Developmental Malformations

Inositol can be obtained from dietary sources or synthesized from D-glucose by the sequential action of hexokinase (HK), myo-inositol-1-phosphate synthase (MIPS), and inositol monophosphatase (IMPas). The structures of myo-inositol and phosphatidylinositol (inositol lipids are shaded gray) form the backbone for synthesis of inositol phosphate (IP) and phosphoinositide (PI) molecules through the action of multiple kinases and/or phosphatases. Phosphorylation/dephosphorylation steps can be mediated by several enzymes (kinases in blue text, phosphatases in purple text). Some kinases exist in multiple isoforms (eg, PIP5K and PI3K [PI3-kinase]), whereas several phosphatases can act to dephosphorylate PI(3,4,5)P3 (eg, INPP5E, SHIP1, and SHIP2). Some enzymes act at multiple steps (eg, IPMK acts to phosphorylate inositol at several steps). Downstream functional effects of key molecules are indicated in italics (green text). Abbreviations: PLC: phospholipase C; DAG: diacylglycerol; PKC: protein kinase C; IPMK: inositol phosphate multikinase; ITPK1: inositol 1,3,4-triphosphate 5/6 kinase. (Source: Greene ND, Leung KY, Copp AJ. Inositol, neural tube closure and the prevention of neural tube defects. Birth Defects Res 2017;109[2]:68-80. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Most tissues can synthesize myo-inositol following phosphorylation of D-glucose to glucose-6-phosphate with subsequent synthesis of myo-inositol-1-phosphate, which then forms free myo-inositol after dephosphorylation. Myo-inositol can be incorporated into the phosphoinositides cycle, further catabolized to D-glucuronate for renal excretion or converted back to glucose-6-phosphate after a series of enzymatic reactions. Myo-inositol can also be converted to D-chiro-inositol by the enzymatic action of an epimerase. (Source: D’Souza SW, Copp AJ, Greene ND, Glazier JD. Maternal inositol status and neural tube defects: a role for the human yolk sac in embryonic inositol delivery? Adv Nutr 2021;12[1]:212-22. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Wall-eyed stereo view of ECG modeled into the folate-binding site of human dihydrofolate reductase (DHFR). Abbreviations: ECG: (-)-epicatechin gallate; DHFR: dihydrofolate reductase. Carbon atoms of the ECG ligand and surrounding protein are colored green and grey, respectively. Residue Phe-31, located behind the ECG, is unlabeled. Four different ligands from human and chicken DHFR crystal structures were used to define a binding envelope, shown in cyan. These were placed in a common orientation by superimposing backbone atoms from a common set of protein residues located around the ligands. (Source: Sanchez-del-Campo L, Sáez-Ayala M, Chazarra S, Cabezas-Herrera J, Rodríguez-López JN. Binding of natural and synthetic polyphenols to human dihydrofolate reductase. Int J Mol Sci 2009;10[12]:5398-410. Creative Commons Attribution [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Structural comparison of natural (ECG) and synthetic (TMECG) polyphenols with classical (MTX) and non-classical (TQD) antifolates. Abbreviations: ECG: (-)-epicatechin gallate; MTX: methotrexate; TMECG: 3-O-(3,4,5-trimethoxybenzoyl)-(-)- epicatechin; TQD: (R)-6-{[methyl-(3,4,5-trimethoxyphenyl)-amino]methyl}-5,6,7,8-tetrahydroquinazoline- 2,4-diamine. (Source: Sanchez-del-Campo L, Sáez-Ayala M, Chazarra S, Cabezas-Herrera J, Rodríguez-López JN. Binding of natural and synthetic polyphenols to human dihydrofolate reductase. Int J Mol Sci 2009;10[12]:5398-410. Creative Commons Attribution [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Flavonoids present in tea with epicatechin (ECG, EGCG) and catechin configurations (CG). Catechins are major components of tea. Catechins contain a benzopyran skeleton with a phenyl group substituted at the 2-position and a hydroxyl (or ester) function at the 3-position. Variations in the catechin structure include variations in the stereochemistry of the 2,3-substituents and the number of hydroxyl groups in the B-ring and D-ring. Belonging to the flavanol class of flavonoids, the most abundant catechins found in tea leaves include catechin-3-gallate (CG), epicatechin-3-gallate (ECG), epigallocatechin-3-gallate (EGCG). (Source: Saez-Ayala M, Fernández-Pérez MP, Chazarra S, Mchedlishvili N, Tárraga-Tomás A, Rodríguez-López JN. Factors influencing the antifolate activity of synthetic tea-derived catechins. Molecules 2013;18[7]:8319-41. Creative Commons Attribution [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

(Source: van der Windt M, Schoenmakers S, van Rijn B, Galjaard S, Steegers-Theunissen R, van Rossem L. Epidemiology and (patho)physiology of folic acid supplement use in obese women before and during pregnancy. Nutrients 2021;13[2]:331. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Overview potential underlying (patho)physiological pathways of folate deficiency and NTDs in obese women. Abbreviation: NTD = neural tube defect. (Source: van der Windt M, Schoenmakers S, van Rijn B, Galjaard S, Steegers-Theunissen R, van Rossem L. Epidemiology and (patho)physiology of folic acid supplement use in obese women before and during pregnancy. Nutrients 2021;13[2]:331. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: AHCY: S-adenosylhomocysteine hydrolase; DHF: dihydrofolate; DHFR: dihydrofolate reductase; MS: methionine synthase; MTHFR: methylene tetrahydrofolate reductase; 5-MTHF: 5-methyltetrahydrofolate reductase; THF: tetrahydrofolate; SAH: S-adenosyl-homocysteine; SAM: S-adenosyl-methionine. (Source: van der Windt M, Schoenmakers S, van Rijn B, Galjaard S, Steegers-Theunissen R, van Rossem L. Epidemiology and (patho)physiology of folic acid supplement use in obese women before and during pregnancy. Nutrients 2021;13[2]:331. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Courtesy of Wikimedia Commons. Public domain.)

(Source: Mansch A. Medical world: gallery of contemporaries in the field of medical science. Berlin: Adolf Eckstein's Pub House, 1915[?]. Courtesy of the Wellcome Collection, London, England. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Courtesy of the US National Library of Medicine. Also available on Wikimedia Commons. Public domain.)

Human embryos of His' Normentafel [normal plates]. The embryos figured are of the first month (after Keibel and Elze 1908). (Source: Prentiss CW. A laboratory manual and text-book of embryology. Philadelphia and London: WB Saunders, 1915:94. From: Keibel F, Elze C. Normentafel zur Entwicklungsgeschichte des Menschen. Jena: Gustav Fischer, 1908. Based on: His W. Anatomie menschlicher Embryonen. Vol 3: Zur Geschichte der Organe. Leipzig: Vogel, 1885.)

(A) dorsal surface (B) median sagittal section (After Graf Spee). (Source: Prentiss CW. A laboratory manual and textbook of embryology. Philadelphia and London: WB Saunders, 1915:84.)

(After Eternod). (Source: Prentiss CW. A laboratory manual and textbook of embryology. Philadelphia and London: WB Saunders, 1915:86.)

(After Graf Spee.) Abbreviations: ceph: cephalic; med: medullary. (Source: Keith A. Human embryology and morphology. London: E Arnold, 1902:192. Public domain.)

(Source: OpenStax. Illustration from Anatomy & Physiology, Connexions Web site: openstax.org/books/anatomy-and-physiology/pages/1-introduction. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: OpenStax. Textbook OpenStax Anatomy and Physiology, Version 8.25 (2016). Available at: openstax.org/books/anatomy-and-physiology/pages/preface. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normal cortical layer organization in sham (top row) and loss of any cellular layer organization in exencephaly (bottom row) (left to right in each row: 10x, 20x, and 40x, hematoxylin and eosin). Abbreviations: MZ: marginal zone; CP: cortical plate; SP: sub plate; IZ: intermediate zone. (Source: Oria M, Duru S, Figueira RL, et al. Cell necrosis, intrinsic apoptosis and senescence contribute to the progression of exencephaly to anencephaly in a mice model of congenital chranioschisis. Cell Death Dis 2019;10[10]:721. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normal structured cerebral cortex (left) and brain cortex with no structures in exencephaly (right) (20x, hematoxylin and eosin). (Source: Oria M, Duru S, Figueira RL, et al. Cell necrosis, intrinsic apoptosis and senescence contribute to the progression of exencephaly to anencephaly in a mice model of congenital chranioschisis. Cell Death Dis 2019;10[10]:721. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cerebellum and brainstem in normal fetuses (left) and hypertrophic brainstem in exencephaly fetuses (right) (10x, hematoxylin and eosin). (Source: Oria M, Duru S, Figueira RL, et al. Cell necrosis, intrinsic apoptosis and senescence contribute to the progression of exencephaly to anencephaly in a mice model of congenital chranioschisis. Cell Death Dis 2019;10[10]:721. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normal (left) and exencephalic (right) fetal head in mouse model of congenital cranioschisis. Sagittal section of normal (left) and exencephalic (right) fetal head at embryonic day 17 (4x, hematoxylin and eosin). (Source: Oria M, Duru S, Figueira RL, et al. Cell necrosis, intrinsic apoptosis and senescence contribute to the progression of exencephaly to anencephaly in a mice model of congenital chranioschisis. Cell Death Dis 2019;10[10]:721. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Neural tube defect rates per 10,000 population, by race/ethnicity and fortification period status. Data from 25 population-based birth defect programs. In 1996, Food and Drug Administration established regulations requiring fortification with 140 μg folic acid/100 g of all standardized enriched cereal grain products sold in the United States by 1998. In 1998, mandatory fortification took effect. (Source: Centers for Disease Control and Prevention 2010. Public domain.)

Prevalence of neural tube defects (anencephaly and spina bifida) before and after mandatory folic acid fortification, by maternal race/ethnicity--19 population-based birth defect surveillance programs, United States, 1995–2011. (Source: Williams J, Mai CT, Mulinare J, et al. Updated estimates of neural tube defects prevented by mandatory folic acid fortification - United States, 1995-2011. MMWR Morb Mortal Wkly Rep 2015;64[1]:1-5. Public domain.)

(Source: Mathews TJ, Honein MA, Erickson JD. Spina bifida and anencephaly prevalence: United States, 1991-2001. MMWR Recomm Rep 2002;51 [RR-13]:9-11. Public domain.)

(Source: Ssentongo P, Heilbrunn ES, Ssentongo AE, Ssenyonga LVN, Lekoubou A. Birth prevalence of neural tube defects in eastern Africa: a systematic review and meta-analysis. BMC Neurol 2022;22[1]:202. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ssentongo P, Heilbrunn ES, Ssentongo AE, Ssenyonga LVN, Lekoubou A. Birth prevalence of neural tube defects in Eastern Africa: a systematic review and meta-analysis. BMC Neurol 2022;22[1]:202. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ssentongo P, Heilbrunn ES, Ssentongo AE, Ssenyonga LVN, Lekoubou A. Birth prevalence of neural tube defects in eastern Africa: a systematic review and meta-analysis. BMC Neurol 2022;22[1]:202. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ssentongo P, Heilbrunn ES, Ssentongo AE, Ssenyonga LVN, Lekoubou A. Birth prevalence of neural tube defects in eastern Africa: a systematic review and meta-analysis. BMC Neurol 2022;22[1]:202. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ssentongo P, Heilbrunn ES, Ssentongo AE, Ssenyonga LVN, Lekoubou A. Birth prevalence of neural tube defects in eastern Africa: a systematic review and meta-analysis. BMC Neurol 2022;22[1]:202. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Autopsy imaging with radiography demonstrating complete rachischisis (white arrowheads), the single lower limb containing two femora and two tibiae (white dashed arrows), and some metatarsals and phalanges (white open arrowhead). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Macroscopic view of the aborted fetus showing absence of the right upper limb (white open arrow). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Macroscopic view of the aborted fetus showing craniorachischisis totalis (white arrowheads). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Macroscopic views of the aborted fetus. External examination showed exencephaly/anencephaly (white arrow), fused lower limbs, and nine toes (white dashed arrow). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Three-dimensional HDlive rendered images at 17 weeks of gestation showing findings consistent with sirenomelia: the lower extremities were completely fused, and the feet were fused with the heels, which were immobile (white dashed arrows). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Three-dimensional HDlive rendered images at 17 weeks of gestation showing an extensive spinal cleft in the posterior part of the fetal vertebrae from the upper cervical region to the sacrum (white arrowheads). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Three-dimensional HDlive rendered images at 17 weeks of gestation with deformed and degenerated brain tissues (white arrow), and absence of the right upper limb (white open arrow). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The lower limbs appeared to be fused together in fixed extension with two femora and two tibiae (white dashed arrows). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Two-dimensional ultrasound images at 17 weeks of gestation. Absence of vertebral posterior elements with splaying of the lamina at the thoracic level (white arrowhead). (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Two-dimensional ultrasound images at 17 weeks of gestation showing typical features of exencephaly (“Mickey Mouse” sign; white arrows). The calvarium is absent, and the brain is “floating” in the amniotic fluid. (Source: Sugiura T, Sato Y, Nakanami N, Tsukimori K. Prenatal sonographic image of sirenomelia with anencephaly and craniorachischisis totalis. Case Rep Obstet Gynecol 2018;2018:7058253. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dystroglycan is a transmembrane protein connecting the cell to extracellular ligands, such as laminin. Alpha- and beta-dystroglycan (DG) are shown in purple. The site of action of each glycosyltransferase mutated in dystroglycanopathies is indicated at the respective bonds on the functional glycan. Abbreviations: Man= mannose, GlcNac=N-acetylglucosamine, GalNac=N-acetylgalactosamine, Gal=galactose, RboP=ribitol phosphate, Xyl=xylose, GlcA=glucuronic acid. (The figure was partially created with BioRender. Contributed by Dr. Maria Chiara Manzini.)

The upper panel of the schematic shows all pathogenic variants in patients in whom a congenital myasthenic syndrome was the main feature, whereas the mutations in the lower panel are the pathogenic variants in patients diagnosed with D/L-2-HGA. (Source: Li W, Zhang M, Zhang L, et al. A case report of an intermediate phenotype between congenital myasthenic syndrome and D-2- and L-2-hydroxyglutaric aciduria due to novel SLC25A1 variants. BMC Neurol 2020;20[1]:278. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0. The figure has been modified by Dr. Douglas J Lanska.)

The patient had severe ptosis with compensatory over-activation of the frontalis muscle as well as mild facial weakness. This is case 1 from family 3. (Source: Balaraju S, Töpf A, McMacken G, et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet 2020;28[3]:373-7. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The patient had ptosis and mild facial weakness. This is case 2 from family 2. (Source: Balaraju S, Töpf A, McMacken G, et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet 2020;28[3]:373-7. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The patient had symmetrical facial weakness and ophthalmoparesis. This is case 1 from family 2. (Source: Balaraju S, Töpf A, McMacken G, et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet 2020;28[3]:373-7. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Guo J, Zhang R, Yang Z, Duan Z, Yin D, Zhou Y. Biological roles and therapeutic applications of IDH2 mutations in human cancer. Front Oncol 2021;11:644857. Creative Commons Attribution License [CC BY].)

Mutation of either IDH1 or IDH2 imparts a "neomorphic enzymatic activity" on the encoded enzymes, resulting in the gain-of-function ability to convert alpha-ketoglutarate (α-KG) into the oncometabolite 2-hydroxyglutarate (2-HG), while simultaneously converting NADPH to NADP+.

Abbreviations: 2-HG, 2-hydroxyglutarate; α-KG, alpha-ketoglutarate; IDH, isocitrate dehydrogenase; NADP+/NADPH nicotinamide adenine dinucleotide phosphate; PDH, pyruvate dehydrogenase.

(Source: Guo J, Zhang R, Yang Z, Duan Z, Yin D, Zhou Y. Biological roles and therapeutic applications of IDH2 mutations in human cancer. Front Oncol 2021;11:644857. Creative Commons Attribution License [CC BY].)

The mitochondrial enzyme D-2 hydroxyglutarate dehydrogenase catalyzes the irreversible oxidation of D-2-hydroxyglutarate; inactivation of this enzyme by mutations causes D-2-hydroxyglutaric aciduria type I. D-2-hydroxyglutarate can be produced from alpha-ketoglutarate by four different enzymes. Hydroxyacid-oxoacid transhydrogenase (HOT) oxidizes 4-hydroxybutyrate using alpha-ketoglutarate as an electron acceptor. 3-P- glycerate dehydrogenase, an enzyme involved in the serine synthesis pathway (not shown), has side activity on alpha-ketoglutarate due to the structural similarity of alpha-ketoglutarate with the normal product of this enzyme (ie, 3-phosphohydroxypyruvate). Mutated forms of IDH2 in D-2-hydroxyglutaric aciduria type II and mutated forms of IDH1 and IDH2 in glioblastomas and various other cancers efficiently catalyze the reduction of alpha-ketoglutarate to D-2-hydroxyglutarate; in this situation, the metabolic capacity of D-2-hydroxyglutarate dehydrogenase is exceeded, and D-2-hydroxyglutarate accumulates. (Source: Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. J Inherit Metab Dis 2020;43[1]:14-24. Creative Commons Attribution License.)

The predicted structure of the protein L2HGDH in cartoon (a) and surface mode (b). The mutation site 136 of the protein (shown in red spheres) is located in the pocket (shown in a black ellipse) of the FAD/NAD(P)-binding domain (highlighted in orange). (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MRI in the index case of a Chinese family with L-2-hydroxyglutaric aciduria showed symmetrical, high-signal changes in the cerebellar dentate nuclei, and the right cerebellar hemisphere and vermis showed dysplasia. (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MR images in the index case of a Chinese family with L-2-hydroxyglutaric aciduria revealed symmetrical, high-signal changes in the subcortical white matter and basal ganglia, and the lateral ventricular wall showed multiple nodular, gray-matter heterotopia. (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MR images in the index case of a Chinese family with L-2-hydroxyglutaric aciduria revealed symmetrical, high-signal changes in the subcortical white matter and basal ganglia, and the lateral ventricular wall showed multiple nodular, gray-matter heterotopia. (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The computationally predicted L2HGDH c.178G>A mutation is indicated by the black circle. (Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

EEG in case VI:4 shows epileptiform changes. (Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MRI in case VI:4 shows diffuse hyperintense signal abnormality in the subcortical white matter and bilateral symmetrical T2 hyperintense signals in bilateral basal ganglia. (Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

In mutated L2HGDH, interacting sites within the FAD domain are lost due to the resulting frameshift and protein truncation. However, the mutant enzyme predictably showed interaction with its substrate at different positions (ie, Arg-42, Cys-38, Gly-40, and Cys-27) through conventional hydrogen bonds and at Gly-28 through a carbon-hydrogen bond. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

Interaction studies for L2HGDH and its substrate L-2-hydroxyglutarate predicted five amino acids (ie, Gln-89, Tyr-195, Val-404, Ala-402, and Gly-403) of wild-type L2HGDH are involved in the interaction with its substrate via conventional hydrogen bonding. All these binding sites are within the FAD-dependent enzyme domain. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

Key: (a) Normal L2HGDH protein model; (b) mutant L2HGDH protein model; (c) superimposed structure. Due to misfolding the 3D structures of wild type and mutated L2HGDH failed to overlap when superimposed, confirming that the identified frameshift mutation results in structural distortion of L2HGDH. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The images show extensive white matter abnormalities. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

Pedigree analysis shows an autosomal recessive mode of disease segregation. The genotype status is represented as -/- (homozygous deletion) or -/G (heterozygous carrier). (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

The scheme shows how L-2-hydroxyglutarate is formed and degraded. It also shows the initial steps of the major lysine catabolic pathway (via saccharopine) present in mammalian tissues and of the minor pathway (via L-pipecolate) present in brain and the inhibition exerted by L-2-hydroxyglutarate. (1) Lysine-alpha-ketoglutarate reductase; (2) Saccharopine dehydrogenase; (3) alpha-aminoadipate semialdehyde dehydrogenase; (4) alpha-aminoadipate transaminase; (5) imine reductase; (6) L-pipecolate oxidase. (Source: Rzem R, Achouri Y, Marbaix E, et al. A mouse model of L-2-hydroxyglutaric aciduria, a disorder of metabolite repair. PloS One 2015;10[3]: e0119540. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Public domain.)

Mutations inactivating metabolite repair enzymes lead to various diseases. An example is L-2-hydroxyglutaric aciduria in which mutations in L-2-hydroxyglutarate dehydrogenase prevent the conversion of toxic L-2 hydroxy-glutarate to alpha-ketoglutarate, ultimately resulting in leukoencephalopathy. (Source: Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. J Inherit Metab Dis 2020;43[1]:14-24. Creative Commons Attribution License.)

2-Hydroxyglutarate (2-HG) derives from the promiscuity of lactate dehydrogenase A (LDHA), malate dehydrogenase 1 (MDH1), and PHGDH in the cytoplasm and malate dehydrogenase 2 (MDH2) in the mitochondria. Mutations of IDH1 and IDH2 endow them with neomorphic enzyme activity to convert alpha-KG to D-2HG (Dang et al 2009; Ward et al 2010; Showalter et al 2017; Du and Hu 2021). L-2HG and D-2HG are removed from the mitochondria by L2HGDH and D2HGDH, respectively. Abbreviations: D-2HG, D-2-hydroxyglutarate; D2HGDH, D-2-hydroxyglutarate dehydrogenase; FAD/FADH2, flavin adenine dinucleotide; 2-HG, 2-hydroxyglutarate; IDH, isocitrate dehydrogenase; L-2HG, L-2-hydroxyglutarate; L2HGDH, L-2-hydroxyglutarate dehydrogenase; LDHA, lactate dehydrogenase A; MDH, malate dehydrogenase; NAD+/NADH, nicotinamide adenine dinucleotide ; NADP+/NADPH, nicotinamide adenine dinucleotide phosphate; PHGDH, phosphoglycerate dehydrogenase.

References cited:
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462(7274):739-44.
Du X, Hu H. The roles of 2-hydroxyglutarate. Front Cell Dev Biol 2021;9:651317.
Showalter MR, Hatakeyama J, Cajka T, et al. Replication study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Elife 2017;6:e26030.
Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010;17(3):225-34.

(Source: Du X, Hu H. The roles of 2-hydroxyglutarate. Front Cell Dev Biol 2021;9:651317. Creative Commons Attribution License [CC BY].)

Many enzymes catalyze side reactions leading to the production of abnormal metabolites. These metabolites may be toxic (eg, if they inhibit other enzymes). Fortunately, under normal circumstances, these abnormal metabolites are generally destroyed by metabolite repair enzymes and so become unable to exert toxic effects. (Source: Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. J Inherit Metab Dis 2020;43[1]:14-24. Creative Commons Attribution License.)

(Public domain.)

(Public domain.)

(Public domain.)

Scan performed using the transabdominal probe in 2D rendering in a 20-year-old gravida 1, para 0 woman at 25 weeks gestational age. Ultrasound diagnosis was anencephaly, confirmed at autopsy. Coronal cross-section. Cranial sonographic findings: "frog eyes." Amniotic fluid slightly echogenic. Yellow arrows: degenerated brain structures. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 3D rendering in a 25-year-old gravida 1, para 0 woman at 16 weeks gestational age with cytomegalovirus infection. Ultrasound diagnosis was anencephaly, confirmed at autopsy. Sagittal cross-section. Cranial sonographic findings: "frog eyes." Amniotic fluid slightly echogenic. Yellow arrows: degenerated brain structures. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 2D rendering in a 25-year-old gravida 1, para 0 woman at 16 weeks gestational age with cytomegalovirus infection. Ultrasound diagnosis was anencephaly, confirmed at autopsy. Coronal cross-section. Cranial sonographic findings: "frog eyes." Amniotic fluid slightly echogenic. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transvaginal probe in 2D rendering in a 24-year-old gravida 2, para 1 woman at 16 weeks gestational age. Ultrasound diagnosis was exencephaly, confirmed at autopsy. Sagittal cross-section. Cranial sonographic findings: disorganized brain tissue. Amniotic fluid anechoic. Yellow arrows: brain structures divided into lobes with uneven external contour. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 2D rendering in a 29-year-old gravida 3, para 1 woman at 12 weeks gestational age. Ultrasound diagnosis was exencephaly, confirmed at autopsy. Sagittal cross-section. Cranial sonographic findings: disorganized brain tissue. Amniotic fluid anechoic. Yellow arrows: brain structures divided into lobes with uneven external contour. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transvaginal probe in 2D rendering in a 22-year-old gravida 1, para 0 woman at 13 weeks gestational age. Ultrasound diagnosis was exencephaly, confirmed at autopsy. Sagittal cross-section. Cranial sonographic findings: disorganized brain tissue. Amniotic fluid anechoic. Yellow arrows: brain structures divided into lobes with uneven external contour. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transvaginal probe in 2D rendering in a 21-year-old gravida 1, para 0 woman at 13 weeks gestational age. Ultrasound diagnosis was acrania, confirmed at autopsy. Coronal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transvaginal probe in 3D rendering in a 21-year-old gravida 1, para 0 woman at 13 weeks gestational age. Ultrasound diagnosis was acrania, confirmed at autopsy. Sagittal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transvaginal probe in 2D rendering in a 21-year-old gravida 1, para 0 woman at 13 weeks gestational age. Ultrasound diagnosis was acrania, confirmed at autopsy. Sagittal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 3D rendering in a 30-year-old gravida 3, para 0 woman with diabetes at 13 weeks gestational age. Ultrasound diagnosis was acrania, but autopsy at 32 weeks showed anencephaly. Sagittal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 2D rendering in a 30-year-old gravida 3, para 0 woman with diabetes at 13 weeks gestational age. Ultrasound diagnosis was acrania, but autopsy at 32 weeks showed anencephaly. Sagittal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 3D rendering in a 25-year-old gravida 1, para 0 woman with prior Cesarean section at 13 weeks gestational age with cytomegalovirus infection. Ultrasound diagnosis was acrania, confirmed at autopsy. Sagittal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 2D rendering in a 25-year-old gravida 1, para 0 woman with prior Cesarean section at 13 weeks gestational age with cytomegalovirus infection. Ultrasound diagnosis was acrania, confirmed at autopsy. Sagittal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 2D rendering in a 37-year-old gravida 4, para 2 woman with prior Cesarean section at 13 weeks gestational age. Ultrasound diagnosis was acrania, confirmed at autopsy. Sagittal cross-section. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Scan performed using the transabdominal probe in 2D rendering in a 35-year-old gravida 3, para 1 woman at 12 weeks gestational age. Sagittal cross-section. Ultrasound diagnosis was acrania, confirmed at autopsy. Amniotic fluid anechoic. Yellow arrows: brain structures covered with rippling thin membrane similar to meninges--the “beret” sign. Blue arrows: orbits. Red arrows: bone edge on the border of calvarium defect. (Source: Szkodziak P, Krzyżanowski J, Krzyżanowski A, et al. The role of the "beret" sign and other markers in ultrasound diagnostic of the acrania-exencephaly-anencephaly sequence stages. Arch Gynecol Obstet 2020;302[3]:619-28. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

(Source: Shrestha HK, Koirala S, Shrestha I. Misoprostol induced expulsion of fetus following diagnosis of anencephaly on ultrasound: a case report. JNMA J Nepal Med Assoc 2021;59[236]:396-8. Creative Commons Attribution 4.0 International License, (http://creativecommons.org/licenses/by/4.0.)

(Source: Shrestha HK, Koirala S, Shrestha I. Misoprostol induced expulsion of fetus following diagnosis of anencephaly on ultrasound: a case report. JNMA J Nepal Med Assoc 2021;59[236]:396-8. Creative Commons Attribution 4.0 International License, (http://creativecommons.org/licenses/by/4.0.)

Fetus from about 8 months weighing 1750 g with facial cleft and frontal encephalocele, abdominal cleft, hepatic ectopia, and amniotic bands. Front view. (a) Encephalocele. (b) Rudimentary ala of the nose. (c) Wedge-shaped piece of soft tissue that fills the visible left palatal cleft. (d) Abdominoschisis. (f) Amniotic band or thread extending from the ulnar aspect of the left wrist to the left heel and placenta amnion. (e) A free strand or band. (g) Feto-fetal ribbon. (h) Amniotic membranes and shreds. (Source: Küstner O. Anomalien des Fötus. In: Die vom Fötus abhängenden Schwangerschafts- und Geburtsstörungen. Handbuch der Geburtshülfe 1888;2:497-815.)

Buhl's fetus with amniotic threads. Fetus from about the 5th month of pregnancy, 21 cm long. The ligament (d) connecting the head at the facial cleft of the placenta is 5 cm long, 112 cm wide. The fetus has lain dead in the uterus for a long time and was in a mummified-lipoid-degenerated state. (b) Atrophied left eye. (c) Encephalocele. (Source: Küstner O. Anomalien des Fötus. In: Die vom Fötus abhängenden Schwangerschafts- und Geburtsstörungen. Handbuch der Geburtshülfe 1888;2:497-815.)

(Source: Tantbirojn P, Taweevisit M, Sritippayawan S, Uerpairojkit B. Diabetic fetopathy associated with bilateral adrenal hyperplasia and ambiguous genitalia: a case report. J Med Case Rep 2008;2:251. Creative Commons Attribution 2.0 Generic License, https://creativecommons.org/licenses/by/2.0/deed.en.)

(Left) The three-vesicle stage comprised, from rostral to causal, of the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). (Right) The five-vesicle stage, in which the prosencephalon has divided into a cleaved telencephalon and the diencephalon. (Source: Nrets. Creative Commons Attribution-Share Alike 2.5 Generic License, https://creativecommons.org/licenses/by-sa/2.5/deed.en.)

Compare with iniencephaly. (Source: CDC.)

(Source: Tanriverdi EC, Delibas IB, Kamalak Z, Kadioglu BG, Bender RA. A fetus with iniencephaly delivered at the third trimester. Case Rep Med 2015;2015:520715. Creative Commons Attribution License, http://creativecommons.org/licenses/by/4.0.)

(a) Gross photograph of iniencephaly showing grotesque hyperextension of the head, short spine, and lack of apparent neck (b) typical “star-gazing” appearance. Also note the low-set ears. (Source: Tanriverdi EC, Delibas IB, Kamalak Z, Kadioglu BG, Bender RA. A fetus with iniencephaly delivered at the third trimester. Case Rep Med 2015;2015:520715. Creative Commons Attribution License, http://creativecommons.org/licenses/by/4.0.)

(Source: CDC [CDC–Beijing Medical University collaborative project].)

Diagram showing characteristic features. (Source: CDC [CDC–Beijing Medical University collaborative project].)

Three-dimensional computed tomographic reconstruction of the skeleton. Overview showing normally developed right twin’s cranium and anencephaly in the left twin. Two separate vertebral columns (purple arrow) and three upper (green arrow) and three lower extremities (blue arrow) can be distinguished. Parapagus twins are conjoined twins that lie side by side with ventrolateral fusion. Parapagus dicephalus is a rare form of partial twinning with two heads side by side on one torso. Infants conjoined this way are sometimes called "two-headed babies" in popular media. If carried to term, most dicephalic twins are stillborn or die soon after birth (regardless of whether one is anencephalic, as in this case). (Source: Bovendeert JF, Nievelstein RA, Bleys RL, Cleypool CG. A parapagus dicephalus tripus tribrachius conjoined twin with a unique morphological pattern: a case report. J Med Case Rep 2020;14[1]:176. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Detailed right-sided view of the genitalia showing two penises (black arrow), of which the lower-positioned one is hypoplastic. The right perineal raphe (black arrowhead) can be followed toward the anal opening (white arrowhead). Parapagus twins are conjoined twins that lie side by side with ventrolateral fusion. Parapagus dicephalus is a rare form of partial twinning with two heads side by side on one torso. Infants conjoined this way are sometimes called "two-headed babies" in popular media. If carried to term, most dicephalic twins are stillborn or die soon after birth (regardless of whether one is anencephalic, as in this case). (Source: Bovendeert JF, Nievelstein RA, Bleys RL, Cleypool CG. A parapagus dicephalus tripus tribrachius conjoined twin with a unique morphological pattern: a case report. J Med Case Rep 2020;14[1]:176. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Lateral overview showing oblique positioning of the heads. The gluteal cleft of the left twin (black arrowhead) and the three lower extremities (black arrow) are distinguishable. Parapagus twins are conjoined twins that lie side by side with ventrolateral fusion. Parapagus dicephalus is a rare form of partial twinning with two heads side by side on one torso. Infants conjoined this way are sometimes called "two-headed babies" in popular media. If carried to term, most dicephalic twins are stillborn or die soon after birth (regardless of whether one is anencephalic, as in this case). (Source: Bovendeert JF, Nievelstein RA, Bleys RL, Cleypool CG. A parapagus dicephalus tripus tribrachius conjoined twin with a unique morphological pattern: a case report. J Med Case Rep 2020;14[1]:176. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

"View from above showing the area cerebrovasculosa quite clearly." (Source: Pfaundler M, Schlossmann A, editors. The diseases of children: a work for the practising physician. English translation by Henry LK Shaw and Linnaeus La Fe'tra. Vol 4. Philadelphia and London: JB Lippincott Company, 1908.)

(Source: CDC [CDC–Beijing Medical University collaborative project].)

(Source: CDC [CDC–Beijing Medical University collaborative project].)

(Photograph by Ed Uthman MD on June 17, 2001. Public domain.)

(Photograph by Ed Uthman MD on June 17, 2001. Public domain.)

(Photograph by Ed Uthman MD on June 17, 2001. Public domain.)

(Source: CDC.)

(Photograph by CostaPPPR in 1986. Public domain.)

(Source: CDC. [Latin American Collaborative Study of Congenital Malformations, ECLAMC; CDC–Beijing Medical University collaborative project.])

(Source: CDC. [Latin American Collaborative Study of Congenital Malformations, ECLAMC; CDC–Beijing Medical University collaborative project.])

Wet preparation in the Anatomisches Museum der Universität, Basel, Switzerland. (Photograph by Mattes on October 5, 2012. Creative Commons Attribution 2.0 Germany License, https://creativecommons.org/licenses/by/2.0/de/deed.en.)

Wet preparation in the Anatomical Museum, Baku, Azerbaidzhan. (Photograph by Stanislav Kozlovskiy on October 28, 2013. Creative Commons Attribution-Share Alike 4.0 International License, https://creativecommons.org/licenses/by-sa/4.0/deed.en.)

(Source: CDC. [Latin American Collaborative Study of Congenital Malformations, ECLAMC; CDC–Beijing Medical University collaborative project.])

(Source: CDC.)

Stillborn. Although this was considered "anencephalia," fetal brain tissue appears to be present without an overlying calvarium. Therefore, this should be considered exencephaly. (Source: Pfaundler M, Schlossmann A, editors. The diseases of children: a work for the practising physician. English translation by Henry LK Shaw and Linnaeus La Fe'tra. Vol 4. Philadelphia and London: JB Lippincott Company, 1908.)

(Source: Source: Kaufmann E. Lehrbuch der speziellen pathologischen anatomie für studierende und arzte. Berlin: Druck und Verlag von Georg Reimer, 1907.)

(Source: Ziegler E. Lehrbuch der allgemeinen und speciellen pathologischen anatomie und pathogenese. Jena: G Fischer, 1889.)

Photograph of "anencephalia." (Source: McFarland J. A text-book of pathology for practitioners and students. Second edition. Philadelphia and London: WB Saunders Co, 1910.)

"Craniorachischisis with total deficiency of the brain and spinal cord. The skull is covered with ragged membranous masses, the open spinal cord groove is covered with a tender skin (pia mater). A few whitish streaks can be seen under the skin in the lowest part of the spinal cord. Kypholordotic curvature and shortening of the spine." (Source: Ziegler E. Lehrbuch der allgemeinen und speciellen pathologischen anatomie und pathogenese. Jena: G Fischer, 1889.)

"Acrania and rachischisis in the cervical cord; immature newborn." (Source: Kaufmann E Lehrbuch der speziellen pathologischen Anatomie für Studierende und Ärzte. Berlin : Druck und Verlag von Georg Reimer, 1907.)

(Source: Ziegler E. Lehrbuch der allgemeinen und speciellen pathologischen Anatomie und Pathogenese. Jena: G Fischer, 1889.)

(Source: Photograph by Dr.sachin23 on December 29, 2011. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)

(Source: Küstner O. Anomalien des Fötus. In: Die vom Fötus abhängenden Schwangerschafts- und Geburtsstörungen. Handbuch der Geburtshülfe 1888;2:497-815.)

Axial MRI in 6-year-old girl with severe congenital microcephaly shows bilateral colpocephaly (corpus callosum present). Genetic diagnosis: primordial microcephalic dwarfism with confirmed COL6A3 mutation. (Contributed by Dr. Laura Flores-Sarnat.)

Midsagittal image shows hypoplasia of the cerebellar vermis and ventral pons with characteristic brainstem kink. (Contributed by Dr. Peter Barth.)

T1-weighted inversion recovery MRI of a 4-month-old male with severe hydrocephalus due to Walker-Warburg syndrome. In this section, the border between cortex and adjacent white matter is irregular because of the irregular structure of the neocortex, a characteristic of cobblestone malformation. (Contributed by Dr. Peter Barth.)

Face of a 10-year-old boy with a lightly pigmented epidermal nevus and a lipomatous mass on the right side of the face; he has right hemimegalencephaly and intellectual disability with left hemiparesis and left-sided epilepsia partialis continua. This case is an example of Heide's syndrome. (Contributed by Dr. Laura Flores-Sarnat.)

Paraffin transverse sections stained with hematoxylin-eosin show normal muscle architecture, no connective tissue proliferation, necrosis, or regeneration, and two populations of fibers by size. Magnification of A is x100, and magnification of B is x250. (Contributed by Dr. Harvey Sarnat.)

The enzyme hydroxyacid-oxoacid transhydrogenase (HOT) (B) oxidizes gamma-hydroxybutyric acid, a potentially toxic metabolite, to succinic semialdehyde, simultaneously reducing 2-ketoglutaric acid to D-2-OH glutaric acid. Accumulation of D-2-OH-glutaric acid due to this interconversion is normally balanced by D-2-hydroxyglutarate dehydrogenase (A). A block in A by D-2-hydroxyglutarate dehydrogenase deficiency shifts the equilibrium in B causing an accumulation of D-2-OH-glutaric acid as well as succinic semialdehyde. The latter in turn causes an increase in GABA. In D-2-hydroxyglutaric aciduria type II, there is no block at A, but accumulation of D-2-OH-glutaric acid arises from excess production due to a molecular change in mitochondrial isocitric dehydrogenase. (Adapted from: Struys EA, Verhoeven NM, Ten Brink HJ, et al. Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias. J Inherit Metab Dis 2005c;28(6):921-30.)

In this metabolic scheme illustrating the normal role of L-2-hydroxyglutarate dehydrogenase, L-malate dehydrogenase interconverts the citric acid intermediates oxaloacetate and L-malate using NADH/NAD+. L-malate dehydrogenase also converts alpha-ketoglutarate to L-2-OH-glutarate, but the reaction equilibrium is shifted towards L-2-OH-glutarate. Therefore, another enzyme, L-2-OH-glutarate dehydrogenase, is needed to convert L-2-OH-glutarate back to alpha-ketoglutarate and prevent toxic accumulation of L-2-OH-glutarate. (Adapted from: Rzem R, Veiga-da-Cunha M, Noel G, et al. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci U S A 2004;101(48):16849-54.)