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.
- MeSH
- biologické markery krev MeSH
- dítě MeSH
- epilepsie krev genetika metabolismus MeSH
- fenotyp MeSH
- lidé MeSH
- mentální retardace krev genetika metabolismus MeSH
- neurodegenerativní nemoci krev genetika metabolismus MeSH
- pohybové poruchy krev genetika metabolismus MeSH
- poruchy metabolismu železa krev genetika metabolismus MeSH
- transportní proteiny genetika MeSH
- železo krev MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Iron is an essential element necessary for energy production, DNA and neurotransmitter synthesis, myelination and phospholipid metabolism. Neurodegeneration with brain iron accumulation (NBIA) involves several genetic disorders, two of which, aceruloplasminemia and neuroferritinopathy, are caused by mutations in genes directly involved in iron metabolic pathway, and others, such as pantothenate-kinase 2, phospholipase-A2 and fatty acid 2-hydroxylase associated neurodegeneration, are caused by mutations in genes coding for proteins involved in phospholipid metabolism. Phospholipids are major constituents of myelin and iron accumulation has been linked to myelin derangements. Another group of NBIAs is caused by mutations in lysosomal enzymes or transporters such as ATP13A2, mucolipin-1 and possibly also beta-galactosidase and alpha-fucosidase. Increased cellular iron uptake in these diseases may be caused by impaired recycling of iron which normally involves lysosomes. Abnormal iron utilization by mitochondria, as has been proposed in Friedreich's ataxia, is another possible mechanism of iron accumulation. Other, more common degenerative movement disorders, such as Parkinson's disease, Huntington's disease, multiple system atrophy and progressive supranuclear palsy also exhibit increased brain iron content. Finally, brain iron deficiency has been implicated in restless legs syndrome. This review provides an update on recent findings related to genetics, pathogenic mechanisms, diagnosis, and treatment of movement disorders associated with dysregulation of brain iron. We also propose a new classification of NBIAs.
- MeSH
- dopamin MeSH
- lidé MeSH
- pohybové poruchy metabolismus MeSH
- Check Tag
- lidé MeSH
