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Antenatal manifestations of inborn errors of metabolism: autopsy findings suggestive of a metabolic disorder

  • SSIEM 2015
  • Published:
Journal of Inherited Metabolic Disease

Abstract

This review highlights the importance of performing an autopsy when faced with fetal abortion or termination of pregnancy with suspicion of an inborn error of metabolism. Radiological, macroscopic and microscopic features found at autopsy as well as placental anomalies that can suggest such a diagnosis are detailed. The following metabolic disorders encountered in fetuses are discussed: lysosomal storage diseases, peroxisomal disorders, cholesterol synthesis disorders, congenital disorders of glycosylation, glycogenosis type IV, mitochondrial respiratory chain disorders, transaldolase deficiency, generalized arterial calcification of infancy, hypophosphatasia, arylsulfatase E deficiency, inborn errors of serine metabolism, asparagine synthetase deficiency, hyperphenylalaninemia, glutaric aciduria type I, non-ketotic hyperglycinemia, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, glutamine synthase deficiency, sulfite oxidase and molybdenum cofactor deficiency.

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Abbreviations

ABCC6:

ATP-binding cassette, subfamily C, member 6

AGPS:

Alkylglycerone phosphate synthase

ALG:

Asparagine-linked glycosylation

CDG:

Congenital disorders of glycosylation

CDPX2:

X-linked dominant chondrodysplasia punctata-2

CHARGE:

Coloboma, heart defects, choanal atresia, retardation, genital and ear anomalies

CHILD:

Congenital hemidysplasia ichtyosis limb defect

COG7:

Component of oligomeric Golgi complex 7

CPT II:

Carnitine palmitoyl transferase 2 deficiency

DGUOK:

Deoxyguanosine kinase

ENPP1:

Ectonucleotide pyrophosphatase/phosphodiesterase 1

GACI:

Generalized arterial calcification of infancy

GNPAT:

Glyceronephosphate acyltransferase

GRACILE:

Growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death

GSDII:

Glycogen storage disorder type II

GSDIV:

Glycogen storage disease type IV

HES:

Hematoxylin eosin saffron

IEM:

Inborn error of metabolism

IUGR:

Intra uterine growth restriction

LSD:

Lysosomal storage disorders

MADD:

Multiple acyl-CoA dehydrogenase deficiency

MPS:

Mucopolysaccharidosis

PAS:

Periodic acid-Schiff

PMM2:

Phosphomannomutase 2

POR:

Cytochrome P450 oxidoreductase

RCDP:

Rhizomelic chondrodysplasia punctata

SLC39A8:

Solute carrier family 39 (zinc transporter), member 8

SLO:

Smith-Lemli-Optiz syndrome

SSIEM:

Society for the study of inborn errors of metabolism

TAZ:

Tafazzin

TOP:

Termination of pregnancy

VACTERL:

Vertebral, anal, cardiac, tracheoesophageal renal and limb anomalies

WG:

Weeks of gestation

References

  • Barkovich AJ, Peck WW (1997) MR of Zellweger syndrome. AJNR Am J Neuroradiol 18:1163–1170

    CAS  PubMed  Google Scholar 

  • Bendon RW, Hug G (1985) Morphologic characteristics of the placenta in glycogen storage disease type II (alpha-1,4-glucosidase deficiency). Am J Obstet Gynecol 152:1021–1026

    Article  CAS  PubMed  Google Scholar 

  • Boemer F, Deberg M, Schoos R et al (2015) Diagnostic pitfall in antenatal manifestations of CPT II deficiency. Clin Genet 89:193–197

    Article  PubMed  Google Scholar 

  • Boulet S, Dieterich K, Althuser M et al (2010) Brachytelephalangic chondrodysplasia punctata: prenatal diagnosis and postnatal outcome. Fetal Diagn Ther 28:186–190

    Article  CAS  PubMed  Google Scholar 

  • Bouvier R, Maire I (1997) Diagnostic des maladies de surcharge lysosomale à révélation foetale. Ann Pathol 17:277–280

    CAS  PubMed  Google Scholar 

  • Bouvier R, Cordier M, Loget P et al (2008) Maladies métaboliques. In: Pathologie foetale et placentaire pratique. Montpellier, France: Sauramps Médical, pp 465–484

  • Brassier A, Ottolenghi C, Boddaert N et al (2012) Prenatal symptoms and diagnosis of inherited metabolic diseases. Arch Pediatr 19:959–969

    Article  CAS  PubMed  Google Scholar 

  • Braverman NE, D’Agostino MD, Maclean GE (2013) Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev 17:187–196

    Article  PubMed  Google Scholar 

  • Burin MG, Scholz AP, Gus R et al (2004) Investigation of lysosomal storage diseases in nonimmune hydrops fetalis. Prenat Diagn 24:653–657

    Article  PubMed  Google Scholar 

  • Chen CP (2008) Syndromes, disorders and maternal risk factors associated with neural tube defects (V). Taiwan J Obstet Gynecol 47:259–266

    Article  PubMed  Google Scholar 

  • Corbacioglu Esmer A, Kalelioglu I, Omeroglu RE et al (2015) Prenatal ultrasonographic diagnosis of generalized arterial calcification of infancy. J Clin Ultrasound 43:50–54

    PubMed  Google Scholar 

  • Cormier-Daire V, Rustin P, Rötig A et al (1996) Craniofacial anomalies and malformations in respiratory chain deficiency. Am J Med Genet 66:457–463

    Article  CAS  PubMed  Google Scholar 

  • Cylwik B, Naklicki M, Chrostek L, Gruszewska E (2013) Congenital disorders of glycosylation. Part I. Defects of protein N-glycosylation. Acta Biochim Pol 60:151–161

    CAS  PubMed  Google Scholar 

  • Damian MS, Seibel P, Schachenmayr W, Reichmann H, Dorndorf W (1996) VACTERL with the mitochondrial NP 3243 point mutation. Am J Med Genet 62:398–403

    Article  CAS  PubMed  Google Scholar 

  • Danks DM, Tippett P, Adams C, Campbell P (1975) Cerebro-hepato-renal syndrome of Zellweger. A report of eight cases with comments upon the incidence, the liver lesion, and a fault in pipecolic acid metabolism. J Pediatr 86:382–387

    Article  CAS  PubMed  Google Scholar 

  • Delezoide AL, M Le Merrer (2008) Pathologie squelettique. In: Pathologie fœtale et placentaire pratique. Montpellier, France: Sauramps Médical, pp 289–321

  • Devisme L, Bouchet C, Gonzalès M, et al (2012) Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain 135:469–482

  • Fellman V, Rapola J, Pihko H, Varilo T, Raivio KO (1998) Iron-overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria. Lancet 351:490–493

  • Froissart R, Cheillan D, Bouvier R et al (2005) Clinical, morphological, and molecular aspects of sialic acid storage disease manifesting in utero. J Med Genet 42:829–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldenberg A, Wolf C, Chevy F et al (2004) Antenatal manifestations of Smith-Lemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases. Am J Med Genet A 124A:423–426

    Article  PubMed  Google Scholar 

  • Gürgey A, Ozalp I, Rötig A et al (1996) A case of Pearson syndrome associated with multiple renal cysts. Pediatr Nephrol 10:637–638

    Article  PubMed  Google Scholar 

  • Häberle J, Görg B, Rutsch F et al (2005) Congenital glutamine deficiency with glutamine synthetase mutations. N Engl J Med 353:1926–1933

    Article  PubMed  Google Scholar 

  • Ho AC, Fung CW, Siu TS et al (2014) Lathosterolosis: a disorder of cholesterol biosynthesis resembling smith-lemli-opitz syndrome. JIMD Rep 12:129–134

    Article  CAS  PubMed  Google Scholar 

  • Illsinger S, Das AM (2010) Impact of selected inborn errors of metabolism on prenatal and neonatal development. IUBMB Life 62:403–413

    CAS  PubMed  Google Scholar 

  • Kelley RI (1983) Review: the cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet 16:503–517

  • Konstantinidou A, Anninos H, Dertinger S et al (2008a) Placental involvement in glycogen storage disease type IV. Placenta 29:378–381

    Article  CAS  PubMed  Google Scholar 

  • Konstantinidou A, Karadimas C, Waterham HR et al (2008b) Pathologic, radiographic and molecular findings in three fetuses diagnosed with HEM/Greenberg skeletal dysplasia. Prenat Diagn 28:309–312

    Article  CAS  PubMed  Google Scholar 

  • Kranz C, Basinger AA, Güçsavaş-Calikoğlu M et al (2007) Expanding spectrum of congenital disorder of glycosylation Ig (CDG-Ig): sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality. Am J Med Genet A 15(143A):1371–1378

    Article  Google Scholar 

  • L’hermine-Coulomb A, Beuzen F, Bouvier R et al (2005) Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family. Am J Med Genet A 139A:118–122

    Article  PubMed  Google Scholar 

  • Labarthe F, Dobbelaere D, Devisme L et al (2005) Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency. J Hepatol 43:333–341

    Article  CAS  PubMed  Google Scholar 

  • Lee RW, Conley SK, Gropman A, Porter FD, Baker EH (2013) Brain magnetic resonance imaging findings in Smith–Lemli–Opitz syndrome. Am J Med Genet A 161A:2407–2419

    PubMed  Google Scholar 

  • Lepais L, Cheillan D, Collardeau-Frachon S et al (2015) ALG3-CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation. Am J Med Genet A 167A:2748–2754

    Article  PubMed  Google Scholar 

  • Léticée N, Bessières-Grattagliano DT et al (2010) Should PMM2-deficiency (CDG Ia) be searched in every case of unexplained hydrops fetalis? Mol Gent Metab 101:253–257

    Article  Google Scholar 

  • Maroteaux P (1989) Brachytelephalangic chondrodysplasia punctata: a possible X-linked recessive form. Hum Genet 82:167–170

    Article  CAS  PubMed  Google Scholar 

  • McGlaughlin KL, Witherow H, Dunaway DJ, David DJ, Anderson PJ (2010) Spectrum of Antley-Bixler syndrome. J Craniofac Surg 21:1560–1564

    Article  PubMed  Google Scholar 

  • Mellerio C, Marignier S, Roth P et al (2008) Prenatal cerebral ultrasound and MRI findings in glutaric aciduria Type 1: a de novo case. Ultrasound Obstet Gynecol 31:712–714

    Article  CAS  PubMed  Google Scholar 

  • Mignot C, Gelot A, De Villemeur TB (2013) Gaucher disease. Handb Clin Neurol 113:1709–1715

    Article  PubMed  Google Scholar 

  • Morava E, Zeevaert R, Korsch E et al (2007) A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation. VSD and episodes of hyperthermia. Eur J Hum Genet 15:638–645

    Article  CAS  PubMed  Google Scholar 

  • Mornet E (2007) Hypophosphatasia. Orphanet J Rare Dis 4(2):40

    Article  Google Scholar 

  • Nitschke Y, Baujat G, Botschen U et al (2012) Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. AmJ HumGenet 90:25–39

    CAS  Google Scholar 

  • Nolte KW, Janecke AR, Vorgerd M, Weis J, Schröder JM (2008) Congenital type IV glycogenosis: the spectrum of pleomorphic polyglucosan bodies in muscle, nerve, and spinal cord with two novel mutations in the GBE1 gene. Acta Neuropathol 116:491–506

    Article  CAS  PubMed  Google Scholar 

  • Park JH, Hogrebe M, Grüneberg M et al (2015) SLC39A8 deficiency: a disorder of manganese transport and glycosylation. Am J Hum Genet 97:894–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Passemard S, Kaindl AM, Verloes A (2013) Microcephaly. Handb Clin Neurol 111:129–141

    Article  PubMed  Google Scholar 

  • Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW (2012) The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 105:34–43

    Article  CAS  PubMed  Google Scholar 

  • Paupe A, Bidat L, Sonigo P, Lenclen R, Molho M, Ville Y (2002) Prenatal diagnosis of hypoplasia of the corpus callosum in association with non-ketotic hyperglycinemia. Ultrasound Obstet Gynecol 20:616–619

    Article  CAS  PubMed  Google Scholar 

  • Peters V, Penzien JM, Reiter G et al (2002) Congenital disorder of glycosylation IId (CDG-IId) – a new entity: clinical presentation with Dandy-Walker malformation and myopathy. Neuropediatrics 33:27–32

    Article  CAS  PubMed  Google Scholar 

  • Poll-The BT, Gärtner J (2012) Clinical diagnosis, biochemical findings and MRI spectrum of peroxisomal disorders. Biochim Biophys Acta 1822:1421–1429

    Article  CAS  PubMed  Google Scholar 

  • Prasad AN, Bunzeluk K, Prasad C, Chodirker BN, Magnus KG, Greenberg CR (2007) Agenesis of the corpus callosum and cerebral anomalies in inborn errors of metabolism. Congenit Anom (Kyoto) 47:125–135

    Article  CAS  Google Scholar 

  • Prick BW, Hop WC, Duvekot JJ (2012) Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr 95:374–382

    Article  CAS  PubMed  Google Scholar 

  • Quelin C, Loget P, Verloes A et al (2012) Phenotypic spectrum of fetal smith–lemli–opitz syndrome. Eur J Med Genet 55:81–90

    Article  PubMed  Google Scholar 

  • Rossi M, Hall CM, Bouvier R et al (2015) Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis. Pediatr Radiol 45:965–976

    Article  PubMed  Google Scholar 

  • Rötig A, Cormier V, Blanche S et al (1990) Pearson’s marrow-pancreas syndrome: a multisystem mitochondrial disorder in infancy. J Clin Invest 1990(86):1601–1608

    Article  Google Scholar 

  • Rutch F, Ruf N, Vaingankar S et al (2003) Mutations in ENNP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34:379–381

    Article  Google Scholar 

  • San Millan B, Teijeira S, Domínguez C, Vieitez I, Navarro C (2010) Chorionic villi ultrastructure in the prenatal diagnosis of glycogenosis type II. J Inherit Metab Dis 33(Suppl 3):S105–S111

    Article  PubMed  Google Scholar 

  • Sarfati R, Hubert A, Dugué-Maréchaud M, Biran-Mucignat V, Pierre F, Bonneau D (2000) Prenatal diagnosis of Gaucher's disease type 2. Ultrasonographic, biochemical and histological aspects. Prenat Diagn 20:340–343

    Article  CAS  PubMed  Google Scholar 

  • Sawyer T, Stacey M, Mulreany M et al (2009) Generalized arterial calcification of infancy associated with meconium peritonitis: a case report and review of the literature. Am J Perinatol 26:711–716

    Article  PubMed  Google Scholar 

  • Sergi C, Himbert U, Weinhardt F et al (2001) Hepatic failure with neonatal tissue siderosis of hemochromatotic type in an infant presenting with meconium ileus. Case report and differential diagnosis of the perinatal iron storage disorders. Pathol Res Pract 197:699–713

  • Shaheen R, Rahbeeni Z, Alhashem A et al (2014) Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH. Am J Hum Genet 94:898–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soma H, Yamada K, Osawa H, Hata T, Oguro T, Kudo M (2000) Identification of Gaucher cells in the chorionic villi associated with recurrent hydrops fetalis. Placenta 21:412–416

    Article  CAS  PubMed  Google Scholar 

  • Spennato P, Mirone G, Nastro A et al (2011) Hydrocephalus in Dandy-Walker malformation. Childs Nerv Syst 27:1665–1681

  • Squier W, Jansen A (2014) Polymicrogyria: pathology, fetal origins and mechanisms. Acta Neuropathol Commun 22(2):80

    Article  Google Scholar 

  • Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E (2009) Lysosomal storage disorders in the newborn. Pediatrics 123:1191–1207

    Article  PubMed  PubMed Central  Google Scholar 

  • Stevenson DA, Steiner RD (2013) Skeletal abnormalities in lysosomal storage diseases. Pediatr Endocrinol Rev 10(Suppl 2):406–416

    PubMed  Google Scholar 

  • Steward CG, Newbury-Ecob RA, Hastings R et al (2010) Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth. Prenat Diagn 30:970–976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thurberg BL, Politei JM (2012) Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature. Hum Pathol 43:610–614

    Article  Google Scholar 

  • Tian L, Zhou Q, Zhou J, Zeng S, Cao D, Zhang M (2015) Ventricular non-compaction cardiomyopathy: prenatal diagnosis and pathology. Prenat Diagn 35:221–227

    Article  PubMed  Google Scholar 

  • Valayannopoulos V, Verhoeven NM, Mention K et al (2006) Transaldolase deficiency: a new cause of hydrops fetalis and neonatal multi-organ disease. J Pediatr 149:713–717

    Article  PubMed  Google Scholar 

  • Val-Bernal JF, Garijo MF, Rodriguez-Villar D, Val D (2010) Non-compaction of the ventricular myocardium: a cardiomyopathy in search of a pathoanatomical definition. Histol Histopathol 25:495–503

    PubMed  Google Scholar 

  • Vianey-Saban C, Bouvier R, Cochat P et al (2000) Antenatal expression of multiple acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 23:345–348

    Article  CAS  PubMed  Google Scholar 

  • von Kleist-Retzow JC, Cormier-Daire V, Viot G et al (2003) Antenatal manifestations of mitochondrial respiratory chain deficiency. J Pediatr 143:208–212

    Article  Google Scholar 

  • Wada N, Matsuishi T, Nonaka M, Naito E, Yoshino M (2004) Pyruvate dehydrogenase E1alpha subunit deficiency in a female patient: evidence of antenatal origin of brain damage and possible etiology of infantile spasms. Brain Dev 26:57–60

  • Waterham HR, Ebberink MS (2012) Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta 1822:1430–1441

    Article  CAS  PubMed  Google Scholar 

  • Whybra C, Mengel E, Russo A et al (2012) Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF): more common than assumed? Report of four cases with transient NIHF and a review of the literature. Orphanet J Rare Dis 7:86

    Article  PubMed  PubMed Central  Google Scholar 

  • Wolman M, Sterk VV, Gatt S, Frenkel M (1961) Primary familial xanthomatosis with involvement and calcification of the adrenals. Pediatrics 28:742–757

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors particularly thank the members of the SOFFOET for providing their autopsy cases of inborn errors of metabolism. We also thank Dr Raymonde Bouvier who was our mentor in pediatric and perinatal pathology with special interests in metabolic disorders.

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Authors and Affiliations

  1. Department of Pathology, Hôpital-Femme-Mère-Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France

    Sophie Collardeau-Frachon

  2. Université Claude Bernard Lyon I, CHU de Lyon, France

    Sophie Collardeau-Frachon & Laurent Guibaud

  3. SOFFOET, Société Française de Fœtopathologie, Lyon, France

    Sophie Collardeau-Frachon

  4. Department of Genetics, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France

    Marie-Pierre Cordier & Massimiliano Rossi

  5. Department of Fetal and Pediatric Imaging, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France

    Laurent Guibaud

  6. Department of Department of Biochemistry, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France

    Christine Vianey-Saban

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  1. Sophie Collardeau-Frachon
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Correspondence to Sophie Collardeau-Frachon.

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Collardeau-Frachon, S., Cordier, MP., Rossi, M. et al. Antenatal manifestations of inborn errors of metabolism: autopsy findings suggestive of a metabolic disorder. J Inherit Metab Dis 39, 597–610 (2016). https://doi.org/10.1007/s10545-016-9937-x

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