripts and publish with ACS Chemical Neuroscience. In short, HPE is a CNS disorder characterized by a failure of the prosencephalon (or forebrain) to divide during the fourth to sixth week of gestation leading to a single-lobed brain structure (Figure 1), resulting in severe facial features. The majority of cases of HPE are so severe that the fetus dies before birth, though in milder cases, children do survive.5−9 HPE is subdivided into four types based on severity: (1) alobar (most severe in which the brain has not divided at all, extreme facial features), (2) semilobar (brain hemispheres somewhat divided), (3) lobar (evidence of separated hemispheres, brain function might be normal), and (4) middle interhemispheric variant (MIHV), wherein the brain is fused in the middle (leads to closely set eyes and narrow nose). In the most extreme cases, alobar babies are born with a single eye (cyclpsia) and a tubular proboscis above the eye (Figure 1D), possibly the origin of the Greek cyclops, or very closely spaced eyes or absent eyes. In the milder forms, cleft lip and/or palate are observed. Interestingly, the face abnormalities predict brain morphology 80% of the time.9 Life expectancy is short. Children with severe HPE are typically stillborn or die at birth, while less severe cases can live past one year. The etiology of HPE is unclear. There is a genetic component, but not in every case. Like FFI,4 nonsyndromic HPE is autosomal dominant, but other inherited causes include chromosomal abnormalities (trisomy 13, del(13q), trisomy 18, del(18p)) and single gene mutations (14 identified to date).5−9 Numerous candidate genes include SHH (sonic hedgehog), Pax-2, Pax-6, ZIC2, SIX3, TGIF, PTCH, GLI2, FAST1, TDGF1, and DHCR7.5−9 In addition, many nongenetic factors come into play as well including gestational diabetes, transplacental infections, or a history of miscarriage. Correlations also exist when pregnant mothers take medications (labeled as unsafe for expecting mothers) such as insulin, birth control pills, aspirin, lithium, and retinoic acid. Furthermore, there are links to HPE with nicotine use, alcohol consumption, and toxins in cigarettes. Thus, there is no one singular cause of HPE, as there is with the prion disease, FFI.4 I actually find this more frightening, as there are so many possible causes of HPE. More work needs to be done to understand this disease, but the rarity and diverse etiology confounds the issue. Still, what a frightening disease for a family to experience. I encourage submissions on the topic of HPE as Reviews, Viewpoints, Letters, and Articles. A deeper understanding of this rare/neglected disease of the CNS is needed. As always, © 2018 American Chemical Society
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Craig W. Lindsley, Editor-in-Chief AUTHOR INFORMATION
ORCID
Craig W. Lindsley: 0000-0003-0168-1445 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Lindsley, C. W. (2017) Embarking on a 5 year journey to highlight genetic and rare diseases of the central nervous system. ACS Chem. Neurosci. 8, 2349. (2) https://rarediseases.info.nih.gov/GARD. (3) National Organization for Rare Diseases (https://rarediseases. org). (4) Lindsley, C. W. (2017) Genetic and Rare Disease of the CNS. Part I: Fatal Familial Insomnia (FFI). ACS Chem. Neurosci. 8, 2570− 2572. (5) Carter Center for Brain Research in Holoprosencephaly and Related Malformations (https://rarediseases.org/organizations/cartercenters-for-brain-research-in-holoprosencephaly-and-relatedmalformations/). (6) Neuropathology (http://neuropathology-web.org). (7) Cohen, M. M., Jr (2006) Holoprosencephaly: Clinical, anatomical and molecular dimensions. Birth Defects Res., Part A 76, 658−673. (8) Roessler, E., and Muenke, M. (2010) The molecular genetics of holoprosencephaly. Am. J. Med. Genet., Part C 154C, 52−61. (9) DeMeyer, W. E., Zeman, W., and Palmer, C. G. (1964) The face predicts the brain: diagnostic significance of median facial abnormalities for holoprosencephaly (arhinencephalpy). Pediatrics 34, 256−263.
Published: April 18, 2018 626
DOI: 10.1021/acschemneuro.8b00135 ACS Chem. Neurosci. 2018, 9, 626−627
ACS Chemical Neuroscience
Editorial
Figure 1. Images of holoprosencephaly (HPE). (A) Dissected brain with alobar holoprosencephaly; (B) facial abnormalities from the patient of the brain in (A); (C) HPE hallmarks: fusion of the frontal lobes and caudate nuclei and absence of the corpus callosum; (D) the most severe form of facial abnormality with HPE, cyclopsia. (Reprinted with permission courtesy of Dr. Dimitri Agamanolis and http://neuropathology-web.org.)
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DOI: 10.1021/acschemneuro.8b00135 ACS Chem. Neurosci. 2018, 9, 626−627
