- Email: [email protected]
Intraventricular Glioblastoma Multiforme in A Child with L2-Hydroxyglutaric Aciduria
Accepted Manuscript Intraventricular glioblastoma multiforme in a child with L2-hydroxyglutaric aciduria Ai Peng Tan, MD, FRCR, Kshitij Mankad, MD, FRCR PII:
S1878-8750(17)32029-6
DOI:
10.1016/j.wneu.2017.11.106
Reference:
WNEU 6937
To appear in:
World Neurosurgery
Received Date: 15 October 2017 Revised Date:
15 November 2017
Accepted Date: 17 November 2017
Please cite this article as: Tan AP, Mankad K, Intraventricular glioblastoma multiforme in a child with L2hydroxyglutaric aciduria, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.11.106. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Intraventricular glioblastoma multiforme in a child with L2hydroxyglutaric aciduria. First/Corresponding author:
RI PT
Ai Peng Tan; MD, FRCR Department of Diagnostic Radiology, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074. Phone : +6597378620
SC
Email : [email protected]
Kshitij Mankad; MD, FRCR
M AN U
Second author:
Department of Neuroradiology, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London WC1N 3JH
Key words :
TE D
Email : [email protected]
Intraventricular glioblastoma multiforme
•
L2-hydroxyglutaric aciduria
•
Neoplasm
AC C
EP
•
Abbreviations:
L2-HGA : L2-hydroxyglutaric aciduria L2-HG : L2-hydroxyglutarate GBM : glioblastoma multiforme MRI : Magnetic resonance imaging
ACCEPTED MANUSCRIPT Funding Source: No funding was secured for this study. Author Disclosure: Ai Peng Tan – Reports no disclosure
RI PT
Kshitij Mankad – Reports no disclosure Conflict of Interest: The authors have no conflicts of interest to disclose.
All authors approved the final manuscript as submitted and agree to be accountable for all
AC C
EP
TE D
M AN U
SC
aspects of the work.
ACCEPTED MANUSCRIPT
Intraventricular glioblastoma multiforme in a child with L2-hydroxyglutaric aciduria
RI PT
Abstract L2-hydroxyglutaric aciduria (L2-HGA) is a rare neurometabolic disease characterised by accumulation of L2-hydroxyglutarate (L2-HG), a potential oncometabolite resulting in
SC
significant lifetime risk for cerebral tumors. Here in, we present a case of intraventricular glioblastoma multiforme (GBM) in a 16-year-old child with L2-HGA who presented with
M AN U
rapid functional decline and persistent vomiting. The tumour was completely resected and the patient remained well at 2-year follow up. Clinicians should be aware of the usual insidious nature of the disease. Rapid deterioration is unusual and should raise the suspicion of tumour development. This case also illustrates the importance of surveillance neuroimaging in
TE D
patients with L2-HGA. To the best our knowledge, only one case of GBM has been reported
AC C
EP
and it was sited in the temporal lobe, unlike the unusual intraventricular location in our case.
ACCEPTED MANUSCRIPT
Key words : ● Intraventricular glioblastoma multiforme
RI PT
● L2-hydroxyglutaric aciduria ● Neoplasm Abbreviations:
SC
L2-HGA : L2-hydroxyglutaric aciduria
GBM : glioblastoma multiforme
AC C
EP
TE D
MRI : Magnetic resonance imaging
M AN U
L2-HG : L2-hydroxyglutarate
ACCEPTED MANUSCRIPT A 16-year-old child with L2-HGA presented with rapid functional decline and persistent vomiting. Magnetic resonance imaging (MRI) of the brain (Figure 1) was performed and showed a large, predominantly solid mass within the left lateral ventricle, extending into the left foramina of Monro, resulting in upstream hydrocephalus. Background
RI PT
imaging findings characteristic of L2-HGA were also noted; predominantly subcortical white matter signal abnormalities as well as signal abnormalities within the dentate nuclei. In view of the hydrocephalus, an external ventricular drainage catheter was inserted. A few days later,
SC
the mass was surgically removed, with histopathological confirmation of glioblastoma multiforme. Microscopic examination showed fragments of necrotic tissue, with significant
M AN U
pleomorphism, focal multinucleation and frequent mitotic and apoptotic figures. Most tumor cells were positive for GFAP and negative for synaptophysin. INI1 staining was retained and there was no significant staining for mutant IDH1. There was loss of 1p (TP73) with no evidence of 19q (GLTSCR) loss by FISH analysis. There was also no evidence of mutation in
TE D
exon 1 of the HISTIH3B or H3F3A genes by direct sequence analysis. HISTIH3B and H3F3A genes have been found in 22% and 14% of glioblastomas respectively. After surgery, the child underwent adjuvant chemotherapy and radiotherapy. Follow up imaging over a
EP
period of two years showed no evidence of tumour recurrence.
AC C
L2-HGA is a rare neurometabolic disease caused by mutation of the L2HGDH gene which is inherited in an autosomal recessive manner 1. The gene product of L2HGDH catalyses the conversion of L2-HG (an oncometabolite) to alpha-ketoglutarate
2
.
Accumulation of L2-HG in patients with L2-HGA explains the increased lifetime risk for development of cerebral neoplasms 3. High levels of L2-HG have been found in brain neoplasms that have IDH1 mutations 4. More than 80% of diffuse gliomas (WHO grade II/III) and secondary glioblastomas harbor an IDH1 mutation, which promotes conversion
ACCEPTED MANUSCRIPT of isocitrate to excessive amount of 2-HG5–7. The mechanism behind the oncogenetic and myelinotoxic effect of excess accumulation of L2-HG remains unclear. L2-HGA runs a slow progressive course and lacks acute metabolic decompensation,
RI PT
unlike other organic acidurias 4. Patients with L2-HGA are not routinely followed up with neuroimaging due to its insidious course and absence of treatment. In 1993, Wilcken et al. reported the first case of cerebral neoplasm in a 15-year-old girl with L2-HGA8. From 1997 to 2012, 17 reported cases of L2-HGA with cerebral neoplasms were identified
3,4,17,9–16
. In
SC
addition, a case of successive high grade gliomas in a patient with L2-HGA was reported by
M AN U
Patay et al in 201518. Glioblastoma is a rare tumor in the pediatric population, accounting for less than 3% of all primary central nervous system (CNS) tumors among children, with an estimated incidence of 1.4 per 1,000,000
19
. Pediatric GBM has a more favorable prognosis
compared to its adult counterpart 20, expresses different oncogenic mutations 21, and does not always respond to the same chemotherapeutic treatments as adult GBM. Its occurrence in
TE D
association with L2-HGA has never been reported before. Pediatric glioblastomas are differentiated from their adult counterpart by frequent gain of chromosome 1q and the
EP
paucity of chromosome 7 gains and 10q losses 21. IDH1-mutations at codon 132 is present in approximately 85% of adult secondary glioblastoma, but is extremely rare in the pediatric 22
. PDGFRA is the predominant target of focal amplification in pediatric HGG.
AC C
population
On the other hand, EGFR is the most common target in adult glioblastoma. Rapid deterioration is unusual for L2-HGA and should be viewed with caution as it
may denote development of cerebral neoplasm 3. Majority of cerebral tumours develop after 10 years of age, except in two cases, a 3-year-old child with medulloblastoma and a 9-yearold child with low grade astrocytoma 3,4,8,9,16–18. This suggests prolonged exposure to L2-HG as the underlying mechanism of tumorigenesis. Interestingly, L2-HG level does not appear to determine the risk of tumour development
14
. Further research is needed to determine other
ACCEPTED MANUSCRIPT factors that may attribute to tumorigenesis in patients with L2-HGA as this will greatly
AC C
EP
TE D
M AN U
SC
RI PT
impact patient management.
ACCEPTED MANUSCRIPT Figure legend Figure 1. A 16-year-old child with background history of L2-hydroxyglutaric aciduria presented with rapid functional decline and persistent vomiting. MRI brain shows (a,b)
RI PT
leukoencephalopathy with a centripetal gradient and areas of rarefaction within the subcortical white matter. (c) Signal changes in the dentate nuclei are also noted. Findings are characteristic of L2-HGA. (d-g) A large minimally enhancing left intraventricular mass with restricted diffusion is seen, causing upstream hydrocephalus. The mass was surgically
AC C
EP
TE D
M AN U
SC
removed, with histopathological confirmation of glioblastoma multiforme (GBM).
ACCEPTED MANUSCRIPT References 1. Topçu, M., Jobard, F., Halliez, S., Coskun, T., Yalçinkayal, C., Gerceker, F.O., Wanders, R.J.A., Prud’homme, J.-F., Lathrop, M., Ozguc, M., et al. (2004). L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13, 2803–2811.
RI PT
2. Rzem, R., Van Schaftingen, E., and Veiga-da-Cunha, M. (2006). The gene mutated in l-2hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 88, 113– 116. 3. Moroni, I., Bugiani, M., D’Incerti, L., Maccagnano, C., Rimoldi, M., Bissola, L., Pollo, B., Finocchiaro, G., and Uziel, G. (2004). L-2-hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology 62, 1882–1884.
SC
4. Patay, Z., Mills, J.C., Löbel, U., Lambert, A., Sablauer, A., and Ellison, D.W. (2012). Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data. AJNR Am J Neuroradiol 33, 940–943.
M AN U
5. Dang, L., White, D.W., Gross, S., Bennett, B.D., Bittinger, M.A., Driggers, E.M., Fantin, V.R., Jang, H.G., Jin, S., Keenan, M.C., et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744. 6. Parsons, D.W., Jones, S., Zhang, X., Lin, J.C.-H., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G.L., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812.
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7. Balss, J., Meyer, J., Mueller, W., Korshunov, A., Hartmann, C., and von Deimling, A. (2008). Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116, 597–602.
EP
8. Wilcken, B., Pitt, J., Heath, D., Walsh, P., Wilson, G., and Buchanan, N. (1993). L-2hydroxyglutaric aciduria: three Australian cases. J Inherit Metab Dis 16, 501–504. 9. Ozişik, P.A., Akalan, N., Palaoğlu, S., and Topçu, M. (2002). Medulloblastoma in a child with the metabolic disease L-2-hydroxyglutaric aciduria. Pediatr Neurosurg 37, 22–26.
AC C
10. Vilarinho, L., Cardoso, M.L., Gaspar, P., Barbot, C., Azevedo, L., Diogo, L., Santos, M., Carrilho, I., Fineza, I., Kok, F., et al. (2005). Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin. Hum Mutat 26, 395–396. 11. Topçu, M., Aydin, O.F., Yalçinkaya, C., Haliloğlu, G., Aysun, S., Anlar, B., Topaloğlu, H., Turanli, G., Yalnizoğlu, D., Kesimer, M., et al. (2005). L-2-hydroxyglutaric aciduria: a report of 29 patients. Turk J Pediatr 47, 1–7. 12. Haliloglu, G., Temucin, C.M., Oguz, K.K., Celiker, A., Coskun, T., Sass, J.O., Fischer, J., and Topcu, M. (2009). Peripheral neuropathy in a patient with D-2-hydroxyglutaric aciduria. J Inherit Metab Dis 32 Suppl 1, S21-5. 13. Haliloglu, G., Jobard, F., Oguz, K.K., Anlar, B., Akalan, N., Coskun, T., Sass, J.O., Fischer, J., and Topcu, M. (2008). L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics 39, 119–122.
ACCEPTED MANUSCRIPT 14. Aghili, M., Zahedi, F., and Rafiee, E. (2009). Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol 91, 233–236. 15. Steenweg, M.E., Salomons, G.S., Yapici, Z., Uziel, G., Scalais, E., Zafeiriou, D.I., RuizFalco, M.L., Mejaski-Bosnjak, V., Augoustides-Savvopoulou, P., Wajner, M., et al. (2009). L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology 251, 856–865.
RI PT
16. Barbot, C., Fineza, I., Diogo, L., Maia, M., Melo, J., Guimarães, A., Pires, M.M., Cardoso, M.L., and Vilarinho, L. (1997). L-2-Hydroxyglutaric aciduria: clinical, biochemical and magnetic resonance imaging in six Portuguese pediatric patients. Brain Dev 19, 268–273.
SC
17. Wanders, R.J., Vilarinho, L., Hartung, H.P., Hoffmann, G.F., Mooijer, P.A., Jansen, G.A., Huijmans, J.G., de Klerk, J.B., ten Brink, H.J., Jakobs, C., et al. (1997). L-2-Hydroxyglutaric aciduria: normal L-2-hydroxyglutarate dehydrogenase activity in liver from two new patients. J Inherit Metab Dis 20, 725–726.
M AN U
18. Patay, Z., Orr, B.A., Shulkin, B.L., Hwang, S.N., Ying, Y., Broniscer, A., Boop, F.A., and Ellison, D.W. (2015). Successive distinct high-grade gliomas in L-2-hydroxyglutaric aciduria. J Inherit Metab Dis 38, 273–277. 19. Kaatsch, P., Rickert, C.H., Kühl, J., Schüz, J., and Michaelis, J. (2001). Population-based epidemiologic data on brain tumors in German children. Cancer 92, 3155–3164.
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20. Song, K.S., Phi, J.H., Cho, B.-K., Wang, K.-C., Lee, J.Y., Kim, D.G., Kim, I.H., Ahn, H.S., Park, S.-H., and Kim, S.-K. (2010). Long-term outcomes in children with glioblastoma. J Neurosurg Pediatr 6, 145–149. 21. Paugh, B.S., Qu, C., Jones, C., Liu, Z., Adamowicz-Brice, M., Zhang, J., Bax, D.A., Coyle, B., Barrow, J., Hargrave, D., et al. (2010). Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28, 3061–3068.
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EP
22. Cancer Genome Atlas Research Network (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061– 1068.
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EP
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M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1878-8750(17)32029-6
DOI:
10.1016/j.wneu.2017.11.106
Reference:
WNEU 6937
To appear in:
World Neurosurgery
Received Date: 15 October 2017 Revised Date:
15 November 2017
Accepted Date: 17 November 2017
Please cite this article as: Tan AP, Mankad K, Intraventricular glioblastoma multiforme in a child with L2hydroxyglutaric aciduria, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.11.106. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Intraventricular glioblastoma multiforme in a child with L2hydroxyglutaric aciduria. First/Corresponding author:
RI PT
Ai Peng Tan; MD, FRCR Department of Diagnostic Radiology, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074. Phone : +6597378620
SC
Email : [email protected]
Kshitij Mankad; MD, FRCR
M AN U
Second author:
Department of Neuroradiology, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London WC1N 3JH
Key words :
TE D
Email : [email protected]
Intraventricular glioblastoma multiforme
•
L2-hydroxyglutaric aciduria
•
Neoplasm
AC C
EP
•
Abbreviations:
L2-HGA : L2-hydroxyglutaric aciduria L2-HG : L2-hydroxyglutarate GBM : glioblastoma multiforme MRI : Magnetic resonance imaging
ACCEPTED MANUSCRIPT Funding Source: No funding was secured for this study. Author Disclosure: Ai Peng Tan – Reports no disclosure
RI PT
Kshitij Mankad – Reports no disclosure Conflict of Interest: The authors have no conflicts of interest to disclose.
All authors approved the final manuscript as submitted and agree to be accountable for all
AC C
EP
TE D
M AN U
SC
aspects of the work.
ACCEPTED MANUSCRIPT
Intraventricular glioblastoma multiforme in a child with L2-hydroxyglutaric aciduria
RI PT
Abstract L2-hydroxyglutaric aciduria (L2-HGA) is a rare neurometabolic disease characterised by accumulation of L2-hydroxyglutarate (L2-HG), a potential oncometabolite resulting in
SC
significant lifetime risk for cerebral tumors. Here in, we present a case of intraventricular glioblastoma multiforme (GBM) in a 16-year-old child with L2-HGA who presented with
M AN U
rapid functional decline and persistent vomiting. The tumour was completely resected and the patient remained well at 2-year follow up. Clinicians should be aware of the usual insidious nature of the disease. Rapid deterioration is unusual and should raise the suspicion of tumour development. This case also illustrates the importance of surveillance neuroimaging in
TE D
patients with L2-HGA. To the best our knowledge, only one case of GBM has been reported
AC C
EP
and it was sited in the temporal lobe, unlike the unusual intraventricular location in our case.
ACCEPTED MANUSCRIPT
Key words : ● Intraventricular glioblastoma multiforme
RI PT
● L2-hydroxyglutaric aciduria ● Neoplasm Abbreviations:
SC
L2-HGA : L2-hydroxyglutaric aciduria
GBM : glioblastoma multiforme
AC C
EP
TE D
MRI : Magnetic resonance imaging
M AN U
L2-HG : L2-hydroxyglutarate
ACCEPTED MANUSCRIPT A 16-year-old child with L2-HGA presented with rapid functional decline and persistent vomiting. Magnetic resonance imaging (MRI) of the brain (Figure 1) was performed and showed a large, predominantly solid mass within the left lateral ventricle, extending into the left foramina of Monro, resulting in upstream hydrocephalus. Background
RI PT
imaging findings characteristic of L2-HGA were also noted; predominantly subcortical white matter signal abnormalities as well as signal abnormalities within the dentate nuclei. In view of the hydrocephalus, an external ventricular drainage catheter was inserted. A few days later,
SC
the mass was surgically removed, with histopathological confirmation of glioblastoma multiforme. Microscopic examination showed fragments of necrotic tissue, with significant
M AN U
pleomorphism, focal multinucleation and frequent mitotic and apoptotic figures. Most tumor cells were positive for GFAP and negative for synaptophysin. INI1 staining was retained and there was no significant staining for mutant IDH1. There was loss of 1p (TP73) with no evidence of 19q (GLTSCR) loss by FISH analysis. There was also no evidence of mutation in
TE D
exon 1 of the HISTIH3B or H3F3A genes by direct sequence analysis. HISTIH3B and H3F3A genes have been found in 22% and 14% of glioblastomas respectively. After surgery, the child underwent adjuvant chemotherapy and radiotherapy. Follow up imaging over a
EP
period of two years showed no evidence of tumour recurrence.
AC C
L2-HGA is a rare neurometabolic disease caused by mutation of the L2HGDH gene which is inherited in an autosomal recessive manner 1. The gene product of L2HGDH catalyses the conversion of L2-HG (an oncometabolite) to alpha-ketoglutarate
2
.
Accumulation of L2-HG in patients with L2-HGA explains the increased lifetime risk for development of cerebral neoplasms 3. High levels of L2-HG have been found in brain neoplasms that have IDH1 mutations 4. More than 80% of diffuse gliomas (WHO grade II/III) and secondary glioblastomas harbor an IDH1 mutation, which promotes conversion
ACCEPTED MANUSCRIPT of isocitrate to excessive amount of 2-HG5–7. The mechanism behind the oncogenetic and myelinotoxic effect of excess accumulation of L2-HG remains unclear. L2-HGA runs a slow progressive course and lacks acute metabolic decompensation,
RI PT
unlike other organic acidurias 4. Patients with L2-HGA are not routinely followed up with neuroimaging due to its insidious course and absence of treatment. In 1993, Wilcken et al. reported the first case of cerebral neoplasm in a 15-year-old girl with L2-HGA8. From 1997 to 2012, 17 reported cases of L2-HGA with cerebral neoplasms were identified
3,4,17,9–16
. In
SC
addition, a case of successive high grade gliomas in a patient with L2-HGA was reported by
M AN U
Patay et al in 201518. Glioblastoma is a rare tumor in the pediatric population, accounting for less than 3% of all primary central nervous system (CNS) tumors among children, with an estimated incidence of 1.4 per 1,000,000
19
. Pediatric GBM has a more favorable prognosis
compared to its adult counterpart 20, expresses different oncogenic mutations 21, and does not always respond to the same chemotherapeutic treatments as adult GBM. Its occurrence in
TE D
association with L2-HGA has never been reported before. Pediatric glioblastomas are differentiated from their adult counterpart by frequent gain of chromosome 1q and the
EP
paucity of chromosome 7 gains and 10q losses 21. IDH1-mutations at codon 132 is present in approximately 85% of adult secondary glioblastoma, but is extremely rare in the pediatric 22
. PDGFRA is the predominant target of focal amplification in pediatric HGG.
AC C
population
On the other hand, EGFR is the most common target in adult glioblastoma. Rapid deterioration is unusual for L2-HGA and should be viewed with caution as it
may denote development of cerebral neoplasm 3. Majority of cerebral tumours develop after 10 years of age, except in two cases, a 3-year-old child with medulloblastoma and a 9-yearold child with low grade astrocytoma 3,4,8,9,16–18. This suggests prolonged exposure to L2-HG as the underlying mechanism of tumorigenesis. Interestingly, L2-HG level does not appear to determine the risk of tumour development
14
. Further research is needed to determine other
ACCEPTED MANUSCRIPT factors that may attribute to tumorigenesis in patients with L2-HGA as this will greatly
AC C
EP
TE D
M AN U
SC
RI PT
impact patient management.
ACCEPTED MANUSCRIPT Figure legend Figure 1. A 16-year-old child with background history of L2-hydroxyglutaric aciduria presented with rapid functional decline and persistent vomiting. MRI brain shows (a,b)
RI PT
leukoencephalopathy with a centripetal gradient and areas of rarefaction within the subcortical white matter. (c) Signal changes in the dentate nuclei are also noted. Findings are characteristic of L2-HGA. (d-g) A large minimally enhancing left intraventricular mass with restricted diffusion is seen, causing upstream hydrocephalus. The mass was surgically
AC C
EP
TE D
M AN U
SC
removed, with histopathological confirmation of glioblastoma multiforme (GBM).
ACCEPTED MANUSCRIPT References 1. Topçu, M., Jobard, F., Halliez, S., Coskun, T., Yalçinkayal, C., Gerceker, F.O., Wanders, R.J.A., Prud’homme, J.-F., Lathrop, M., Ozguc, M., et al. (2004). L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13, 2803–2811.
RI PT
2. Rzem, R., Van Schaftingen, E., and Veiga-da-Cunha, M. (2006). The gene mutated in l-2hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 88, 113– 116. 3. Moroni, I., Bugiani, M., D’Incerti, L., Maccagnano, C., Rimoldi, M., Bissola, L., Pollo, B., Finocchiaro, G., and Uziel, G. (2004). L-2-hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology 62, 1882–1884.
SC
4. Patay, Z., Mills, J.C., Löbel, U., Lambert, A., Sablauer, A., and Ellison, D.W. (2012). Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data. AJNR Am J Neuroradiol 33, 940–943.
M AN U
5. Dang, L., White, D.W., Gross, S., Bennett, B.D., Bittinger, M.A., Driggers, E.M., Fantin, V.R., Jang, H.G., Jin, S., Keenan, M.C., et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744. 6. Parsons, D.W., Jones, S., Zhang, X., Lin, J.C.-H., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G.L., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812.
TE D
7. Balss, J., Meyer, J., Mueller, W., Korshunov, A., Hartmann, C., and von Deimling, A. (2008). Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116, 597–602.
EP
8. Wilcken, B., Pitt, J., Heath, D., Walsh, P., Wilson, G., and Buchanan, N. (1993). L-2hydroxyglutaric aciduria: three Australian cases. J Inherit Metab Dis 16, 501–504. 9. Ozişik, P.A., Akalan, N., Palaoğlu, S., and Topçu, M. (2002). Medulloblastoma in a child with the metabolic disease L-2-hydroxyglutaric aciduria. Pediatr Neurosurg 37, 22–26.
AC C
10. Vilarinho, L., Cardoso, M.L., Gaspar, P., Barbot, C., Azevedo, L., Diogo, L., Santos, M., Carrilho, I., Fineza, I., Kok, F., et al. (2005). Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin. Hum Mutat 26, 395–396. 11. Topçu, M., Aydin, O.F., Yalçinkaya, C., Haliloğlu, G., Aysun, S., Anlar, B., Topaloğlu, H., Turanli, G., Yalnizoğlu, D., Kesimer, M., et al. (2005). L-2-hydroxyglutaric aciduria: a report of 29 patients. Turk J Pediatr 47, 1–7. 12. Haliloglu, G., Temucin, C.M., Oguz, K.K., Celiker, A., Coskun, T., Sass, J.O., Fischer, J., and Topcu, M. (2009). Peripheral neuropathy in a patient with D-2-hydroxyglutaric aciduria. J Inherit Metab Dis 32 Suppl 1, S21-5. 13. Haliloglu, G., Jobard, F., Oguz, K.K., Anlar, B., Akalan, N., Coskun, T., Sass, J.O., Fischer, J., and Topcu, M. (2008). L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics 39, 119–122.
ACCEPTED MANUSCRIPT 14. Aghili, M., Zahedi, F., and Rafiee, E. (2009). Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol 91, 233–236. 15. Steenweg, M.E., Salomons, G.S., Yapici, Z., Uziel, G., Scalais, E., Zafeiriou, D.I., RuizFalco, M.L., Mejaski-Bosnjak, V., Augoustides-Savvopoulou, P., Wajner, M., et al. (2009). L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology 251, 856–865.
RI PT
16. Barbot, C., Fineza, I., Diogo, L., Maia, M., Melo, J., Guimarães, A., Pires, M.M., Cardoso, M.L., and Vilarinho, L. (1997). L-2-Hydroxyglutaric aciduria: clinical, biochemical and magnetic resonance imaging in six Portuguese pediatric patients. Brain Dev 19, 268–273.
SC
17. Wanders, R.J., Vilarinho, L., Hartung, H.P., Hoffmann, G.F., Mooijer, P.A., Jansen, G.A., Huijmans, J.G., de Klerk, J.B., ten Brink, H.J., Jakobs, C., et al. (1997). L-2-Hydroxyglutaric aciduria: normal L-2-hydroxyglutarate dehydrogenase activity in liver from two new patients. J Inherit Metab Dis 20, 725–726.
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