BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) are a group of clinically and genetically heterogeneous diseases characterized by iron overload in basal ganglia and progressive neurodegeneration. Little is known about the epidemiology of NBIA disorders. In the absence of large-scale population-based studies, obtaining reliable epidemiological data requires innovative approaches. METHODS: All pathogenic variants were collected from the 13 genes associated with autosomal recessive NBIA (PLA2G6, PANK2, COASY, ATP13A2, CP, AP4M1, FA2H, CRAT, SCP2, C19orf12, DCAF17, GTPBP2, REPS1). The allele frequencies of these disease-causing variants were assessed in exome/genome collections: the Genome Aggregation Database (gnomAD) and our in-house database. Lifetime risks were calculated from the sum of allele frequencies in the respective genes under assumption of Hardy-Weinberg equilibrium. FINDINGS: The combined estimated lifetime risk of all 13 investigated NBIA disorders is 0.88 (95% confidence interval 0.70-1.10) per 100,000 based on the global gnomAD dataset (n = 282,912 alleles), 0.92 (0.65-1.29) per 100,000 in the European gnomAD dataset (n = 129,206), and 0.90 (0.48-1.62) per 100,000 in our in-house database (n = 44,324). Individually, the highest lifetime risks (>0.15 per 100,000) are found for disorders caused by variants in PLA2G6, PANK2 and COASY. INTERPRETATION: This population-genetic estimation on lifetime risks of recessive NBIA disorders reveals frequencies far exceeding previous population-based numbers. Importantly, our approach represents lifetime risks from conception, thus including prenatal deaths. Understanding the true lifetime risk of NBIA disorders is important in estimating disease burden, allocating resources and targeting specific interventions. FUNDING: This work was carried out in the framework of TIRCON ("Treat Iron-Related Childhood-Onset Neurodegeneration").

• Klíčová slova
• Autosomal recessive NBIA disorders, CoPAN, Lifetime risk, Neurodegeneration, PKAN, PLAN,
• MeSH
• databáze genetické MeSH
• dítě MeSH
• jaderné proteiny MeSH
• komplexy ubikvitinligas MeSH
• lidé MeSH
• mitochondriální proteiny genetika   MeSH
• mozek patologie   MeSH
• neuroaxonální dystrofie * epidemiologie   genetika   patologie   MeSH
• neurodegenerativní nemoci * epidemiologie   genetika   patologie   MeSH
• poruchy metabolismu železa * genetika   patologie   MeSH
• proteiny vázající vápník MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• C19orf12 protein, human MeSH Prohlížeč
• DCAF17 protein, human MeSH Prohlížeč
• jaderné proteiny MeSH
• komplexy ubikvitinligas MeSH
• mitochondriální proteiny MeSH
• proteiny vázající vápník MeSH
• REPS1 protein, human MeSH Prohlížeč

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

• Klíčová slova
• MRI, NBIA, chelation, ferroptosis, iron accumulation, neurodegeneration, siderosis,
• MeSH
• lidé MeSH
• mozek patologie   MeSH
• neuroaxonální dystrofie * patologie   MeSH
• neurodegenerativní nemoci * patologie   MeSH
• poruchy metabolismu železa * patologie   MeSH
• železo farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• železo MeSH

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.

• Klíčová slova
• C19orf12 mutation, MPAN, iron accumulation, neurodegeneration, parkinsonism,
• MeSH
• dospělí MeSH
• interleukiny genetika   MeSH
• lidé MeSH
• mladý dospělý MeSH
• neuroaxonální dystrofie * diagnostické zobrazování   genetika   patofyziologie   MeSH
• poruchy metabolismu železa * diagnostické zobrazování   genetika   patofyziologie   MeSH
• transportní proteiny mitochondriální membrány * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• interleukiny MeSH
• MYDGF protein, human MeSH Prohlížeč
• transportní proteiny mitochondriální membrány * MeSH

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of neurodegeneration with brain iron accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression and to estimate sample sizes for clinical trials. We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites. Linear mixed-effect modelling (LMEM) was used to calculate annual progression rates for the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia (BAD) scale, Schwab and England Activities of Daily Living (SE-ADL) scale and the Pediatric Quality of Life Inventory (PedsQL). We investigated 85 MPAN patients cross-sectionally, with functional outcome data collected in 45. Median age at onset was 9 years and the median diagnostic delay was 5 years. The most common findings were gait disturbance (99%), pyramidal involvement (95%), dysarthria (90%), vision disturbances (82%), with all but dysarthria presenting early in the disease course. After 16 years with the disease, 50% of patients were wheelchair dependent. LMEM showed an annual progression rate of 4.5 points in total UPDRS. The total BAD scale score showed no significant progression over time. The SE-ADL scale and the patient- and parent-reported PedsQL showed a decline of 3.9%, 2.14 and 2.05 points, respectively. No patient subpopulations were identified based on longitudinal trajectories. Our cross-sectional results define the order of onset and frequency of symptoms in MPAN, which will inform the diagnostic process, help to shorten diagnostic delay and aid in counselling patients, parents and caregivers. Our longitudinal findings define the natural history of MPAN, reveal the most responsive outcomes and highlight the need for an MPAN-specific rating approach. Our sample size estimations inform the design of upcoming clinical trials.

• Klíčová slova
• MPAN, NBIA, mitochondrial membrane protein-associated neurodegeneration, neurodegeneration with brain iron accumulation,
• MeSH
• činnosti denního života MeSH
• dítě MeSH
• dysartrie MeSH
• dystonické poruchy * MeSH
• dystonie * MeSH
• fenotyp MeSH
• kohortové studie MeSH
• kvalita života MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mitochondriální membrány MeSH
• mutace genetika   MeSH
• neurodegenerativní nemoci * genetika   MeSH
• opožděná diagnóza MeSH
• průřezové studie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové proteiny MeSH

Pantothenate-kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by iron deposits in basal ganglia. The aim of this study was to quantify iron concentrations of deep gray matter structures in heterozygous PANK2 mutation carriers and in PKAN patients using quantitative susceptibility mapping MRI. By determining iron concentration, we intended to find mutation-specific brain parenchymal stigmata in heterozygous PANK2 mutation carriers in comparison to age-matched healthy volunteers. We studied 11 heterozygous PANK2 gene mutation carriers (mean age: 43.4 years; standard deviation [SD]: 10.5), who were found to be clinically asymptomatic by neurological examination. These carriers were compared to 2 clinically affected PKAN patients 21 and 32 years of age and to 13 age-matched, healthy controls (mean age: 39.7; SD, 13.6). Scanning was performed on a 7.0-Tesla whole-body scanner applying three-dimensional susceptibility-weighted gradient echo acquisitions. Susceptibility maps were calculated by threshold-based k-space division with single-orientation acquisition. Magnetic susceptibility values, relative to the occipital white matter, were determined for the following regions of interest (ROI): globus pallidus (GP), thalamus, putamen, internal capsule (IC), caudate nucleus, substantia nigra (SN), and red nucleus. Heterozygous PANK2 mutation carriers did not show increased brain iron concentrations, compared to healthy controls (P > 0.05), in any of the examined ROIs. In PKAN patients, more than 3 times higher concentrations of iron were found in the GP, SN, and IC. Our results suggest that heterozygous mutations in PANK2 gene do not cause brain iron accumulation nor do they cause movement disorders.

• Klíčová slova
• 7‐Tesla MRI, iron, neurodegeneration with brain iron accumulation (NBIA), pantothenate kinase associated neurodegeneration (PKAN), quantitative susceptibility mapping,
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• INDUSTRIAL HYGIENE *,
• MeSH
• hygiena práce * MeSH
• lidé MeSH
• neuroaxonální dystrofie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• MICROBIOLOGY/education *,
• MeSH
• lékaři * MeSH
• lidé MeSH
• mikrobiologie výchova   MeSH
• neuroaxonální dystrofie * MeSH
• plánování péče o pacienty * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• ECONOMICS, MEDICAL *,
• MeSH
• ekonomika lékařská * MeSH
• lidé MeSH
• neuroaxonální dystrofie * MeSH
• plánování péče o pacienty * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• NEUROLOGY *,
• MeSH
• lidé MeSH
• neuroaxonální dystrofie * MeSH
• neurologie * MeSH
• plánování péče o pacienty * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Československo MeSH

Disturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.

• Klíčová slova
• Friedreich’s ataxia, Iron chelation, Multiple sclerosis, NBIA, Parkinson’s disease, Superficial siderosis,
• MeSH
• chelátory železa terapeutické užití   MeSH
• lidé MeSH
• neurodegenerativní nemoci farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• chelátory železa MeSH