Prenatal and foetal autopsy findings in glutaric aciduria type II.
ETFDH gene
foetal autopsy
glutaric aciduria type II
perinatal findings
Journal
Birth defects research
ISSN: 2472-1727
Titre abrégé: Birth Defects Res
Pays: United States
ID NLM: 101701004
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
07
07
2020
revised:
12
08
2020
accepted:
02
09
2020
pubmed:
23
9
2020
medline:
19
8
2021
entrez:
22
9
2020
Statut:
ppublish
Résumé
Glutaric aciduria type 2 is a rare, lethal disorder that affects metabolism of fatty acids caused by genetic defects in electron transfer (ETF) or in electron transfer flavoprotein dehydrogenase (ETFDH). We aimed to describe the pathological findings of 15 week old foetus, born from a consanguineous couple with 3 previous perinatal deaths. The last son died at 4 days of life and genetic analyses revealed a novel probably pathogenic variant at ETFDH (c.706dupG + c.706dupG) that codifies for a truncated protein (p.Glu236Glyfs*5 + p.Glu236Glyfs*5). During the gestation, due to the medical familial history, prenatal echography and a chorial biopsy for ETFDH-associated glutaric aciduria analysis were carried out. Sanger sequencing confirmed the presence of the homozygous familial variant in the ETFDH gene. The gestation was terminated and the foetal autopsy performed. Autopsy revealed prominent forehead, flat nasal bridge, malformed ears, intrauterine growth retardation, polycystic kidneys and steatosis in the liver, consistent with the diagnosis of glutaric aciduria type II. The comparison of present cases with the previously reported in the literature confirmed the presence of classical criteria, but also revealed the association with urogenital deformities, not previously stated. Clinical and foetal findings allowed the characterisation of the novel variant (c.706dupG at ETDFH) as pathogenic. Genotype-phenotype relationship is important when studying rare genetic disorders such as glutaric aciduria type II, as variants are usually family-specific, leading to a difficulty in the characterisation of their pathogenicity.
Sections du résumé
BACKGROUND
Glutaric aciduria type 2 is a rare, lethal disorder that affects metabolism of fatty acids caused by genetic defects in electron transfer (ETF) or in electron transfer flavoprotein dehydrogenase (ETFDH). We aimed to describe the pathological findings of 15 week old foetus, born from a consanguineous couple with 3 previous perinatal deaths. The last son died at 4 days of life and genetic analyses revealed a novel probably pathogenic variant at ETFDH (c.706dupG + c.706dupG) that codifies for a truncated protein (p.Glu236Glyfs*5 + p.Glu236Glyfs*5).
CASE
During the gestation, due to the medical familial history, prenatal echography and a chorial biopsy for ETFDH-associated glutaric aciduria analysis were carried out. Sanger sequencing confirmed the presence of the homozygous familial variant in the ETFDH gene. The gestation was terminated and the foetal autopsy performed. Autopsy revealed prominent forehead, flat nasal bridge, malformed ears, intrauterine growth retardation, polycystic kidneys and steatosis in the liver, consistent with the diagnosis of glutaric aciduria type II. The comparison of present cases with the previously reported in the literature confirmed the presence of classical criteria, but also revealed the association with urogenital deformities, not previously stated.
CONCLUSIONS
Clinical and foetal findings allowed the characterisation of the novel variant (c.706dupG at ETDFH) as pathogenic. Genotype-phenotype relationship is important when studying rare genetic disorders such as glutaric aciduria type II, as variants are usually family-specific, leading to a difficulty in the characterisation of their pathogenicity.
Substances chimiques
Electron-Transferring Flavoproteins
0
Iron-Sulfur Proteins
0
Oxidoreductases Acting on CH-NH Group Donors
EC 1.5.-
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1738-1749Informations de copyright
© 2020 Wiley Periodicals LLC.
Références
Ando, H. (2010). Embryology of the biliary tract. Digestive Surgery, 27(2), 87-89. http://doi.org/10.1159/000286463
Archie, J. G., Collins, J. S., & Lebel, R. R. (2006). Quantitative standards for fetal and neonatal autopsy. American Journal of Clinical Pathology, 126(2), 255-265. http://doi.org/10.1309/FK9D5WBA1UEPT5BB
Banta-Wright, S. A., & Steiner, R. D. (2003). Not so rare: Errors of metabolism during the neonatal period. Newborn and Infant Nursing Reviews, 3(4), 143-155. http://doi.org/10.1053/S1527-3369(03)00116-8
Bellomo-Brandao, M. A., Escanhoela, C. A. F., Meirelles, L. R., Porta, G., & Hessel, G. (2009). Analysis of the histologic features in the differential diagnosis of intrahepatic neonatal cholestasis. World Journal of Gastroenterology, 15(4), 478-483. http://doi.org/10.3748/wjg.15.478
Bennett, M. J., Curnock, D. A., Engel, P. C., Shaw, L., Gray, R. G. F., Hull, D., … Pollitt, R. J. (1984). Glutaric aciduria type II: biochemical investigation and treatment of a child diagnosed prenatally. Journal of Inherited Metabolic Disease, 7(2), 57-61. http://doi.org/10.1007/bf01805802
Bennett, M. J., Pollitt, R. J., Land, J. M., Turner, M. J., & Cheetham, C. H. (1987). Lethal multiple acyl-CoA dehydrogenation deficiency with dysmorphic features. Journal of Inherited Metabolic Disease, 10(1), 95-96. http://doi.org/10.1007/bf01799495
Berry, G. T., Yudkoff, M., & Segai, S. (1988). Isovaleric acidemia: Medical and neurodevelopmental effects of long-term therapy. The Journal of Pediatrics, 113(1), 58-64. http://doi.org/10.1016/S0022-3476(88)80528-6
Böhm, N., Uy, J., Kiessling, M., & Lehnert, W. (1982). Multiple Acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. European Journal of Pediatrics, 139(1), 60-65. http://dx.doi.org/10.1007/bf00442082.
Burton, B. K. (1998). Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. Pediatrics, 102(6), e69-e69. http://doi.org/10.1542/peds.102.6.e69
Chalmers, R. A., Tracey, B. M., King, G. S., Pettit, B., Rocchiccioli, F., Saudubray, J. M., … Lindenbaum, R. H. (1985). The prenatal diagnosis of glutaric aciduria type II, using quantitative GC-MS. Journal of Inherited Metabolic Disease, 8(S2), 145-146. http://doi.org/10.1007/BF01811501
Colevas, A. D., Edwards, J. L., Hruban, R. H., Mitchell, G. A., Valle, D., & Hutchins, G. M. (1988). Glutaric acidemia type II. Comparison of pathologic features in two infants. Archives of Pathology & Laboratory Medicine, 112(11), 1133-1139.
Coude, F. X., Ogier, H., Charpentier, C., Thomassin, G., Checoury, A., Amedee-Manesme, O., … Frezal, J. (1981). Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder. Human Genetics, 59(3), 263-265. http://doi.org/10.1007/bf00283677
De Paepe, M. E., Friedman, R. M., Gundogan, F., & Pinar, H. (2005). Postmortem lung weight/body weight standards for term and preterm infants. Pediatric Pulmonology, 40(5), 445-448. http://doi.org/10.1002/ppul.20218
Distelmaier, F., Vogel, M., Spiekerkötter, U., Gempel, K., Klee, D., Braunstein, S., … Schwahn, B. (2007). Cystic renal dysplasia as a leading sign of inherited metabolic disease. Pediatric Nephrology, 22(12), 2119-2124. http://doi.org/10.1007/s00467-007-0536-9
Domizio, S., Romanelli, A., Brindisino, P., Puglielli, C., Conte, E., Domizio, R., … Sabatino, G. (2005). Glutaric aciduria type II: a case report. International Journal of Immunopathology and Pharmacology, 18(4), 805-808. http://doi.org/10.1177/039463200501800425
Dusheiko, G., Kew, M. C., Joffe, B. I., Lewin, J. R., Mantagos, S., & Tanaka, K. (1979). Recurrent hypoglycemia associated with glutaric aciduria type II in an adult. The New England Journal of Medicine, 301(26), 1405-1409. http://doi.org/10.1056/NEJM197912273012601
Ernst, L. M. (2015). A pathologist’s perspective on the perinatal autopsy. Seminars in Perinatology, 39(1), 55-63. http://doi.org/10.1053/j.semperi.2014.10.008
Goodman, S. I., McCabe, E. R., Fennessey, P. V., & Mace, J. W. (1980). Multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II) with transient hypersarcosinemia and sarcosinuria; possible inherited deficiency of an electron transfer flavoprotein. Pediatric Research, 14(1), 12-17. http://doi.org/10.1203/00006450-198001000-00004
Goodman, S. I., Reale, M., & Berlow, S. (1983). Glutaric acidemia type II: a form with deleterious intrauterine effects. The Journal of Pediatrics, 102(3), 411-413. http://doi.org/10.1016/s0022-3476(83)80665-9
Goodman, S. I., Stene, D. O., McCabe, E. R. B., Norenberg, M. D., Shikes, R. H., Stumpf, D. A., & Blackburn, G. K. (1982). Glutaric acidemia type II: Clinical, biochemical, and morphologic considerations. The Journal of Pediatrics, 100(6), 946-950. http://doi.org/10.1016/S0022-3476(82)80525-8
Grünert, S. C. (2014). Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet Journal of Rare Diseases, 9(1), 1-8. http://doi.org/10.1186/s13023-014-0117-5
Hackl, A., Mehler, K., Gottschalk, I., Vierzig, A., Eydam, M., Hauke, J., … Habbig, S. (2017). Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease-different clinical entities and comparable perinatal renal abnormalities. Pediatric Nephrology (Berlin, Germany), 32(5), 791-800. http://doi.org/10.1007/s00467-016-3556-5
Harkin, J. C., Gill, W. L., & Shapira, E. (1986). Glutaric acidemia type II. Phenotypic findings and ultrastructural studies of brain and kidney. Archives of Pathology & Laboratory Medicine, 110(5), 399-401.
Henderson, H. E., Balla, R., de Jong, G., Piek, C. J., Mienie, L. J., & Erasmus, E. (1987). Postnatal and antenatal laboratory diagnosis of glutaric aciduria II in a South African family. South African Medical Journal = Suid-Afrikaanse Tydskrif Vir Geneeskunde, 71(9), 589-591.
Jacques, T. S., & Harding, B. N. (2018). Metabolic and neurodegenerative diseases of childhood. In S. Love, A. Perry, J. Ironside, & H. Budka (Eds.), Greenfield’s Neuropathology - Two Volume Set (p. 427). London: CRC Press. http://doi.org/10.1201/9781315382715
Kamiya, M., Eimoto, T., Kishimoto, H., Tsudzuki, T., Morishita, H., Wada, Y., & Masroor, K. (1990). Glutaric aciduria type II: autopsy study of a case with electron-transferring flavoprotein dehydrogenase deficiency. Pediatric Pathology, 10(6), 1007-1019. http://dx.doi.org/10.3109/15513819009064735.
KJAERGAARD, S., GRAEM, N., LARSEN, T., & SKOVBY, F. (2009). Recurrent fetal polycystic kidneys associated with glutaric aciduria type II. APMIS, 106(7-12), 1188-1193. http://doi.org/10.1111/j.1699-0463.1998.tb00276.x
Lee, H.-C. H., Lai, C.-K., Siu, T.-S., Yuen, Y.-P., Chan, K.-Y., Chan, A. Y.-W., … Lam, C.-W. (2010). Role of postmortem genetic testing demonstrated in a case of glutaric aciduria type II. Diagnostic Molecular Pathology : The American Journal of Surgical Pathology, Part B, 19(3), 184-186. http://doi.org/10.1097/PDM.0b013e3181c9a8a8
Mantagos, S., Genel, M., & Tanaka, K. (1979). Ethylmalonic-adipic aciduria. in vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases. The Journal of Clinical Investigation, 64(6), 1580-1589. http://doi.org/10.1172/JCI109619
Matsui, S. M., Mahoney, M. J., & Rosenberg, L. E. (1983). The Natural History of the Inherited Methylmalonic Acidemias. New England Journal of Medicine, 308(15), 857-861. http://doi.org/10.1056/NEJM198304143081501
Naga, O. (2015). The Acutely III Child. In O. Naga (Ed.). Pediatric Board Study Guide (pp. 57-63). Switzerland: Springer, Cham. http://link.springer.com/10.1007/978-3-319-10115-6
Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., & Gregersen, N. (2003). Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Human Mutation, 22(1), 12-23. http://doi.org/10.1002/humu.10226
Przyrembel, H., Wendel, U., Becker, K., Bremer, H. J., Bruinvis, L., Ketting, D., & Wadman, S. K. (1976). Glutaric aciduria type II: report on a previously undescribed metabolic disorder. Clinica Chimica Acta; International Journal of Clinical Chemistry, 66(2), 227-239. http://doi.org/10.1016/0009-8981(76)90060-7
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., … Rehm, H. L. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 17(5), 405-423. http://doi.org/10.1038/gim.2015.30
Singla, M., Guzman, G., Griffin, A. J., & Bharati, S. (2008). Cardiomyopathy in multiple acyl-CoA dehydrogenase deficiency: A clinico-pathological correlation and review of literature. Pediatric Cardiology, 29(2), 446-451. http://doi.org/10.1007/s00246-007-9119-6
Slukvin, I. I., Salamat, M. S., & Chandra, S. (2002). Morphologic studies of the placenta and autopsy findings in neonatal-onset glutaric acidemia type II. Pediatric and Developmental Pathology : The Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society, 5(3), 315-321. http://doi.org/10.1007/s10024001-0213-0
Stöckler, S., Radner, H., Karpf, E. F., Hauer, A., & Ebner, F. (1994). Symmetric hypoplasia of the temporal cerebral lobes in an infant with glutaric aciduria type II (multiple acyl-coenzyme A dehydrogenase deficiency). The Journal of Pediatrics, 124(4), 601-604. http://doi.org/10.1016/s0022-3476(05)83142-7
Sweetman, L., Wiliams, J. (2001). Branched chain organic acidurias. In B. Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D., Childs, B., Kinzler, K. W., and Vogelstein (Ed.), The Metabolic and Molecular Bases of Inherited Disease (8th ed., pp. 2125-2164). New York: McGraw-Hill.
Sweetman, L., Nyhan, W. L., Tauner, D. A., Merritt, T. A., & Singh, M. (1980). Glutaric aciduria Type II. The Journal of Pediatrics, 96(6), 1020-1026. http://doi.org/10.101/s0022-3476(80)80629-9
Whitfield, J., Hurst, D., Bennett, M. J., Sherwood, W. G., Hogg, R., & Gonsoulin, W. (1996). Fetal polycystic kidney disease associated with glutaric aciduria type II: an inborn error of energy metabolism. American Journal of Perinatology, 13(3), 131-134. http://doi.org/10.1055/s-2007-994309
Wilson, G. N., de Chadarévian, J. P., Kaplan, P., Loehr, J. P., Frerman, F. E., & Goodman, S. I. (1989). Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. American Journal of Medical Genetics, 32(3), 395-401. http://doi.org/10.1002/ajmg.1320320326
Zhang, Z., Hou, Z., Lin, X., Teng, G., Meng, H., Zang, F., … Liu, S. (2013). Development of the fetal cerebral cortex in the second trimester: assessment with 7T postmortem MR imaging. American Journal of Neuroradiology, 34(7), 1462-1467. http://doi.org/10.3174/ajnr.A3406.