Neonatal Alexander Disease: Novel GFAP Mutation and Comparison to Previously Published Cases

Abstract

Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.

Keywords

drug-resistant seizures - hydrocephalus - neuroimaging - leukodystrophy

Note

The work was performed at Oulu University Hospital, the University of Oulu, and the University of Helsinki.

^* Knuutinen and Kousi contributed equally (first author).

^# Lehesjoki and Vieira contributed equally (senior author).

• References

• 1 Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 2001; 27 (01) 117-120
• 2 Li R, Johnson AB, Salomons G. , et al. Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 2005; 57 (03) 310-326
• 3 Sawaishi Y. Review of Alexander disease: beyond the classical concept of leukodystrophy. Brain Dev 2009; 31 (07) 493-498
• 4 Johnson AB, Brenner M. Alexander's disease: clinical, pathologic, and genetic features. J Child Neurol 2003; 18 (09) 625-632
• 5 Prust M, Wang J, Morizono H. , et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 2011; 77 (13) 1287-1294
• 6 Meins M, Brockmann K, Yadav S. , et al. Infantile Alexander disease: a GFAP mutation in monozygotic twins and novel mutations in two other patients. Neuropediatrics 2002; 33 (04) 194-198
• 7 Vázquez E, Macaya A, Mayolas N, Arévalo S, Poca MA, Enríquez G. Neonatal Alexander disease: MR imaging prenatal diagnosis. AJNR Am J Neuroradiol 2008; 29 (10) 1973-1975
• 8 Yoo IH, Hong WG, Kim H. , et al. A neonatal form of alexander disease presented with intractable seizures and obstructive hydrocephalus. J Genet Med 2013; 10: 113-116
• 9 Springer S, Erlewein R, Naegele T. , et al. Alexander disease--classification revisited and isolation of a neonatal form. Neuropediatrics 2000; 31 (02) 86-92
• 10 van der Knaap MS, Salomons GS, Li R. , et al. Unusual variants of Alexander's disease. Ann Neurol 2005; 57 (03) 327-338
• 11 Bassuk AG, Joshi A, Burton BK, Larsen MB, Burrowes DM, Stack C. Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene. Neurology 2003; 61 (07) 1014-1015
• 12 Rodriguez D, Gauthier F, Bertini E. , et al. Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet 2001; 69 (05) 1134-1140
• 13 Singh N, Bixby C, Etienne D, Tubbs RS, Loukas M. Alexander's disease: reassessment of a neonatal form. Childs Nerv Syst 2012; 28 (12) 2029-2031
• 14 van der Knaap MS, Naidu S, Breiter SN. , et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001; 22 (03) 541-552
• 15 Butler KM, da Silva C, Alexander JJ, Hegde M, Escayg A. Diagnostic yield from 339 epilepsy patients screened on a clinical gene panel. Pediatr Neurol 2017; 77: 61-66
• 16 Weckhuysen S, Mandelstam S, Suls A. , et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012; 71 (01) 15-25
• 17 González-Pérez A, López-Bigas N. Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet 2011; 88 (04) 440-449
• 18 Niroula A, Urolagin S, Vihinen M. PON-P2: prediction method for fast and reliable identification of harmful variants. PLoS One 2015; 10 (02) e0117380
• 19 Richards S, Aziz N, Bale S. , et al; 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; 17 (05) 405-424
• 20 Waisman Center. GFAP variants associated with Alexander disease. Available at: http://www.waisman.wisc.edu/alexander-disease/mutation-table.pdf . Accessed January 13, 2017
• 21 Brismar J, Brismar G, Gascon G, Ozand P. Canavan disease: CT and MR imaging of the brain. AJNR Am J Neuroradiol 1990; 11 (04) 805-810
• 22 Warmuth-Metz M, Hofmann E, Büsse M, Solymosi L. Uncommon morphologic characteristics in Leigh's disease. AJNR Am J Neuroradiol 1999; 20 (06) 1158-1160