Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN)

Gore, Ethan; Appleby, Brian S.; Cohen, Mark L.; DeBrosse, Suzanne D.; Leverenz, James B.; Miller, Bruce L.; Siedlak, Sandra L.; Zhu, Xiongwei; Lerner, Alan J.

doi:10.1080/13554794.2016.1247458

Cited by 18 publications

(14 citation statements)

References 50 publications

(54 reference statements)

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“…Transgenic Drosophila models of MPAN manifested in a shorter lifespan and locomotor impairment, but the most remarkable trait was the accumulation of degenerative vacuoles in the brain [ 135 ]. In patients, in addition to the classical iron accumulation in SN and GP, post mortem brain examination revealed neuroinflammation marks such as α-synuclein-positive Lewy bodies, axonal spheroids and neuronal inclusions containing hyperphosphorylated tau protein [ 128 , 136 , 137 ].…”

Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

et al. 2020

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The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

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Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

et al. 2020

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“… Gore, E. et al, 2016. [ 57 ] Case report MPAN 1M 35 Kuwaiti NA ✓ Early behavioural change. Hayflick, S.J.…”

Section: Table A1mentioning

confidence: 99%

Parkinson’s Disease and Metal Storage Disorders: A Systematic Review

2018

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Metal storage disorders (MSDs) are a set of rare inherited conditions with variable clinical pictures including neurological dysfunction. The objective of this study was, through a systematic review, to identify the prevalence of Parkinsonism in patients with MSDs in order to uncover novel pathways implemented in Parkinson’s disease. Human studies describing patients of any age with an MSD diagnosis were analysed. Foreign language publications as well as animal and cellular studies were excluded. Searches were conducted through PubMed and Ovid between April and September 2018. A total of 53 publications were identified including 43 case reports, nine cross-sectional studies, and one cohort study. The publication year ranged from 1981 to 2018. The most frequently identified MSDs were Pantothenate kinase-associated neurodegeneration (PKAN) with 11 papers describing Parkinsonism, Hereditary hemochromatosis (HH) (7 papers), and Wilson’s disease (6 papers). The mean ages of onset of Parkinsonism for these MSDs were 33, 53, and 48 years old, respectively. The Parkinsonian features described in the PKAN and HH patients were invariably atypical while the majority (4/6) of the Wilson’s disease papers had a typical picture. This paper has highlighted a relationship between MSDs and Parkinsonism. However, due to the low-level evidence identified, further research is required to better define what the relationship is.

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“…Previous studies in MPAN using clinical MRI at 3.0 T showed caudate iron accumulation only in late-onset or long-standing cases. 5 In this study, taking advantage of the enhanced sensitivity to iron-induced field inhomogeneities at ultrahigh magnetic field strengths, we have shown that caudate nucleus iron accumulation is a common feature of MPAN patients with typical age at onset and relatively short disease duration. None of the patients displayed an "eye-of-the-tiger sign," which is considered to be pathognomonic of PKAN, but has also been observed, albeit in a less pronounced form, in MPAN.…”

Section: Mpan Findingsmentioning

confidence: 79%

“…In this study, however, we detected early susceptibility changes in the caudate nucleus and putamen of heterozygous mutation carriers in the absence of detectable atrophy, suggesting that iron deposition may be an upstream event preceding cell loss in the caudate nucleus of MPAN patients. Previous studies in MPAN using clinical MRI at 3.0 T showed caudate iron accumulation only in late‐onset or long‐standing cases . In this study, taking advantage of the enhanced sensitivity to iron‐induced field inhomogeneities at ultrahigh magnetic field strengths, we have shown that caudate nucleus iron accumulation is a common feature of MPAN patients with typical age at onset and relatively short disease duration.…”

Section: Discussionmentioning

confidence: 99%

“…In MPAN, brain MRI typically shows focal abnormalities consistent with increased iron levels in the GP and SN . In older patients with long disease duration and/or late onset, iron deposits were observed also in the putamen and caudate nucleus . Additionally, white matter (WM) hyperintensities primarily affecting the periventricular region, and cortical hypometabolism on brain fluorodeoxyglucose PET, have also been described.…”

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confidence: 99%

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Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

et al. 2019

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Background Mitochondrial membrane protein‐associated neurodegeneration is an autosomal‐recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia. Objectives The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1H MR spectroscopy in clinically manifesting membrane protein‐associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers. Methods We present data of 4 clinically affected membrane protein‐associated neurodegeneration patients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age‐matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole‐body system, consisting of whole‐brain gradient‐echo scans and short echo time, single‐volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state‐of‐the‐art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN. Results and Conclusion In membrane protein‐associated neurodegeneration patients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non‐manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein‐associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein‐associated neurodegeneration patients. © 2019 International Parkinson and Movement Disorder Society

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Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN)

Cited by 18 publications

References 50 publications

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

Parkinson’s Disease and Metal Storage Disorders: A Systematic Review

Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

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