New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN.

UHS NHS Foundation Trust (N.C.F., S.R.H.) and Department of Human Genetics and Genomic Medicine, Faculty of Medicine (N.C.F.), University of Southampton, Southampton, UK
Neurology (Impact Factor: 8.3). 12/2012; DOI: 10.1212/WNL.0b013e31827e07be
Source: PubMed

ABSTRACT OBJECTIVE: To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype. METHODS: Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject. RESULTS: A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures. CONCLUSIONS: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase-associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.

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    ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with movement disorders and brain iron deposits. In addition to NBIA subtypes caused by mutations in PANK2 and PLA2G6, mutations in the C19orf12 gene were recently described as the third frequent cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Additionally, the X-linked gene WDR45 was found causative for a special subtype named static encephalopathy in childhood with neurodegeneration in adulthood (also called BPAN); however, analysis of this gene in a broader spectrum of NBIA has not been reported yet. In a heterogeneous cohort of 69 patients with suspected NBIA that did not carry mutations in PANK2 and PLA2G6, the coding region of C19orf12 was evaluated by Sanger sequencing. The WDR45 gene was analyzed via high resolution melting and subsequent sequence analysis. Previously described homozygous C19orf12 mutations were found in 3/69 NBIA patients (4.3%). Analysis of the WDR45 gene revealed a novel heterozygous missense mutation in one female NBIA patient showing psychomotor retardation with secondary decline. C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood. Copyright © 2014 Elsevier B.V. All rights reserved.
    Journal of the Neurological Sciences 01/2015; 349(1-2). DOI:10.1016/j.jns.2014.12.036 · 2.26 Impact Factor
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    ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.
    01/2015; 8(1):1-13. DOI:10.14802/jmd.14034
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    ABSTRACT: Therapeutic trials for Neurodegeneration with Brain Iron Accumulation have aimed at a reduction of cerebral iron content. A 13-year-old girl with mitochondrial membrane protein-associated neurodegeneration treated with an iron-chelating agent was monitored by R2 relaxometry, R2* relaxometry, and quantitative susceptibility mapping to estimate the brain iron content. The highly increased brain iron content slowly decreased in the substantia nigra but remained stable for globus pallidus. The estimated iron content was higher by R2* compared to R2 and quantitative susceptibility mapping, a finding not previously observed in the brain of healthy volunteers. A hypothesis explaining this discrepancy is offered.
    12/2014; DOI:10.1002/acn3.116


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May 22, 2014