Excessive Seizure Clusters in an Otherwise Well-Controlled Epilepsy as a Possible Hallmark of Untreated Vitamin B6-Responsive Epilepsy due to a Homozygous PLPBP Missense VariantFunding None.
25 December 2018
11 March 2019
20 April 2019 (online)
Recently, mutations in the PLPBP gene were described as a novel cause for vitamin B6-responsive epilepsy. We report the outcome in case of a male adolescent with a novel homozygous missense variant in PLPBP who was never treated with pyridoxine until the age of 16 years. He presented with only mild cognitive impairment and an early-onset, well-controlled epilepsy. In our patient, excessive seizure clusters and anxiety states occurred intermittently, suggesting that the combination might be a hallmark in untreated patients. Thus, mutations in PLPBP should be addressed even in adolescent patients with only mild learning disabilities and relatively good seizure control over the years.
J.J. collected the clinical data and drafted the article. P.D., L.H., and K.H. also collected clinical data. T.B., M.H., and K.K. performed genetic analyses. All authors interpreted the data in the clinical context. T.B., P.D., K.H., K.K., and J.D. revised the manuscript.
- 1 Darin N, Reid E, Prunetti L. , et al. Mutations in PROSC disrupt cellular pyridoxal phosphate homeostasis and cause vitamin-B6-dependent epilepsy. Am J Hum Genet 2016; 99 (06) 1325-1337
- 2 Plecko B, Zweier M, Begemann A. , et al. Confirmation of mutations in PROSC as a novel cause of vitamin B 6 -dependent epilepsy. J Med Genet 2017; 54 (12) 809-814
- 3 Kernohan KD, Hartley T, Naumenko S. , et al. Diagnostic clarity of exome sequencing following negative comprehensive panel testing in the neonatal intensive care unit. Am J Med Genet A 2018; 176 (07) 1688-1691
- 4 Tremiño L, Forcada-Nadal A, Rubio V. Insight into vitamin B6 -dependent epilepsy due to PLPBP (previously PROSC) missense mutations. Hum Mutat 2018; 39 (07) 1002-1013
- 5 Shiraku H, Nakashima M, Takeshita S. , et al. PLPBP mutations cause variable phenotypes of developmental and epileptic encephalopathy. Epilepsia Open 2018; 3 (04) 495-502
- 6 Blau N, Duran M, Gibson KM, Dionisi-Vici C, Blaskovics ME. , eds. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Heidelberg: Springer; 2014: 247-264
- 7 Footitt EJ, Heales SJ, Mills PB, Allen GF, Oppenheim M, Clayton PT. Pyridoxal 5′-phosphate in cerebrospinal fluid; factors affecting concentration. J Inherit Metab Dis 2011; 34 (02) 529-538
- 8 Hempel M, Cremer K, Ockeloen CW. , et al. De novo mutations in CHAMP1 cause intellectual disability with severe speech impairment. Am J Hum Genet 2015; 97 (03) 493-500
- 9 Lessel D, Vaz B, Halder S. , et al. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet 2014; 46 (11) 1239-1244
- 10 Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 2014; 46 (03) 310-315
- 11 Ioannidis NM, Rothstein JH, Pejaver V. , et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 2016; 99 (04) 877-885
- 12 Jagadeesh KA, Wenger AM, Berger MJ. , et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet 2016; 48 (12) 1581-1586
- 13 Adzhubei IA, Schmidt S, Peshkin L. , et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
- 14 Fisher RS, Cross JH, D'Souza C. , et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia 2017; 58 (04) 531-542
- 15 Dakshinamurti K, Paulose CS, Viswanathan M, Siow YL. Neuroendocrinology of pyridoxine deficiency. Neurosci Biobehav Rev 1988; 12 (3-4): 189-193