Article Sidebar
Submitted
November 2, 2020
Published
December 11, 2021
Statistic
Read Counter :
2598
Download : 830
Main Article Content
Abstract
We report about a family with three of five siblings affected by a variable remitting-relapsing disease with epileptic seizures, coma and abdominal crises, and lethal outcome in all. In the youngest son and in one of his deceased brothers we identified two disease causing compound heterozygous POLG mutations. One of these was inherited from the mother, but the other was absent in the father`s blood, saliva, buccal swab and hair bulbs although his paternity was proven genetically. Thus, we assume germline mosaicism for this mutation in the father. Very low 5-methyltetrahydrofolate (5-MTHF) and absence of folate receptor-alpha was repeatedly found in the CSF of the youngest brother indicating a secondary cerebral folate transport deficiency. Folinic acid supplementation over 18 months resulted in some improvement of the neurological condition; however, it did not prevent progression of the systemic disease.
Keywords
polymerase gamma gene, Alpers-Huttenlocher Syndrome, MNGIE, gastric dysmotility, CSF 5-MTHF, folinic acid
Article Details
License
Copyright (c) 2021 Rudolf Korinthenberg, Janbernd Kirschner, Matthias Eckenweiler, Robert Steinfeld, Nana Nino Tatishvili, Rita Horvath, Stephanie Kleinle, Angela Abicht
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Authors who publish with this journal agree to the following terms:
Authors retain copyright in their work and grant the Journal of the International Child Neurology Association (JICNA) the right of first publication. The work is simultaneously licensed under a Creative Commons Attribution–NonCommercial–ShareAlike 4.0 International License (CC BY-NC-SA 4.0).
Under this licence, others may share and adapt the work provided that they:
-
give appropriate credit to the author(s) and acknowledge the work's initial publication in JICNA;
-
do not use the work for commercial purposes; and
-
distribute any adapted material under the same licence.
Authors may enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work, for example, by depositing it in an institutional repository or including it in a book, provided that its initial publication in JICNA is acknowledged.
Authors are permitted and encouraged to post their work online, including in institutional repositories and on personal or institutional websites, prior to and during the submission process, as this may facilitate scholarly exchange and increase the visibility and citation of published work.
How to Cite
1.
Korinthenberg R, Kirschner J, Eckenweiler M, Steinfeld R, Tatishvili NN, Horvath R, et al. Alpers- and MNGIE-like disease with disturbed CSF folate transport and an unusual mode of genetic transmission of POLG mutations: a case report. JICNA [Internet]. 2021 Dec. 11 [cited 2026 Sep. 8];1(1). Available from: https://jicna.org/index.php/journal/article/view/216
How to Cite
1.
Korinthenberg R, Kirschner J, Eckenweiler M, Steinfeld R, Tatishvili NN, Horvath R, et al. Alpers- and MNGIE-like disease with disturbed CSF folate transport and an unusual mode of genetic transmission of POLG mutations: a case report. JICNA [Internet]. 2021 Dec. 11 [cited 2026 Sep. 8];1(1). Available from: https://jicna.org/index.php/journal/article/view/216
References
-
1. Hikmat O, Tzoulis C, Chong WK, Chentouf L, Klingenberg C, Fratter C, Carr LJ, Prabhakar P, Kumaraguru N, Gissen P, et al. The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations. Genet Med. 2017;19:1217-1225. Available from: doi: 10.1038/gim.2017.35.
2. Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019;15:40-52. Available from: doi: 10.1038/s41582-018-0101-0.
3. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CM, Brodtkorb E, Ostergaard E, de Coo IFM, Pias-Peleteiro L, et al. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020;43:726-736. Available from: doi: 10.1002/jimd.12211.
4. AlJabri MA, Kamal NM, HalabI A, Korbi H , Alsayyali MMA, Alzahrani YA. Lethal neonatal mitochondrial phenotype caused by a novel polymerase subunit gamma mutation: A case report. Medicine. 2018;97:e12591. Available from: doi: 10.1097/MD.0000000000012591.
5. Dai L, Fang F, Liu Z, Shen D, Ding C, Li J, Ren X, Wu H. Phenotype and genotype of twelve Chinese children with mitochondrial DNA depletion syndromes. Chin J Pediatr 2019;57: 211-216. Available from: doi: 10.3760/cma.j.issn.0578-1310.2019.03.011
6. Han XD, Fang F, Li H, Liu ZM, Shi YQ, Wang JL, Ren XT, Ding CH, Chen CH, Li JW, et al. Clinical and genetic characteristics of 62 children with mitochondrial epilepsy. Chin J Pediatr. 2019;57:844-851. Available from: doi: 10.3760/cma.j.issn.0578-1310.2019.11.006.
7. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. 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;17:405-424. Available from: doi: 10.1038/gim.2015.30.
8. Tsiatis AC, Norris-Kirby A, Rich RG, Hafez MJ, Gocke CD, Eshleman JR, Murphy KM. Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J Mol Diagn. 2010;12:425-432. Available from: doi:10.2353/jmoldx.2010.090188
9. de Lange IM, Koudijs MJ, van ’t Slot R, Sonsma ACM, Mulder I, Carbo EC, van Kempen MJA, Nijman IJ, Ernst RF, Savelberg SMC, et al. Assessment of parental mosaicism in SCN1A-related epilepsy by single-molecule molecular inversion probes and next-generation sequencing J Med Genet. 2019;56:75–80. Available from: doi:10.1136/jmedgenet-2018-105672
10. Møller RS, Liebmann N, Larsen LHG, Stiller M, Hentschel J, Kako N, Abdin D, Di Donato N, Pal DK, Zacher P, et al. Parental mosaicism in epilepsies due to alleged de novo variants Epilepsia. 2019;60:e63–e66. Available from: doi: 10.1111/epi.15187
11. Anazi S, Al-Sabban E, Alkuraya FS. Gonadal mosaicism as a rare cause of autosomal recessive inheritance. Clin Genet. 2014;85:278-81. Available from: doi: 10.1111/cge.12156.
12. Voltolini Velho R, Alegra T, Sperb F, Ludwig NF, Saraiva-Pereira ML, Matte U, Schwartz IVD. A de novo or germline mutation in a family with Mucolipidosis III gamma: Implications for molecular diagnosis and genetic counseling. Mol Genet Metab Rep. 2014;1:98-102. Available from: doi: 10.1016/j.ymgmr.2014.01.002.
13. Wolf N, Rahman S, Schmitt B, Taanman J-W, Duncan AJ, Harting I, Wohlrab G, Ebinger F, Rating D, Bast T. Status epilepticus in children with Alpers’ disease caused by POLG1 mutations: EEG and MRI features. Epilepsia. 2009; 50:1596–1607, Available from: doi: 10.1111/j.1528-1167.2008.01877.x
14. Tang S, Dimberg EL, Milone M, Wong L-JC. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations. J Neurol. 2012; 259: 86-8. Available from: doi: 10.1007/s00415-011-6268-6.
15. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005; 352: 1985-1991. Available from: doi: 10.1056/NEJMoa043160.
16. Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski St, Helms G, Dechent P, Wevers R, Grosso S, Gärtner J. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009; 85: 354-363. Available from: doi: 10.1016/j.ajhg.2009.08.005.
17. Grapp M, Just IA, Linnankivi T, Wolf P, Lücke T, Häusler M, Gärtner J, Steinfeld R. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012;135:2022-31. Available from: doi: 10.1093/brain/aws122.
18. Grapp M, Wrede A, Schweizer M, Hüwel S, Galla HJ, Snaidero N, Simons M, Bückers J, Low PS, Urlaub H, et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123. Available from: doi: 10.1038/ncomms3123.
19. Tanji K, Schon EA, DiMauro S, Bonilla E. Kearns-sayre syndrome: oncocytic transformation of choroid plexus epithelium. J Neurol Sci. 2000;178:29-36. Available from: doi: 10.1016/s0022-510x(00)00354-3.
20. Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet Metab 2010;99:58-61. Available from: doi: 10.1016/j.ymgme.2009.08.005.
21. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CME, Brodtkorb E, Fiskerstrand T, Isohanni P, Uusimaa J, et al. Elevated cerebrospinal fluid protein in POLG-related epilepsy: Diagnostic and prognostic implications. Epilepsia. 2018;59:1595-1602. Available from: doi: 10.1111/epi.14459.
References
1. Hikmat O, Tzoulis C, Chong WK, Chentouf L, Klingenberg C, Fratter C, Carr LJ, Prabhakar P, Kumaraguru N, Gissen P, et al. The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations. Genet Med. 2017;19:1217-1225. Available from: doi: 10.1038/gim.2017.35.
2. Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019;15:40-52. Available from: doi: 10.1038/s41582-018-0101-0.
3. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CM, Brodtkorb E, Ostergaard E, de Coo IFM, Pias-Peleteiro L, et al. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020;43:726-736. Available from: doi: 10.1002/jimd.12211.
4. AlJabri MA, Kamal NM, HalabI A, Korbi H , Alsayyali MMA, Alzahrani YA. Lethal neonatal mitochondrial phenotype caused by a novel polymerase subunit gamma mutation: A case report. Medicine. 2018;97:e12591. Available from: doi: 10.1097/MD.0000000000012591.
5. Dai L, Fang F, Liu Z, Shen D, Ding C, Li J, Ren X, Wu H. Phenotype and genotype of twelve Chinese children with mitochondrial DNA depletion syndromes. Chin J Pediatr 2019;57: 211-216. Available from: doi: 10.3760/cma.j.issn.0578-1310.2019.03.011
6. Han XD, Fang F, Li H, Liu ZM, Shi YQ, Wang JL, Ren XT, Ding CH, Chen CH, Li JW, et al. Clinical and genetic characteristics of 62 children with mitochondrial epilepsy. Chin J Pediatr. 2019;57:844-851. Available from: doi: 10.3760/cma.j.issn.0578-1310.2019.11.006.
7. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. 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;17:405-424. Available from: doi: 10.1038/gim.2015.30.
8. Tsiatis AC, Norris-Kirby A, Rich RG, Hafez MJ, Gocke CD, Eshleman JR, Murphy KM. Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J Mol Diagn. 2010;12:425-432. Available from: doi:10.2353/jmoldx.2010.090188
9. de Lange IM, Koudijs MJ, van ’t Slot R, Sonsma ACM, Mulder I, Carbo EC, van Kempen MJA, Nijman IJ, Ernst RF, Savelberg SMC, et al. Assessment of parental mosaicism in SCN1A-related epilepsy by single-molecule molecular inversion probes and next-generation sequencing J Med Genet. 2019;56:75–80. Available from: doi:10.1136/jmedgenet-2018-105672
10. Møller RS, Liebmann N, Larsen LHG, Stiller M, Hentschel J, Kako N, Abdin D, Di Donato N, Pal DK, Zacher P, et al. Parental mosaicism in epilepsies due to alleged de novo variants Epilepsia. 2019;60:e63–e66. Available from: doi: 10.1111/epi.15187
11. Anazi S, Al-Sabban E, Alkuraya FS. Gonadal mosaicism as a rare cause of autosomal recessive inheritance. Clin Genet. 2014;85:278-81. Available from: doi: 10.1111/cge.12156.
12. Voltolini Velho R, Alegra T, Sperb F, Ludwig NF, Saraiva-Pereira ML, Matte U, Schwartz IVD. A de novo or germline mutation in a family with Mucolipidosis III gamma: Implications for molecular diagnosis and genetic counseling. Mol Genet Metab Rep. 2014;1:98-102. Available from: doi: 10.1016/j.ymgmr.2014.01.002.
13. Wolf N, Rahman S, Schmitt B, Taanman J-W, Duncan AJ, Harting I, Wohlrab G, Ebinger F, Rating D, Bast T. Status epilepticus in children with Alpers’ disease caused by POLG1 mutations: EEG and MRI features. Epilepsia. 2009; 50:1596–1607, Available from: doi: 10.1111/j.1528-1167.2008.01877.x
14. Tang S, Dimberg EL, Milone M, Wong L-JC. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations. J Neurol. 2012; 259: 86-8. Available from: doi: 10.1007/s00415-011-6268-6.
15. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005; 352: 1985-1991. Available from: doi: 10.1056/NEJMoa043160.
16. Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski St, Helms G, Dechent P, Wevers R, Grosso S, Gärtner J. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009; 85: 354-363. Available from: doi: 10.1016/j.ajhg.2009.08.005.
17. Grapp M, Just IA, Linnankivi T, Wolf P, Lücke T, Häusler M, Gärtner J, Steinfeld R. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012;135:2022-31. Available from: doi: 10.1093/brain/aws122.
18. Grapp M, Wrede A, Schweizer M, Hüwel S, Galla HJ, Snaidero N, Simons M, Bückers J, Low PS, Urlaub H, et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123. Available from: doi: 10.1038/ncomms3123.
19. Tanji K, Schon EA, DiMauro S, Bonilla E. Kearns-sayre syndrome: oncocytic transformation of choroid plexus epithelium. J Neurol Sci. 2000;178:29-36. Available from: doi: 10.1016/s0022-510x(00)00354-3.
20. Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet Metab 2010;99:58-61. Available from: doi: 10.1016/j.ymgme.2009.08.005.
21. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CME, Brodtkorb E, Fiskerstrand T, Isohanni P, Uusimaa J, et al. Elevated cerebrospinal fluid protein in POLG-related epilepsy: Diagnostic and prognostic implications. Epilepsia. 2018;59:1595-1602. Available from: doi: 10.1111/epi.14459.
2. Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019;15:40-52. Available from: doi: 10.1038/s41582-018-0101-0.
3. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CM, Brodtkorb E, Ostergaard E, de Coo IFM, Pias-Peleteiro L, et al. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020;43:726-736. Available from: doi: 10.1002/jimd.12211.
4. AlJabri MA, Kamal NM, HalabI A, Korbi H , Alsayyali MMA, Alzahrani YA. Lethal neonatal mitochondrial phenotype caused by a novel polymerase subunit gamma mutation: A case report. Medicine. 2018;97:e12591. Available from: doi: 10.1097/MD.0000000000012591.
5. Dai L, Fang F, Liu Z, Shen D, Ding C, Li J, Ren X, Wu H. Phenotype and genotype of twelve Chinese children with mitochondrial DNA depletion syndromes. Chin J Pediatr 2019;57: 211-216. Available from: doi: 10.3760/cma.j.issn.0578-1310.2019.03.011
6. Han XD, Fang F, Li H, Liu ZM, Shi YQ, Wang JL, Ren XT, Ding CH, Chen CH, Li JW, et al. Clinical and genetic characteristics of 62 children with mitochondrial epilepsy. Chin J Pediatr. 2019;57:844-851. Available from: doi: 10.3760/cma.j.issn.0578-1310.2019.11.006.
7. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. 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;17:405-424. Available from: doi: 10.1038/gim.2015.30.
8. Tsiatis AC, Norris-Kirby A, Rich RG, Hafez MJ, Gocke CD, Eshleman JR, Murphy KM. Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J Mol Diagn. 2010;12:425-432. Available from: doi:10.2353/jmoldx.2010.090188
9. de Lange IM, Koudijs MJ, van ’t Slot R, Sonsma ACM, Mulder I, Carbo EC, van Kempen MJA, Nijman IJ, Ernst RF, Savelberg SMC, et al. Assessment of parental mosaicism in SCN1A-related epilepsy by single-molecule molecular inversion probes and next-generation sequencing J Med Genet. 2019;56:75–80. Available from: doi:10.1136/jmedgenet-2018-105672
10. Møller RS, Liebmann N, Larsen LHG, Stiller M, Hentschel J, Kako N, Abdin D, Di Donato N, Pal DK, Zacher P, et al. Parental mosaicism in epilepsies due to alleged de novo variants Epilepsia. 2019;60:e63–e66. Available from: doi: 10.1111/epi.15187
11. Anazi S, Al-Sabban E, Alkuraya FS. Gonadal mosaicism as a rare cause of autosomal recessive inheritance. Clin Genet. 2014;85:278-81. Available from: doi: 10.1111/cge.12156.
12. Voltolini Velho R, Alegra T, Sperb F, Ludwig NF, Saraiva-Pereira ML, Matte U, Schwartz IVD. A de novo or germline mutation in a family with Mucolipidosis III gamma: Implications for molecular diagnosis and genetic counseling. Mol Genet Metab Rep. 2014;1:98-102. Available from: doi: 10.1016/j.ymgmr.2014.01.002.
13. Wolf N, Rahman S, Schmitt B, Taanman J-W, Duncan AJ, Harting I, Wohlrab G, Ebinger F, Rating D, Bast T. Status epilepticus in children with Alpers’ disease caused by POLG1 mutations: EEG and MRI features. Epilepsia. 2009; 50:1596–1607, Available from: doi: 10.1111/j.1528-1167.2008.01877.x
14. Tang S, Dimberg EL, Milone M, Wong L-JC. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations. J Neurol. 2012; 259: 86-8. Available from: doi: 10.1007/s00415-011-6268-6.
15. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005; 352: 1985-1991. Available from: doi: 10.1056/NEJMoa043160.
16. Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski St, Helms G, Dechent P, Wevers R, Grosso S, Gärtner J. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009; 85: 354-363. Available from: doi: 10.1016/j.ajhg.2009.08.005.
17. Grapp M, Just IA, Linnankivi T, Wolf P, Lücke T, Häusler M, Gärtner J, Steinfeld R. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012;135:2022-31. Available from: doi: 10.1093/brain/aws122.
18. Grapp M, Wrede A, Schweizer M, Hüwel S, Galla HJ, Snaidero N, Simons M, Bückers J, Low PS, Urlaub H, et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123. Available from: doi: 10.1038/ncomms3123.
19. Tanji K, Schon EA, DiMauro S, Bonilla E. Kearns-sayre syndrome: oncocytic transformation of choroid plexus epithelium. J Neurol Sci. 2000;178:29-36. Available from: doi: 10.1016/s0022-510x(00)00354-3.
20. Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet Metab 2010;99:58-61. Available from: doi: 10.1016/j.ymgme.2009.08.005.
21. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CME, Brodtkorb E, Fiskerstrand T, Isohanni P, Uusimaa J, et al. Elevated cerebrospinal fluid protein in POLG-related epilepsy: Diagnostic and prognostic implications. Epilepsia. 2018;59:1595-1602. Available from: doi: 10.1111/epi.14459.