Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration

Eur J Paediatr Neurol. 2020 Sep:28:81-88. doi: 10.1016/j.ejpn.2020.07.010. Epub 2020 Aug 4.


Background: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism.

Material and methods: We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients.

Results: Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal.

Conclusion: Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.

Keywords: Beta-propeller protein-associated neurodegeneration; Neurodegeneration with brain iron accumulation WDR45, BPAN; Targeted gene panel sequencing.

MeSH terms

  • Biomarkers / blood
  • Carrier Proteins / genetics*
  • Child
  • Epilepsy / blood
  • Epilepsy / genetics
  • Epilepsy / metabolism
  • Female
  • Humans
  • Intellectual Disability / blood
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism
  • Iron / blood*
  • Iron Metabolism Disorders / blood
  • Iron Metabolism Disorders / genetics*
  • Iron Metabolism Disorders / metabolism*
  • Male
  • Movement Disorders / blood
  • Movement Disorders / genetics
  • Movement Disorders / metabolism
  • Neurodegenerative Diseases / blood
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism*
  • Phenotype


  • Biomarkers
  • Carrier Proteins
  • WDR45 protein, human
  • Iron