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.

Children's Hospital Amsterdamer Straße Kliniken der Stadt Köln Cologne Germany

Clinic for Neuropediatrics and Neurorehabilitation Epilepsy Center for Children and Adolescents Schön Klinik Vogtareuth Germany; Research Institute for Rehabilitation Transition and Palliation Paracelsus Medical University Salzburg Austria

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and Motol University Hospital 5 Uvalu 84 15006 Prague Czech Republic

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Neuropaediatrics Centrum for Social Paediatry St Mary´s Children Hospital Landshut Germany

Department of Neuropediatrics University Children's Hospital Tübingen Germany

Department of Paediatric Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Member of the ERN EpiCARE Motol Epilepsy Center 5 Uvalu 84 15006 Prague Czech Republic

Department of Radiology Charles University 2nd Faculty of Medicine and Motol University Hospital 5 Uvalu 84 15006 Prague Czech Republic

Epilepsy Center Paediatric Neurology DRK Kliniken Berlin Westend Berlin Germany

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Cerebral Iron Deposition in Neurodegeneration

A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse