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September 30, 2020
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March 27, 2022
Published
January 11, 2022
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Abstract
More widespread use of exome and genome sequencing combined with improved data sharing platforms have led to the characterization of “new” neurometabolic disorders. This review provides an overview of the folate and polyamine metabolic pathways, summarizes the established disorders, and highlights two recently described disorders of folate and polyamine metabolism. 5,10-methenyltetrahydrofolate synthetase (MTHFS) deficiency is an emerging disorder of folate metabolism that manifests with neurodevelopmental abnormalities, epilepsy, spasticity, short stature, microcephaly, cerebral hypomyelination, and cerebellar atrophy. Cerebrospinal fluid 5-MTHF levels are reduced, with normal peripheral folate levels. MTHFS deficiency may be amenable to treatment with 5-methyltetrahydrofolate, whereas folinic acid, used in other forms of cerebral folate deficiency, may be contraindicated. There are two inborn errors of polyamine metabolism in humans described to date, including the neurodevelopmental disorder Snyder-Robinson syndrome and the recently described ODC1 disorder. ODC1 disorder is associated with a recognizable phenotype, including neurodevelopmental and behavioral abnormalities, macrocephaly, alopecia, craniofacial dysmorphisms, and MRI abnormalities. The pathogenic variants in this gene described to date appear to confer a gain-of-function effect. It is yet to be determined if there is an effective targeted treatment for ODC1 disorder.
Keywords
cerebral folate deficiency, folate metabolism, 5,10-methenyltetrahydrofolate synthetase (MTHFS) deficiency, polyamine metabolism, ornithine decarboxylase 1 (ODC1) deficiency
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How to Cite
Rodan, L. (2022). Update in pediatric neurometabolic disorders: folate and polyamine metabolism. Journal of the International Child Neurology Association, 1(1). https://doi.org/10.17724/jicna.2022.211
References
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[1] Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000; 105(1):e10. https://pubmed.ncbi.nlm.nih.gov/10617747/
[2] Rodan LH, Qi W, Ducker GS, Demirbas D, Laine R, Yang E, Walker MA, Eichler F, Rabinowitz JD, Anselm I, Berry GT; Undiagnosed Diseases Network (UDN). 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metab. 2018; 125(1-2):118-126. https://pubmed.ncbi.nlm.nih.gov/30031689/
[3] Yuxiang Zheng , Lewis C Cantley. Toward a better understanding of folate metabolism in health and disease. J Exp Med. 2019; 216(2):253-266. https://pubmed.ncbi.nlm.nih.gov/30587505/
[4] Simon Pope, Rafael Artuch, Simon Heales, Shamima Rahman. Cerebral folate deficiency: Analytical tests and differential diagnosis. J Inherit Metab Dis. 2019; 42(4):655-672. https://pubmed.ncbi.nlm.nih.gov/30916789/
[5] Desmoulin SK, Hou Z, Gangjee A, Matherly LH. The human proton-coupled folate transporter: Biology and therapeutic applications to cancer. Cancer Biol Ther. 2012; 13(14):1355-73. https://pubmed.ncbi.nlm.nih.gov/22954694/
[6] Ramaekers VT, Sequeira JM, Blau N, Quadros EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. 2008; 50(5): 346–352. https://pubmed.ncbi.nlm.nih.gov/18355335/
[7] Majumdar, R., Yori, A., Rush, P. W., Raymond, K., Gavrilov, D., Tortorelli, S., Matern, D., Rinaldo, P., Feldman, G. L., Oglesbee, D. Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria. Molec. Genet. Genomic Med. 2017; 5:795-799. https://pubmed.ncbi.nlm.nih.gov/29178637/
[8] Bashford MT, Hickey SE, Curry CJ, Toriello HV. Correction: Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2020; 22(9):1568. https://pubmed.ncbi.nlm.nih.gov/32587351/
[9] Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Guéant JL, Landolt MA, Kožich V, Fowler B, Baumgartner MR. Mutation Update and Review of Severe MTHFR Deficiency. Hum Mutat. 2016; 37(5):427-38. https://pubmed.ncbi.nlm.nih.gov/26872964/
[10] L. Knowles, A. A. M. Morris, J. H. Walter. Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency. JIMD Rep. 2016; 29: 103–107. https://pubmed.ncbi.nlm.nih.gov/26898294/
[11] Romero JA, Abdelmoumen I, Hasbani D, Khurana DS, Schneider MC. A case of 5,10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia. Mol Genet Metab Rep. 2019; 21. https://pubmed.ncbi.nlm.nih.gov/31844630/
[12] Misselbeck K, Marchetti L, Priami C, Stover PJ, Field MS. The 5-formyltetrahydrofolate futile cycle reduces pathway stochasticity in an extended hybrid-stochastic model of folate-mediated one-carbon metabolism. Sci Rep. 2019; 9: 4322. https://pubmed.ncbi.nlm.nih.gov/30867454/
[13] Rodan LH, Anyane-Yeboa K, Chong K, Klein Wassink-Ruiter JS, Wilson A, Smith L, Kothare SV, Rajabi F, Blaser S, Ni M, DeBerardinis RJ, Poduri A, Berry GT. Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities. Am J Med Genet A. 2018; 176(12):2554-2560. https://pubmed.ncbi.nlm.nih.gov/30475435/
[14] Nowotarski SL, Woster PM, Casero RA Jr. Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 2013. https://pubmed.ncbi.nlm.nih.gov/23432971/
[15] Snyder RD, Robinson A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities. Report of a family. Clin Pediatr (Philadelphia). 1969; 8: 669–674. https://pubmed.ncbi.nlm.nih.gov/5823961/
[16] Charles E Schwartz CE, Peron A, Kutler MJ. Snyder-Robinson Syndrome. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK144284/, accessed on 9/25/20.
[17] Chong Li, Jennifer M. Brazill, Sha Liu, Christofer Bello, Yi Zhu, Marie Morimoto, Lauren Cascio, Rini Pauly, Zoraida Diaz-Perez, May Christine V. Malicdan, Hongbo Wang, Luigi Boccuto, Charles E. Schwartz, William A. Gahl, Cornelius F. Boerkoel, R. Grace Zha. Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome. Nat Commun. 2018; 9: 337. https://pubmed.ncbi.nlm.nih.gov/29348635/
[18] Bupp CP, Schultz CR, Uhl KL, Rajasekaran S, Bachmann AS. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. Am J Med Genet A. 2018; 176(12):2548-2553. https://pubmed.ncbi.nlm.nih.gov/30239107/
[19] Schultz CR, Bupp CP, Rajasekaran S, Bachmann AS. Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation. Biochem J. 2019; 476(14):2047-2057. https://pubmed.ncbi.nlm.nih.gov/31249027/
References
[1] Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000; 105(1):e10. https://pubmed.ncbi.nlm.nih.gov/10617747/
[2] Rodan LH, Qi W, Ducker GS, Demirbas D, Laine R, Yang E, Walker MA, Eichler F, Rabinowitz JD, Anselm I, Berry GT; Undiagnosed Diseases Network (UDN). 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metab. 2018; 125(1-2):118-126. https://pubmed.ncbi.nlm.nih.gov/30031689/
[3] Yuxiang Zheng , Lewis C Cantley. Toward a better understanding of folate metabolism in health and disease. J Exp Med. 2019; 216(2):253-266. https://pubmed.ncbi.nlm.nih.gov/30587505/
[4] Simon Pope, Rafael Artuch, Simon Heales, Shamima Rahman. Cerebral folate deficiency: Analytical tests and differential diagnosis. J Inherit Metab Dis. 2019; 42(4):655-672. https://pubmed.ncbi.nlm.nih.gov/30916789/
[5] Desmoulin SK, Hou Z, Gangjee A, Matherly LH. The human proton-coupled folate transporter: Biology and therapeutic applications to cancer. Cancer Biol Ther. 2012; 13(14):1355-73. https://pubmed.ncbi.nlm.nih.gov/22954694/
[6] Ramaekers VT, Sequeira JM, Blau N, Quadros EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. 2008; 50(5): 346–352. https://pubmed.ncbi.nlm.nih.gov/18355335/
[7] Majumdar, R., Yori, A., Rush, P. W., Raymond, K., Gavrilov, D., Tortorelli, S., Matern, D., Rinaldo, P., Feldman, G. L., Oglesbee, D. Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria. Molec. Genet. Genomic Med. 2017; 5:795-799. https://pubmed.ncbi.nlm.nih.gov/29178637/
[8] Bashford MT, Hickey SE, Curry CJ, Toriello HV. Correction: Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2020; 22(9):1568. https://pubmed.ncbi.nlm.nih.gov/32587351/
[9] Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Guéant JL, Landolt MA, Kožich V, Fowler B, Baumgartner MR. Mutation Update and Review of Severe MTHFR Deficiency. Hum Mutat. 2016; 37(5):427-38. https://pubmed.ncbi.nlm.nih.gov/26872964/
[10] L. Knowles, A. A. M. Morris, J. H. Walter. Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency. JIMD Rep. 2016; 29: 103–107. https://pubmed.ncbi.nlm.nih.gov/26898294/
[11] Romero JA, Abdelmoumen I, Hasbani D, Khurana DS, Schneider MC. A case of 5,10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia. Mol Genet Metab Rep. 2019; 21. https://pubmed.ncbi.nlm.nih.gov/31844630/
[12] Misselbeck K, Marchetti L, Priami C, Stover PJ, Field MS. The 5-formyltetrahydrofolate futile cycle reduces pathway stochasticity in an extended hybrid-stochastic model of folate-mediated one-carbon metabolism. Sci Rep. 2019; 9: 4322. https://pubmed.ncbi.nlm.nih.gov/30867454/
[13] Rodan LH, Anyane-Yeboa K, Chong K, Klein Wassink-Ruiter JS, Wilson A, Smith L, Kothare SV, Rajabi F, Blaser S, Ni M, DeBerardinis RJ, Poduri A, Berry GT. Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities. Am J Med Genet A. 2018; 176(12):2554-2560. https://pubmed.ncbi.nlm.nih.gov/30475435/
[14] Nowotarski SL, Woster PM, Casero RA Jr. Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 2013. https://pubmed.ncbi.nlm.nih.gov/23432971/
[15] Snyder RD, Robinson A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities. Report of a family. Clin Pediatr (Philadelphia). 1969; 8: 669–674. https://pubmed.ncbi.nlm.nih.gov/5823961/
[16] Charles E Schwartz CE, Peron A, Kutler MJ. Snyder-Robinson Syndrome. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK144284/, accessed on 9/25/20.
[17] Chong Li, Jennifer M. Brazill, Sha Liu, Christofer Bello, Yi Zhu, Marie Morimoto, Lauren Cascio, Rini Pauly, Zoraida Diaz-Perez, May Christine V. Malicdan, Hongbo Wang, Luigi Boccuto, Charles E. Schwartz, William A. Gahl, Cornelius F. Boerkoel, R. Grace Zha. Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome. Nat Commun. 2018; 9: 337. https://pubmed.ncbi.nlm.nih.gov/29348635/
[18] Bupp CP, Schultz CR, Uhl KL, Rajasekaran S, Bachmann AS. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. Am J Med Genet A. 2018; 176(12):2548-2553. https://pubmed.ncbi.nlm.nih.gov/30239107/
[19] Schultz CR, Bupp CP, Rajasekaran S, Bachmann AS. Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation. Biochem J. 2019; 476(14):2047-2057. https://pubmed.ncbi.nlm.nih.gov/31249027/
[2] Rodan LH, Qi W, Ducker GS, Demirbas D, Laine R, Yang E, Walker MA, Eichler F, Rabinowitz JD, Anselm I, Berry GT; Undiagnosed Diseases Network (UDN). 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metab. 2018; 125(1-2):118-126. https://pubmed.ncbi.nlm.nih.gov/30031689/
[3] Yuxiang Zheng , Lewis C Cantley. Toward a better understanding of folate metabolism in health and disease. J Exp Med. 2019; 216(2):253-266. https://pubmed.ncbi.nlm.nih.gov/30587505/
[4] Simon Pope, Rafael Artuch, Simon Heales, Shamima Rahman. Cerebral folate deficiency: Analytical tests and differential diagnosis. J Inherit Metab Dis. 2019; 42(4):655-672. https://pubmed.ncbi.nlm.nih.gov/30916789/
[5] Desmoulin SK, Hou Z, Gangjee A, Matherly LH. The human proton-coupled folate transporter: Biology and therapeutic applications to cancer. Cancer Biol Ther. 2012; 13(14):1355-73. https://pubmed.ncbi.nlm.nih.gov/22954694/
[6] Ramaekers VT, Sequeira JM, Blau N, Quadros EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. 2008; 50(5): 346–352. https://pubmed.ncbi.nlm.nih.gov/18355335/
[7] Majumdar, R., Yori, A., Rush, P. W., Raymond, K., Gavrilov, D., Tortorelli, S., Matern, D., Rinaldo, P., Feldman, G. L., Oglesbee, D. Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria. Molec. Genet. Genomic Med. 2017; 5:795-799. https://pubmed.ncbi.nlm.nih.gov/29178637/
[8] Bashford MT, Hickey SE, Curry CJ, Toriello HV. Correction: Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2020; 22(9):1568. https://pubmed.ncbi.nlm.nih.gov/32587351/
[9] Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Guéant JL, Landolt MA, Kožich V, Fowler B, Baumgartner MR. Mutation Update and Review of Severe MTHFR Deficiency. Hum Mutat. 2016; 37(5):427-38. https://pubmed.ncbi.nlm.nih.gov/26872964/
[10] L. Knowles, A. A. M. Morris, J. H. Walter. Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency. JIMD Rep. 2016; 29: 103–107. https://pubmed.ncbi.nlm.nih.gov/26898294/
[11] Romero JA, Abdelmoumen I, Hasbani D, Khurana DS, Schneider MC. A case of 5,10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia. Mol Genet Metab Rep. 2019; 21. https://pubmed.ncbi.nlm.nih.gov/31844630/
[12] Misselbeck K, Marchetti L, Priami C, Stover PJ, Field MS. The 5-formyltetrahydrofolate futile cycle reduces pathway stochasticity in an extended hybrid-stochastic model of folate-mediated one-carbon metabolism. Sci Rep. 2019; 9: 4322. https://pubmed.ncbi.nlm.nih.gov/30867454/
[13] Rodan LH, Anyane-Yeboa K, Chong K, Klein Wassink-Ruiter JS, Wilson A, Smith L, Kothare SV, Rajabi F, Blaser S, Ni M, DeBerardinis RJ, Poduri A, Berry GT. Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities. Am J Med Genet A. 2018; 176(12):2554-2560. https://pubmed.ncbi.nlm.nih.gov/30475435/
[14] Nowotarski SL, Woster PM, Casero RA Jr. Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 2013. https://pubmed.ncbi.nlm.nih.gov/23432971/
[15] Snyder RD, Robinson A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities. Report of a family. Clin Pediatr (Philadelphia). 1969; 8: 669–674. https://pubmed.ncbi.nlm.nih.gov/5823961/
[16] Charles E Schwartz CE, Peron A, Kutler MJ. Snyder-Robinson Syndrome. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK144284/, accessed on 9/25/20.
[17] Chong Li, Jennifer M. Brazill, Sha Liu, Christofer Bello, Yi Zhu, Marie Morimoto, Lauren Cascio, Rini Pauly, Zoraida Diaz-Perez, May Christine V. Malicdan, Hongbo Wang, Luigi Boccuto, Charles E. Schwartz, William A. Gahl, Cornelius F. Boerkoel, R. Grace Zha. Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome. Nat Commun. 2018; 9: 337. https://pubmed.ncbi.nlm.nih.gov/29348635/
[18] Bupp CP, Schultz CR, Uhl KL, Rajasekaran S, Bachmann AS. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. Am J Med Genet A. 2018; 176(12):2548-2553. https://pubmed.ncbi.nlm.nih.gov/30239107/
[19] Schultz CR, Bupp CP, Rajasekaran S, Bachmann AS. Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation. Biochem J. 2019; 476(14):2047-2057. https://pubmed.ncbi.nlm.nih.gov/31249027/