Clinical and electroencephalographic characteristics of neurodegeneration with brain iron accumulation type 5 in children on the example of 5 cases

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Abstract

Neurodegenerative disease with brain iron accumulation type 5 (OMIM: 300894) manifests itself with early-onset epilepsy, mental retardation with stereotypies that resemble Rett syndrome, and motor disorders under the mask of cerebral palsy in childhood; since adolescence, patients usually have aggravation of parkinsonism and develop complications, such as torsion dystonia. We analyzed medical records of 5 female patients aged between 2.5 and 6 years. There were no family relationships between patients’ families. All children had problems with their motor skills: 4 out of 5 patients could only crawl; none of them could walk independently. We also observed severe speech disorders in these patients: they had no expressive speech along with reduced understanding of speech. Their behavior was characterized by contact disorders and multiple stereotypies. All children had no self-service skills. The assessment of neurological status demonstrated uniform symmetrical paresis (score 3–4; 100 % of cases), increased muscle tone of the extrapyramidal type (40 % of cases), and diffuse muscle hypotension with ataxia (40 % of cases). One patient (with autistic-like behavior) had no motor disorders. Magnetic resonance imaging showed non-specific changes in 100 % of cases (diffuse cortical / subcortical atrophy, secondary hydrocephalus ex vacuo). One patient was found to have hypointense signal in the substantia nigra and globus pallidus on follow-up T2‑weighted magnetic resonance images obtained at the age of 6 years. All patients presented with epilepsy: West syndrome (n = 1), Lennox–Gastaut syndrome (n = 1), focal epilepsy with asymmetric tonic seizures (n = 1), and focal epilepsy with febrile generalized tonic-clonic seizures (n = 2). Remission for more than 1 year was achieved in 4 out of 5 patients. The following electroencephalographic patterns were identified before treatment initiation: hypsarrhythmia with transformation into epilepsy with a pattern of continued spike-and-wave activity during sleep (n = 1), multi-regional epileptiform activity with a tendency to diffuse spread and predominance in the frontal region (n = 3), and regional epileptiform activity in the frontocentral area (n = 1). The initial therapy with first-line drugs was highly effective and ensured remission in 3 patients; one patient had remission in response to hormone therapy; one patient continued to have seizures despite polytherapy with antiepileptic drugs. Interictal epileptiform activity was completely blocked by treatment in 2 cases; the rest of the patients had transformation of epilepsy into benign epileptiform discharges of childhood (n = 3).

About the authors

N. Yu. Perunova

Medical Consultative and Diagnostic Center “Alpha-rhythm”

21 Belorechenskaya St., Yekaterinburg 620102, Russia Russian Federation

M. Yu. Bobylova

Svt. Luka’s Institute of Child Neurology and Epilepsy

Author for correspondence.
Email: mariya_bobylova@mail.ru
5 Nagornaya St., Troitsk, Moscow 108840, Russia Russian Federation

T. M. Prygunova

Nizhny Novgorod Regional Children’s Clinical Hospital

211 Vanaeva St., Nizhniy Novgorod 603136, Russia Russian Federation

References

  1. Zakharova E.Yu., Rudenskaya G.E. New form of neurodegeneration with brain iron accumulation: clinical and genetic characteristics. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry 2014;114(1):4–12. (In Russ.)
  2. Abidi A., Mignon-Ravix C., Cacciagli P. et al. Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient. Eur J Hum Genet 2016;24:615–8.
  3. Dufke A., Grasshoff U., Dufke C. et al. NGS based whole X-exome analysis reveals a familial WDR45 missense mutation in 3 males with intellectual disability and brain iron accumulation. Abstract P08.53-S. European Society of Human Genetics Conference, 2014, Milan.
  4. Gregory A., Kurian M.A., Haack T. et al. Beta-propeller protein-associated neurodegeneration. In: GeneReviews®. Seattle: University of Washington, 1993–2019. Available at: https://www.ncbi.nlm.nih.gov/books/NBK424403/.
  5. Gregory A., Polster B.J., Hayflick S.J. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46:73–80.
  6. Haack T.B., Hogarth P., Kruer M.C. et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet 2012;91:1144–9. doi: 10.1016/j.ajhg.2012.10.019.
  7. Hayflick S.J., Kruer M.C., Gregory A. et al. β-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 2013;136:1708–17. doi: 10.1093/brain/awt095.
  8. Ichinose Y., Miwa M., Onohara A. et al. Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN). Neurol Clin Pract 2014;4:175–7.
  9. Khalifa M., Naffaa L. Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings. Eur J Med Genet 2015;58:381–6. doi: 10.1016/j.ejmg.2015.05.009.
  10. Kruer M.C., Boddaert N., Schneider S.A. et al. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am J Neuroradiol 2012;33: 407–14. doi: 10.3174/ajnr.A2677.
  11. Long M., Abdeen N., Geraghty M.T. et al. Novel WDR45 mutation and pathognomonic BPAN imaging in a young female with mild cognitive delay. Pediatrics 2015;136:e714–7. doi: 10.1542/peds.2015-0750.
  12. Nishioka K., Oyama G., Yoshino H. et al. High frequency of beta-propeller proteinassociated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. Neurobiol Aging 2015;36:2004.e9–15. doi: 10.1016/j.neurobiolaging.2015.01.020.
  13. Ohba C., Nabatame S., Iijima Y. et al. De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain. J Hum Genet 2014;59:292–5. doi: 10.1038/jhg.2014.18.
  14. OMIM: Neurodegeneration with Brain Iron Accumulation 5, NBIA5. Available at: http://omim.org/entry/300894.
  15. Paudel R., Li A., Wiethoff S. et al. Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy. Acta Neuropathol Commun 2015;3:39. doi: 10.1186/s40478-015-0221-3.
  16. Pellock J.M., Hrachovy R., Shinnar S. et al. Infantile spasms: a U.S. consensus report. Epilepsia 2010;51:2175–89. doi: 10.1111/j.1528-1167.2010.02657.x.
  17. Rathore G.S., Schaaf C.P., Stocco A.J. Novel mutation of the WDR45 gene causing beta-propeller protein-associated neurodegeneration. Mov Disord 2014;29:574–5. doi: 10.1002/mds.25868.
  18. Saitsu H., Nishimura T., Muramatsu К. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nature Genet 2013;45:445–9. doi: 10.1038/ng.2562.
  19. Schneider S.A., Bhatia K.P. Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA). J Neural Transm 2013;120:695–703. doi: 10.1007/s00702-012-0922-8.
  20. Verhoeven W.M., Egger J.I., Koolen D.A. et al. Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients. Parkinsonism Relat Disord 2014;20:332–6. doi: 10.1016/j.parkreldis.2013.11.019.
  21. Zarate Y.A., Jones J.R., Jones M.A. et al. Lessons from a pair of siblings with BPAN. Eur J Hum Genet 2016;24:1080–3. doi: 10.1038/ejhg.2015.242.

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Copyright (c) 2020 Perunova N.Y., Bobylova M.Y., Prygunova T.M.

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