Skip to main content
SpringerLink
Log in

Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Introduction

Inborn errors of tetrahydrobiopterin (BH4) biosynthesis or recycling are a group of very rare neurometabolic diseases. Following growing awareness and improved availability of drug treatment the number of patients with BH4 disorders reaching adulthood is constantly increasing. Pregnancy care of patients with these disorders is therefore a new challenge for clinicians.

Methods

This retrospective study summarises for the first time clinical and biochemical monitoring data of 16 pregnancies in seven women with different disorders of BH4 metabolism and evaluates treatment regimens before and during pregnancy in relation to the obstetrical outcome and paediatric follow-up.

Results

Worsening of pre-existing neurological symptoms or occurrence of new symptoms during pregnancy was not observed in most of the cases. Treatment regimens remained mostly unchanged. Pregnancies were not complicated by disease-specific features. Organ abnormalities, miscarriage, prematurity, IUGR and chromosomal changes were occasionally reported, without showing any association with the standard drug treatment for BH4 deficiencies.

Conclusion

Although our data on 16 pregnancies in seven patients did not present any association of standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or paediatric outcome, an intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH4 deficiency is essential since available data on pregnancies in patients with BH4 deficiencies is limited.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

5-HIAA:

5-Hydroxyindolacetic acid

5-HTP:

5-Hydroxytryptophan

MHPG:

3-Methoxy-4-hydroxyphenylglycol

5-MTHF:

5-Methyltetrahydrofolic acid

3-OMD:

3-Orthomethyldopa

PTPS:

6-Pyruvoyl-tetrahydrobiopterin synthase

PTPS-D:

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

ASD:

Atrial septal defect

adGTPCH:

Autosomal dominant guanosine triphosphate cyclohydrolase 1

adGTPCH-D:

Autosomal dominant guanosine triphosphate cyclohydrolase 1 deficiency

arGTPCH:

Autosomal recessive guanosine triphosphate cyclohydrolase 1

arGTPCH-D:

Autosomal recessive guanosine triphosphate cyclohydrolase 1 deficiency

CSF:

Cerebral spinal fluid

CNS:

Central nervous system

DHPR:

Dihydropteridine reductase

DHPR-D:

Dihydropteridine reductase deficiency

DBS:

Dried blood spot

GA:

Gestational age

GW:

Gestational week

HVA:

Homovanillic acid

HPA:

Hyperphenylalaninemia

iNTD:

International Working Group on Neurotransmitter Related Disorders

IUGR:

Intrauterine growth restriction

L-dopa:

Levodopa

LSCS:

Lower segment caesarean section

MPKU:

Maternal phenylketonuria

MPKUS:

Maternal PKU syndrome

NBS:

Newborn screening

NOS:

Nitric oxide synthase

PD:

Parkinson’s disease

Phe:

Phenylalanine

PAH:

Phenylalanine-4-hydroxylase

PKU:

Phenylketonuria

PCD:

Pterin-4 alpha-carbinolamine dehydratase

SR:

Sepiapterin reductase

SR-D:

Sepiapterin reductase deficiency

BH4 :

Tetrahydrobiopterin

TH:

Tyrosine hydroxylase

TPH:

Tryptophan hydroxylase

References

  • Allain H, Bentue-Ferrer D, Milon D, Moran P, Jacquemard F, Defawe G (1989) Pregnancy and parkinsonism. A case report without problem. Clin Neuropharmacol 12(3):217–219

    Article  CAS  PubMed  Google Scholar 

  • American Academy of Pediatrics Committee on Genetics (2008) Policy statement: maternal phenylketonuria. Pediatrics 122:445–449

    Article  Google Scholar 

  • Arai H, Shinotoh H, Hattori T (1997) L-dopa/benserazide during pregnancy in a patient with juvenile parkinsonism. Rinsho Shinkeigaku 37(3):264–265

    CAS  PubMed  Google Scholar 

  • Ball MC, Sagar HJ (1995) Levodopa in pregnancy. Mov Disord 10(1):115

    Article  CAS  PubMed  Google Scholar 

  • Bartholome K (1974) Letter: a new molecular defect in phenylketonuria. Lancet 2(7896):1580

    Article  CAS  PubMed  Google Scholar 

  • Basson CT, Cowley GS, Solomon SD et al (1994) The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 330(13):885–891

    Article  CAS  PubMed  Google Scholar 

  • Beck S, Wojdyla D, Say L et al (2010) The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ 88(1):31–38

    Article  PubMed  Google Scholar 

  • Benbir G, Ertan S, Ozekmekci S (2014) Successful pregnancy and delivery in a patient with Parkinson's disease under pramipexole treatment. Presse Med 43(1):83–85

    Article  PubMed  Google Scholar 

  • Benetello P, Furlanut M, Zara G, Baraldo M, Hassan E (1993) Plasma levels of levodopa and its main metabolites in parkinsonian patients after conventional and controlled-release levodopa-carbidopa associations. Eur Neurol 33(1):69–73

    Article  CAS  PubMed  Google Scholar 

  • Benito-Leon J, Bermejo F, Porta-Etessam J (1999) Pregnancy in Parkinson's disease: a review of the literature and a case report. Mov Disord 14(1):194

    Article  CAS  PubMed  Google Scholar 

  • Blau N, Thöny B, Cotton R, Hyland K (2001) Disorders of tetrahydrobiopterin and related biogenic amines. McGraw-Hill, New York

    Google Scholar 

  • Blau N, van Spronsen FJ (2014) Disorders of phenylalanine and tetrahydrobiopterin metabolism. In: Blau N, Duran M, Dionisi-vici C (eds) Physician's guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. Springer, Heidelberg, pp 3–21

  • Bruggemann N, Spiegler J, Hellenbroich Y et al (2012) Beneficial prenatal levodopa therapy in autosomal recessive guanosine triphosphate cyclohydrolase 1 deficiency. Arch Neurol 69(8):1071–1075

    Article  PubMed  Google Scholar 

  • Brunelli S, Faiella A, Capra V et al (1996) Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 12(1):94–96

    Article  CAS  PubMed  Google Scholar 

  • Capra V, De Marco P, Moroni A et al (1996) Schizencephaly: surgical features and new molecular genetic results. Eur J Pediatr Surg 6(Suppl 1):27–29

    Article  PubMed  Google Scholar 

  • Choi TY, Lee HM, Park WK, Jeong SY, Moon HS (2014) Spontaneous abortion and recurrent miscarriage: a comparison of cytogenetic diagnosis in 250 cases. Obstet Gynecol Sci 57(6):518–525

    Article  PubMed  PubMed Central  Google Scholar 

  • Cook DG, Klawans HL (1985) Levodopa during pregnancy. Clin Neuropharmacol 8(1):93–95

    Article  CAS  PubMed  Google Scholar 

  • Dhondt J-L (2006) Follow-up and outcome of tetrahydrobiopterin deficiencies. In Blau, N PKU and BH4: advances in phenylketonuria and tetrahydrobiopterin. Heilbronn, SPS Verlagsgesellschaft, pp 652–677

  • Dostal M, Weber-Schoendorfer C, Sobesky J, Schaefer C (2013) Pregnancy outcome following use of levodopa, pramipexole, ropinirole, and rotigotine for restless legs syndrome during pregnancy: a case series. Eur J Neurol 20(9):1241–1246

    Article  CAS  PubMed  Google Scholar 

  • Douglas G, Hale AB, Crabtree MJ et al (2015) A requirement for Gch1 and tetrahydrobiopterin in embryonic development. Dev Biol 399(1):129–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feillet F, Muntau AC, Debray FG et al (2014) Use of sapropterin dihydrochloride in maternal phenylketonuria. A European experience of eight cases. J Inherit Metab Dis 37(5):753–762

    Article  CAS  PubMed  Google Scholar 

  • Felix JF, de Jong EM, Torfs CP, de Klein A, Rottier RJ, Tibboel D (2009) Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: an overview of the current concepts. Birth Defects Research Part A: Clin Molec Teratol 85(9):747–754

    Article  CAS  Google Scholar 

  • Fenton TR, Kim JH (2013) A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 13:59

    Article  PubMed  PubMed Central  Google Scholar 

  • Friedman J, Roze E, Abdenur JE et al (2012) Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 71(4):520–530

    Article  CAS  PubMed  Google Scholar 

  • Gershanik OS, Leist A (1987) Juvenile onset Parkinson's disease. Adv Neurol 45:213–216

    CAS  PubMed  Google Scholar 

  • Gizewska M, Hnatyszyn G, Sagan L et al (2009) Maternal tetrahydrobiopterin deficiency: the course of two pregnancies and follow-up of two children in a mother with 6-pyruvoyl-tetrahydropterin synthase deficiency. J Inherit Metab Dis 32(Suppl 1):S83–S89

    Article  PubMed  Google Scholar 

  • Golbe LI (1987) Parkinson's disease and pregnancy. Neurology 37(7):1245–1249

    Article  CAS  PubMed  Google Scholar 

  • Grange DK, Hillman RE, Burton BK et al (2014) Sapropterin dihydrochloride use in pregnant women with phenylketonuria: an interim report of the PKU MOMS sub-registry. Mol Genet Metab 112(1):9–16

    Article  CAS  PubMed  Google Scholar 

  • Hagell P, Odin P, Vinge E (1998) Pregnancy in Parkinson's disease: a review of the literature and a case report. Mov Disord 13(1):34–38

    Article  CAS  PubMed  Google Scholar 

  • Hanley WB, Clarke JT, Schoonheyt W (1987) Maternal phenylketonuria (PKU)--a review. Clin Biochem 20(3):149–156

    Article  CAS  PubMed  Google Scholar 

  • Howe DT, Rankin J, Draper ES (2012) Schizencephaly prevalence, prenatal diagnosis and clues to etiology: a register-based study. Ultrasound Obstet Gynecol 39(1):75–82

    Article  CAS  PubMed  Google Scholar 

  • Irons M, Levy HL, O'Flynn ME et al (1987) Folinic acid therapy in treatment of dihydropteridine reductase deficiency. J Pediatr 110(1):61–67

    Article  CAS  PubMed  Google Scholar 

  • Jacquemard F, Palaric JC, Allain H, Giraud JR (1990) Parkinson disease and pregnancy. Apropos of a case. J Gynecol Obstet Biol Reprod (Paris) 19(4):461–463

    CAS  Google Scholar 

  • Jaggi L, Zurfluh MR, Schuler A et al (2008) Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab 93(3):295–305

    Article  CAS  PubMed  Google Scholar 

  • Koch R, Moseley K, Guttler F (2005) Tetrahydrobiopterin and maternal PKU. Mol Genet Metab 86(Suppl 1):S139–S141

    Article  CAS  PubMed  Google Scholar 

  • Kranick SM, Mowry EM, Colcher A, Horn S, Golbe LI (2010) Movement disorders and pregnancy: a review of the literature. Mov Disord 25(6):665–671

    Article  PubMed  Google Scholar 

  • Levy HL (2003) Historical background for the maternal PKU syndrome. Pediatrics 112(6 Pt 2):1516–1518

    PubMed  Google Scholar 

  • Mabry CC, Denniston JC, Nelson TL, Son CD (1963) Maternal phenylketonuria. A cause of mental retardation in children without the metabolic defect. N Engl J Med 269:1404–1408

    Article  CAS  PubMed  Google Scholar 

  • McIntyre S, Badawi N, Blair E, Nelson KB (2015) Does aetiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy influence the outcome of treatment? Dev Med Child Neurol 57(Suppl 3):2–7

    Article  PubMed  Google Scholar 

  • Merchant CA, Cohen G, Mytilineou C et al (1995) Human transplacental transfer of carbidopa/levodopa. J Neural Transm Park Dis Dement Sect 9(2–3):239–242

    Article  CAS  PubMed  Google Scholar 

  • Mucchiut M, Belgrado E, Cutuli D, Antonini A, Bergonzi P (2004) Pramipexole-treated Parkinson's disease during pregnancy. Mov Disord 19(9):1114–1115

    Article  PubMed  Google Scholar 

  • Murphy E (2015) Pregnancy in women with inherited metabolic disease. Obstet Med 8(2):61–67

    Article  PubMed  PubMed Central  Google Scholar 

  • Narisawa K, Arai N, Ishizawa S et al (1980) Dihydropteridine reductase deficiency: diagnosis by leukocyte enzyme assay. Clin Chim Acta 105(3):335–342

    Article  CAS  PubMed  Google Scholar 

  • Nassar N, Leoncini E, Amar E et al (2012) Prevalence of esophageal atresia among 18 international birth defects surveillance programs. Birth Defects Res Part A: Clin Molec Teratol 94(11):893–899

    Article  CAS  Google Scholar 

  • Neilson JP, Gyte GM, Hickey M, Vazquez JC, Dou L (2013) Medical treatments for incomplete miscarriage. Cochrane Database Syst Rev 3:CD007223

    Google Scholar 

  • Nomoto M, Kaseda S, Iwata S, Osame M, Fukuda T (1997) Levodopa in pregnancy. Mov Disord 12(2):261

    CAS  PubMed  Google Scholar 

  • Opladen T, Cortès-Saladelafont E, Mastrangelo M et al (2016) The InternationalWorking group on neurotransmitter related disorders (iNTD): a worldwide research project focused on primary and secondary neurotransmitter disorders. Molec Genet Metab Rep 9:61–66

    Article  Google Scholar 

  • Opladen T, Hoffmann G, Horster F et al (2011) Clinical and biochemical characterization of patients with early infantile onset of autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia. Mov Disord 26(1):157–161

    Article  PubMed  Google Scholar 

  • Opladen T, Hoffmann GF, Blau N (2012) An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 35(6):963–973

    Article  CAS  PubMed  Google Scholar 

  • Pini Prato A, Carlucci M, Bagolan P et al (2015) A cross-sectional nationwide survey on esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 50(9):1441–1456

    Article  CAS  PubMed  Google Scholar 

  • Ponzone A, Ferraris S, Baglieri S,Spada M (2006) Treatment of tetrahydrobiopterin deficiencies. In Blau, N PKU and BH4: advances in phenylketonuria and tetrahydrobiopterin. Heilbronn, SPS Verlagsgesellschaft, pp 612–637

  • Rey F, Blandin-Savoja F, Rey J (1976) Atypical phenylketonuria with normal dihydropteridine reductase activity. N Engl J Med 295(20):1138–1139

    Article  CAS  PubMed  Google Scholar 

  • Routiot T, Lurel S, Denis E, Barbarino-Monnier P (2000) Parkinson's disease and pregnancy: case report and literature review. J Gynecol Obstet Biol Reprod (Paris) 29(5):454–457

    CAS  Google Scholar 

  • Scott M, Chowdhury M (2005) Pregnancy in Parkinson's disease: unique case report and review of the literature. Mov Disord 20(8):1078–1079

    Article  PubMed  Google Scholar 

  • Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai H (1976) Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 14:215–233

    CAS  PubMed  Google Scholar 

  • Segawa M, Nomura Y, Nishiyama N (2003) Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 54(Suppl 6):S32–S45

    Article  CAS  PubMed  Google Scholar 

  • Serikawa T, Shimohata T, Akashi M et al (2011) Successful twin pregnancy in a patient with parkin-associated autosomal recessive juvenile parkinsonism. BMC Neurol 11:72

    Article  PubMed  PubMed Central  Google Scholar 

  • Sharma D, Shastri S, Sharma P (2016) Intrauterine growth restriction: antenatal and postnatal aspects. Clin Med Insights Pediatr 10:67–83

    PubMed  PubMed Central  Google Scholar 

  • Shintaku H, Ohwada M (2013) Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan. Brain Develop 35(5):406–410

  • Shulman LM, Minagar A, Weiner WJ (2000) The effect of pregnancy in Parkinson's disease. Mov Disord 15(1):132–135

    Article  CAS  PubMed  Google Scholar 

  • Steinberger D, Blau N, Goriuonov D et al (2004) Heterozygous mutation in 5′-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 5(3):187–190

    Article  CAS  PubMed  Google Scholar 

  • Thony B, Blau N (2006) Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum Mutat 27(9):870–878

    Article  CAS  PubMed  Google Scholar 

  • Trender-Gerhard I, Sweeney MG, Schwingenschuh P et al (2009) Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. J Neurol Neurosurg Psychiatry 80(8):839–845

    Article  CAS  PubMed  Google Scholar 

  • van der Linde D, Konings EE, Slager MA et al (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 58(21):2241–2247

    Article  PubMed  Google Scholar 

  • van Spronsen FJ, van Wegberg AM, Ahring K et al (2017) Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol 5(9):743–756

    Article  PubMed  Google Scholar 

  • Ventzke A, Hoffmann J, Crushell E, Monavari A, Mayne PD, Knerr I (2015) 'Malignant Phenylketonuria' (PKU) due to Dihydropteridine reductase (DHPR) deficiency. Ir Med J 108(10):312–314

    CAS  PubMed  Google Scholar 

  • Voigt M, Zels K, Guthmann F, Hesse V, Gorlich Y, Straube S (2011) Somatic classification of neonates based on birth weight, length, and head circumference: quantification of the effects of maternal BMI and smoking. J Perinat Med 39(3):291–297

    Article  PubMed  Google Scholar 

  • Volpe JJ (2012) Neonatal encephalopathy: an inadequate term for hypoxic-ischemic encephalopathy. Ann Neurol 72(2):156–166

    Article  PubMed  Google Scholar 

  • von Graevenitz KS, Shulman LM, Revell SP (1996) Levodopa in pregnancy. Mov Disord 11(1):115–116

    Article  Google Scholar 

  • Watanabe T, Matsubara S (2012) Good obstetric outcome in a patient with Segawa disease. Arq Neuropsiquiatr 70(7):559–560

    Article  PubMed  Google Scholar 

  • Watanabe T, Matsubara S, Baba Y, Tanaka H, Suzuki T, Suzuki M (2009) Successful management of pregnancy in a patient with Segawa disease: case report and literature review. J Obstet Gynaecol Res 35(3):562–564

    Article  PubMed  Google Scholar 

  • Werner ER, Blau N, Thony B (2011) Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 438(3):397–414

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. D. Hübschmann and Dr N. Ishaque for fruitful discussion. This study was partially supported by Dietmar Hopp Stiftung, St. Leon-Rot, Germany.

Funding

No funding was provided for this work.

Author information

Authors and Affiliations

  1. Division of Child Neurology and Metabolic Diseases, University Children‘s Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany

    O. Kuseyri & T. Opladen

  2. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany

    A. Weissbach, N. Bruggemann & C. Klein

  3. Department of Neurology, University of Lübeck, Lübeck, Germany

    A. Weissbach, N. Bruggemann & C. Klein

  4. Department of Paediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology, Pomeranian Medical University in Szczecin, Szczecin, Poland

    M. Giżewska, H. Romanowska & E. Krzywińska-Zdeb

  5. Department of Paediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria

    D. Karall & S. Scholl-Bürgi

  6. National Centre for Inherited Metabolic Disorders, Temple Street Children’s University Hospital, Dublin, Ireland

    A. A. Monavari & I. Knerr

  7. Department of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Z. Yapıcı

  8. Department of Paediatrics and Child Neurology and Psychiatry, Sapienza Università di Roma, Roma, Italy

    V. Leuzzi

Authors
  1. O. Kuseyri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Weissbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Bruggemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Giżewska
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Karall
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Scholl-Bürgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Romanowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E. Krzywińska-Zdeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. A. Monavari
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. I. Knerr
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Z. Yapıcı
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. V. Leuzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T. Opladen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. Kuseyri.

Ethics declarations

Conflict of interest

O. Kuseyri, A. Weissbach, N. Bruggemann, C. Klein, M. Giżewska, D. Karall, S. Scholl-Bürgi, H. Romanowska, E. Krzywińska-Zdeb, A.A. Monavari, I. Knerr, Z. Yapıcı, V. Leuzzi, and T. Opladen declare that they have no conflict of interest.

Studies with animal

This article does not contain any studies with animal subjects performed by the any of the authors.

Additional information

Communicated by: Francois Feillet

Electronic supplementary material

ESM 1

(DOCX 31 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kuseyri, O., Weissbach, A., Bruggemann, N. et al. Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders. J Inherit Metab Dis 41, 849–863 (2018). https://doi.org/10.1007/s10545-018-0169-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-018-0169-0

Search

Navigation