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Neuropediatrics 2018; 49(04): 256-261
DOI: 10.1055/s-0038-1649500
Original Article
Georg Thieme Verlag KG Stuttgart · New York

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

Oula Knuutinen   *
1   PEDEGO Research Unit, University of Oulu, Finland
2   Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland
3   Biocenter Oulu, University of Oulu, Finland
,
Maria Kousi   *
4   Folkhälsan Institute of Genetics, Helsinki, Finland
5   Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, United States
,
Maria Suo-Palosaari
2   Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland
6   Department of Diagnostic Radiology, Oulu University Hospital, Finland
,
Jukka S. Moilanen
1   PEDEGO Research Unit, University of Oulu, Finland
2   Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland
7   Department of Clinical Genetics, Oulu University Hospital, Finland
,
Hannu Tuominen
8   Department of Pathology, Cancer and Translational Medicine Research Unit, University of Oulu and Oulu University Hospital, Finland
,
Leena Vainionpää
9   Clinic for Children and Adolescents, Oulu University Hospital, Finland
,
Tarja Joensuu
4   Folkhälsan Institute of Genetics, Helsinki, Finland
10   Neuroscience Center, University of Helsinki, Finland
11   Research Programs Unit, Molecular Neurology, University of Helsinki, Finland
,
Anna-Kaisa Anttonen
4   Folkhälsan Institute of Genetics, Helsinki, Finland
10   Neuroscience Center, University of Helsinki, Finland
11   Research Programs Unit, Molecular Neurology, University of Helsinki, Finland
12   Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Finland
,
Johanna Uusimaa
1   PEDEGO Research Unit, University of Oulu, Finland
2   Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland
3   Biocenter Oulu, University of Oulu, Finland
9   Clinic for Children and Adolescents, Oulu University Hospital, Finland
,
Anna-Elina Lehesjoki   #
4   Folkhälsan Institute of Genetics, Helsinki, Finland
10   Neuroscience Center, University of Helsinki, Finland
11   Research Programs Unit, Molecular Neurology, University of Helsinki, Finland
,
Päivi Vieira   #
1   PEDEGO Research Unit, University of Oulu, Finland
2   Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland
9   Clinic for Children and Adolescents, Oulu University Hospital, Finland
› Author Affiliations
Further Information

Publication History

14 January 2018

24 March 2018

Publication Date:
25 May 2018 (online)

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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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 3 Sawaishi Y. Review of Alexander disease: beyond the classical concept of leukodystrophy. Brain Dev 2009; 31 (07) 493-498
    CrossrefPubMedSearch in Google Scholar
  • 4 Johnson AB, Brenner M. Alexander's disease: clinical, pathologic, and genetic features. J Child Neurol 2003; 18 (09) 625-632
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 van der Knaap MS, Salomons GS, Li R. , et al. Unusual variants of Alexander's disease. Ann Neurol 2005; 57 (03) 327-338
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Search in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMed
  • 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
    Search in Google Scholar
  • 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
    PubMedSearch in Google Scholar