Highlights
- •First study focusing on potential alterations in blood iron metabolism in BPAN.
- •Elevation of sTfr/log ferrit – possible new biochemical marker of BPAN.
- •Gradually decreasing severity of epilepsy in some BPAN patients.
Abstract
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
Abbreviations:
BPAN- (Beta-propeller protein-associated neurodegeneration), WDR45- (WD-Repeat Domain 45 gene), sTfr/log ferrit- (soluble transferrin receptor/log ferritin ratio)To read this article in full you will need to make a payment
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References
- Neurodegeneration with brain iron accumulation.Handb. Clin. Neurol. 2018; 147: 293-305https://doi.org/10.1016/B978-0-444-63233-3.00019-1
- Neurodegeneration with brain iron accumulation: diagnosis and management.J. Mov. Disord. 2015; 8: 1-13https://doi.org/10.14802/jmd.14034
- Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.Brain. 2013; 136: 1708-1717https://doi.org/10.1093/brain/awt095
- Neuroimaging features of neurodegeneration with brain iron accumulation.Am. J. Neuroradiol. 2012; 33: 407-414https://doi.org/10.3174/ajnr.A2677
- Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.Am. J. Hum. Genet. 2012; 91: 1144-1149https://doi.org/10.1016/j.ajhg.2012.10.019
- De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood.Nat. Genet. 2013; 45: 445
- Beta-propeller protein-associated neurodegeneration.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. 1993 (Seattle (WA))
- High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism.Neurobiol. Aging. 2015; 36 (e9-2004.e15): 2004https://doi.org/10.1016/j.neurobiolaging.2015.01.020
- Lessons from a pair of siblings with BPAN.Eur. J. Hum. Genet. 2016; 24: 1080-1083https://doi.org/10.1038/ejhg.2015.242
- WDR45 mutations in three male patients with West syndrome.J. Hum. Genet. 2016; 61: 653-661https://doi.org/10.1038/jhg.2016.27
- Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient.Eur. J. Hum. Genet. 2015; 24: 615-618https://doi.org/10.1038/ejhg.2015.159
- Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN).Neurol. Clin. Pract. 2014; : 175-177
- Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: additional case report and review of the literature.Am. J. Med. Genet. 2016; 170: 322-328https://doi.org/10.1002/ajmg.a.37432
- Detection Rate of Causal Variants in Severe Childhood Epilepsy Is Highest in Patients with Seizure Onset within the First Four Weeks of Life.2018: 1-8
- Rapid detection of subtelomeric deletion/duplication by novel real-time quantitative PCR using SYBR-green dye.Hum. Mutat. 2004; 23: 368-378https://doi.org/10.1002/humu.20011
- MDS clinical diagnostic criteria for Parkinson's disease.Mov. Disord. 2015; 30: 1591-1601https://doi.org/10.1002/mds.26424
- ClinVar: public archive of interpretations of clinically relevant variants.Nucleic Acids Res. 2016; 44: D862-D868https://doi.org/10.1093/nar/gkv1222
- Atypical late presentation of BPAN in a male: a case report.Park. Relat. Disord. 2018; : 1-2https://doi.org/10.1016/j.parkreldis.2018.09.010
- Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.Epilepsia. 2018; 59: e5-e13https://doi.org/10.1111/epi.13957
- Novel WDR45 mutation and pathognomonic BPAN imaging in a young female with mild cognitive delay.Pediatrics. 2015; 136: e714-e717https://doi.org/10.1542/peds.2015-0750
- Beta-propeller protein-associated neurodegeneration: a case report and review of the literature.Clin. Case Rep. 2018; 6: 353-362https://doi.org/10.1002/ccr3.1358
- Epileptic spasms : a previously unreported manifestation of WDR45 gene mutation.. 2015; 17 (∗): 467-472
- A novel WDR45 mutation in a patient with β-propeller protein-associated neurodegeneration.Neurol. Genet. 2016; 3: 1-4https://doi.org/10.1212/NXG.0000000000000124
- A case of beta-propeller protein-associated neurodegeneration due to a heterozygous deletion of WDR45.Tremor Other Hyperkinetic Movements. 2017; 7: 1-4https://doi.org/10.7916/D8251WB0
- Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct.X-linked dominant form of NBIA. 2012; (1144–9)https://doi.org/10.1016/j.ajhg.2012.10.019
- Neurodegeneration with brain iron accumulation.Handb. Clin. Neurol. 2018; 147: 293-305https://doi.org/10.1016/B978-0-444-63233-3.00019-1
- 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: 381-386https://doi.org/10.1016/j.ejmg.2015.05.009
- Usefulness of soluble transferrin receptor and ferritin in iron deficiency and chronic disease.Scand. J. Clin. Lab. Invest. 2005; 65: 571-576https://doi.org/10.1080/00365510500206542
- Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency.Clin. Chem. 2002; 48: 1066-1076
- A hematologic “gold standard” for iron-deficient States?1.Clin. Chem. 2002; 48: 981-982https://doi.org/10.1093/clinchem/48.7.981
- Iron status determination in pregnancy using the Thomas plot.Int. J. Lab. Hematol. 2016; 38: 119-124https://doi.org/10.1111/ijlh.12448
- Ferrous iron up-regulation in fibroblasts of patients with beta propeller protein-associated neurodegeneration (BPAN).Front. Genet. 2017; 8: 1-7https://doi.org/10.3389/fgene.2017.00018
- Patient affected by beta-propeller protein-associated neurodegeneration: a therapeutic attempt with iron vhelation therapy.Front. Neurol. 2017; 8: 1-5https://doi.org/10.3389/fneur.2017.00385
Article info
Publication history
Published online: August 03, 2020
Accepted:
July 28,
2020
Received in revised form:
July 16,
2020
Received:
April 25,
2020
Identification
Copyright
© 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
