Abstract
Background
Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders that manifests mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders, and autonomic symptoms.
Methodology
A retrospective review of genetically confirmed cases of disorders of tetrahydrobiopterin metabolism over a period of three years (Jan 2018 to Jan 2021) was performed across two paediatric neurology centres from South India.
Results
A total of nine patients(M:F=4:5) fulfilled the eligibility criteria. The genetic variants detected include homozygous mutations in the QDPR(n=6), GCH1(n=2), and PTS(n=1) genes. The median age at onset of symptoms was 6-months(range 3-78 months), while that at diagnosis was 15-months (8-120 months), resulting in a median delay in diagnosis of 9-months. The main clinical manifestations included neuroregression (89%), developmental delay(78%), dystonia(78%) and seizures(55%). Management strategies included a phenylalanine restricted diet, levodopa/carbidopa, 5-Hydroxytryphtophan, and folinic acid. Only, Patient-2 afforded and received BH4 supplementation at a sub-optimal dose later in the disease course. We had a median duration of follow up of 15 months (range 2-48 months). Though the biochemical response has been marked; except for patients with GTPCH deficiency, only mild clinical improvement was noted with regards to developmental milestones, seizures, or dystonia in others.
Conclusion
Tetrahydrobiopterin deficiencies represent a rare yet potentially treatable cause for non-phenylketonuria hyperphenylalaninemia with better outcomes when treated early in life. Screening for disorders of biopterin metabolism in patients with hyperphenylalaninemia prevents delayed diagnosis. This study expands the genotype-phenotype spectrum of patients with disorders of tetrahydrobiopterin metabolism from South India.
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References
Blau N, Barnes I, Dhondt JL (1996a) International database of tetrahydrobiopterin deficiencies. J Inherit Metab Dis. 19(1):8–14. https://doi.org/10.1007/BF01799342
Blau N, Barnes I, Dhondt JL (1996b) International database of tetrahydrobiopterin deficiencies. J Inherit Metab Dis. 19(1):8–14. https://doi.org/10.1007/BF01799342
Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U (2011) Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 104(Suppl):S2–S9. https://doi.org/10.1016/j.ymgme.2011.08.017 Epub 2011 Aug 26
Chien YH, Chiang SC, Huang A, Lin JM, Chiu YN, Chou SP, Chu SY, Wang TR, Hwu WL (2001) Treatment and outcome of Taiwanese patients with 6-pyruvoyltetrahydropterin synthase gene mutations. J Inherit Metab Dis. 24(8):815–823. https://doi.org/10.1023/a:1013984022994
Coughlin CR 2nd, Hyland K, Randall R, Ficicioglu C. Dihydropteridine reductase deficiency and treatment with tetrahydrobiopterin: a case report. JIMD Rep. 2013;10:53-6. doi: 10.1007/8904_2012_202. Epub 2012 Dec 29. PMID: 23430801; PMCID: PMC3755580.
Crabtree MJ, Tatham AL, Al-Wakeel Y, Warrick N, Hale AB, Cai S, Channon KM, Alp NJ (2009) Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression. J Biol Chem. 284(2):1136–1144. https://doi.org/10.1074/jbc.M805403200 Epub 2008 Nov 14
Dhondt JL (1984) Tetrahydrobiopterin deficiencies: preliminary analysis from an international survey. J Pediatr. 104(4):501–508. https://doi.org/10.1016/s0022-3476(84)80537-5
Eastman JW, Sherwin JE, Wong R, Liao CL, Currier RJ, Lorey F, Cunningham G (2000) Use of the phenylalanine:tyrosine ratio to test newborns for phenylketonuria in a large public health screening programme. J Med Screen. 7(3):131–135. https://doi.org/10.1136/jms.7.3.131
Farishian RA, Whittaker JR (1980) Phenylalanine lowers melanin synthesis in mammalian melanocytes by reducing tyrosine uptake: implications for pigment reduction in phenylketonuria. J Invest Dermatol. 74(2):85–89. https://doi.org/10.1111/1523-1747.ep12519975
Gowda VK, Vegda H, Benakappa N, Benakappa A (2018) Dihydropteridine Reductase Deficiency: A Treatable Neurotransmitter Movement Disorder Masquerading as Refractory Epilepsy Due to Novel Mutation. Indian J Pediatr. 85(9):812–813. https://doi.org/10.1007/s12098-018-2671-7 Epub 2018 Mar 28
Han B, Zou H, Han B, Zhu W, Cao Z, Liu Y (2015) Diagnosis, treatment and follow-up of patients with tetrahydrobiopterin deficiency in Shandong province. China. Brain Dev. 37(6):592–598. https://doi.org/10.1016/j.braindev.2014.09.008 Epub 2014 Oct 7
Horvath GA, Stockler-Ipsiroglu SG, Salvarinova-Zivkovic R, Lillquist YP, Connolly M, Hyland K et al (2008) Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: evidence of a phenotypic continuum between dominant and recessive forms. Mol Genet Metab. 94(1):127–131. https://doi.org/10.1016/j.ymgme.2008.01.003 Epub 2008 Feb 13
Jäggi L, Zurflüh MR, Schuler A, Ponzone A, Porta F, Fiori L, Giovannini M, Santer R, Hoffmann GF, Ibel H, Wendel U, Ballhausen D, Baumgartner MR, Blau N (2008) Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab. 93(3):295–305. https://doi.org/10.1016/j.ymgme.2007.10.004 Epub 2007 Dec 3
Kuseyri Hübschmann O, Mohr A, Friedman J, Manti F, Horvath G, Cortès-Saladelafont E, et al., International Working Group on Neurotransmitter Related Disorders (iNTD), Harting I. Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients. J Inherit Metab Dis. 2021 Jan 14. doi: 10.1002/jimd.12360. Epub ahead of print.
Lee NC, Cheng LY, Liu TT, Hsiao KJ, Chiu PC, Niu DM (2006) Long-term follow-up of Chinese patients who received delayed treatment for 6-pyruvoyl-tetrahydropterin synthase deficiency. Mol Genet Metab. 87(2):128–134. https://doi.org/10.1016/j.ymgme.2005.09.028 Epub 2005 Dec 20
Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis. 2009 Jun;32(3):333-42. doi: 10.1007/s10545-009-1067-2. Epub 2009 Feb 9. Erratum in: J Inherit Metab Dis. 2009 Jun;32(3):457.
Manzoni F, Salvatici E, Burlina A, Andrews A, Pasquali M, Longo N. Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth. Mol Genet Metab. 2020 Dec;131(4):380-389. doi: 10.1016/j.ymgme.2020.11.004. Epub 2020 Nov 18. PMID: 33234470; PMCID: PMC7749858.
Ng J, Papandreou A, Heales SJ, Kurian MA (2015) Monoamine neurotransmitter disorders--clinical advances and future perspectives. Nat Rev Neurol. 11(10):567–584. https://doi.org/10.1038/nrneurol.2015.172 Epub 2015 Sep 22
Opladen T, Hoffmann G, Hörster F, Hinz AB, Neidhardt K, Klein C, Wolf N (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. https://doi.org/10.1002/mds.23329 Epub 2010 Sep 3
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. https://doi.org/10.1007/s10545-012-9506-x Epub 2012 Jun 23
Opladen T, Cortès-Saladelafont E, Mastrangelo M, Horvath G, Pons R, Lopez-Laso E, Fernández-Ramos JA, Honzik T, Pearson T, Friedman J, Scholl-Bürgi S, Wassenberg T, Jung-Klawitter S, Kuseyri O, Jeltsch K, Kurian MA, Garcia-Cazorla À; International Working Group on Neurotransmitter related disorders (iNTD). The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders. Mol Genet Metab Rep. 2016 Oct 20;9:61-66. doi: 10.1016/j.ymgmr.2016.09.006. PMID: 27830117; PMCID: PMC5094101.
Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, et al., International Working Group on Neurotransmitter related Disorders (iNTD). Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis. 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8. Erratum in: Orphanet J Rare Dis. 2020 Aug 5;15(1):202. PMID: 32456656; PMCID: PMC7251883.
Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L (2004) Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev. 24(2):127–150. https://doi.org/10.1002/med.10055
Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. 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. Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. PMID: 25741868; PMCID: PMC4544753.
Shintaku H (2002) Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab. 3(2):123–131. https://doi.org/10.2174/1389200024605145
Shintaku H, Ohwada M (2013) Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan. Brain Dev. 35(5):406–410. https://doi.org/10.1016/j.braindev.2012.06.010 Epub 2012 Jul 24
Smith I, Clayton BE, Wolff OH (1975) New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction. Lancet. 1(7916):1108–1111. https://doi.org/10.1016/s0140-6736(75)92498-8
Verma IC, Bijarnia-Mahay S, Jhingan G, Verma J (2015) Newborn screening: need of the hour in India. Indian J Pediatr. 82(1):61–70. https://doi.org/10.1007/s12098-014-1615-0 Epub 2014 Dec 9
Wang L, Yu WM, He C, Chang M, Shen M, Zhou Z, Zhang Z, Shen S, Liu TT, Hsiao KJ (2006) Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency. J Inherit Metab Dis. 29(1):127–134. https://doi.org/10.1007/s10545-006-0080-y
Werner ER, Blau N, Thöny B (2011) Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J. 438(3):397–414. https://doi.org/10.1042/BJ20110293
Winn SR, Scherer T, Thöny B, Harding CO. High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU). Mol Genet Metab. 2016 Jan;117(1):5-11. doi: 10.1016/j.ymgme.2015.11.012. Epub 2015 Nov 26. PMID: 26653793; PMCID: PMC4706464.
Ye J, Yang Y, Yu W, Zou H, Jiang J, Yang R et al (2013) Demographics, diagnosis and treatment of 256 patients with tetrahydrobiopterin deficiency in mainland China: results of a retrospective, multicentre study. J Inherit Metab Dis. 36(5):893–901. https://doi.org/10.1007/s10545-012-9550-6 Epub 2012 Nov 9
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Ray, S., Padmanabha, H., Gowda, V.K. et al. Disorders of Tetrahydrobiopterin Metabolism: Experience from South India. Metab Brain Dis 37, 743–760 (2022). https://doi.org/10.1007/s11011-021-00889-z
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DOI: https://doi.org/10.1007/s11011-021-00889-z