Brain MRI Pattern Recognition in Neurodegeneration With Brain Iron Accumulation

ABSTRACT Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder caused by mutation in the PANK2 gene. It is characterized by abnormal brain iron accumulation, mainly in the globus pallidus. PKAN is included in a group of disorders known as neurodegeneration with brain iron accumulation (NBIA). We report a case of atypical PKAN with its most characteristic presentation, exhibiting marked psychiatric symptoms, speech disorder and focal dystonia. Brain MRI has great diagnostic importance in this group of disorders and, in this case, disclosed the eye-of-the-tiger sign. Genetic testing confirmed the diagnosis.

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Diagnosing neurodegeneration with brain iron accumulation before iron starts to accumulate

Journal of the International Child Neurology Association ◽

10.17724/jicna.2018.117 ◽

2019 ◽

pp. 17

Author(s):

Ine Hoogwijs

Keyword(s):

Genetic Testing ◽

Brain Mri ◽

Molecular Genetic ◽

Iron Accumulation ◽

Brain Iron ◽

Ataxic Gait ◽

Myelinated Nerve ◽

Axonal Spheroids ◽

Elevated Liver Enzymes ◽

Epilepsy Gene

Introduction Neurodegeneration with brain iron accumulation (NBIA) consists of a heterogeneous group of disorders with brain iron accumulation as common radiological endpoint. Mutations in multiple genes have been associated with NBIA. We present 2 cases with a different type of NBIA, in whom the diagnosis was confirmed before brain iron accumulation became evident on MRI. Case description The first patient was referred because of frequent falls at the age of 4 years. She had an ataxic gait and weak Achilles tendon reflexes. Two years later, pyramidal and more prominent cerebellar signs became evident. A skin and muscle biopsy revealed intra-axonal spheroids in the peri-and endomysial myelinated nerve bundles as well as in the motor endplates, which led to the diagnosis of PLA2G6-associated neurodegeneration (PLAN). Brain iron accumulation occurred at follow-up MRI at 9 years of age. The second patient was referred because of developmental stagnation and detection of elevated liver enzymes at 3 months of age. Seizures started at 15 months of age, and were refractory to treatment with multiple anti-epileptic drugs. Molecular genetic testing using an epilepsy gene panel revealed a mutation in the WDR45 gene, a known cause of beta-propeller protein-associated neurodegeneration (BPAN). Brain MRI at 14 months of age showed diffuse hypomyelination in the absence of BIA. Discussion This report highlights that NBIA can be suspected on a clinical basis and confirmed by genetic testing before iron accumulation becomes present on brain MRI. Early diagnosis will provide a longer timeframe for potential disease modulating treatments in the future.

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Analysis of deep grey nuclei susceptibility in early childhood: a quantitative susceptibility mapping and R2* study at 3 Tesla

Neuroradiology ◽

10.1007/s00234-021-02846-0 ◽

2021 ◽

Author(s):

Peter Raab ◽

Stefan Ropele ◽

Eva Bültmann ◽

Rolf Salcher ◽

Heinrich Lanfermann ◽

...

Keyword(s):

Early Childhood ◽

Caudate Nucleus ◽

Grey Matter ◽

Brain Mri ◽

Iron Accumulation ◽

Iron Deposition ◽

3 Tesla ◽

Brain Maturation ◽

Brain Iron ◽

Deep Grey Matter

Abstract Purpose Aging is the most significant determinant for brain iron accumulation in the deep grey matter. Data on brain iron evolution during brain maturation in early childhood are limited. The purpose of this study was to investigate age-related iron deposition in the deep grey matter in children using quantitative susceptibility (QSM) and R2* mapping. Methods We evaluated brain MRI scans of 74 children (age 6–154 months, mean 40 months). A multi-echo gradient-echo sequence obtained at 3 Tesla was used for the QSM and R2* calculation. Susceptibility of the pallidum, head of caudate nucleus, and putamen was correlated with age and compared between sexes. Results Susceptibility changes in all three nuclei correlated with age (correlation coefficients for QSM/R2*: globus pallidus 0.955/0.882, caudate nucleus 0.76/0.65, and putamen 0.643/0.611). During the first 2 years, the R2* values increased more rapidly than the QSM values, indicating a combined effect of iron deposition and myelination, followed by a likely dominating effect of iron deposition. There was no significant gender difference. Conclusion QSM and R2* can monitor myelin maturation processes and iron accumulation in the deep grey nuclei of the brain in early life and may be a promising tool for the detection of deviations of this normal process. Susceptibility in the deep nuclei is almost similar early after birth and increases more quickly in the pallidum. The combined use of QSM and R2* analysis is beneficial.

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Chronic GM1 Gangliosidosis with Characteristic “Wish Bone Sign” on Brain MRI. Another Type of Neurodegeneration with Brain Iron Accumulation?

Movement Disorders Clinical Practice ◽

10.1002/mdc3.12197 ◽

2015 ◽

Vol 2 (3) ◽

pp. 323-325 ◽

Cited By ~ 4

Author(s):

Omkar Hajirnis ◽

Anaita Udwadia-Hegde

Keyword(s):

Brain Mri ◽

Iron Accumulation ◽

Brain Iron ◽

Gm1 Gangliosidosis

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Adult-Onset Case of Undiagnosed Neurodegeneration with Brain Iron Accumulation with Psychotic Symptoms

Case Reports in Psychiatry ◽

10.1155/2014/742042 ◽

2014 ◽

Vol 2014 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Luigi Attademo ◽

Enrico Paolini ◽

Francesco Bernardini ◽

Roberto Quartesan ◽

Patrizia Moretti

Keyword(s):

Brain Mri ◽

Mood Stabilizer ◽

Iron Accumulation ◽

Psychotic Symptoms ◽

Adult Onset ◽

Brain Iron ◽

Radiographic Evidence ◽

Rate Of Progression ◽

Hypointense Signal ◽

The Brain

Neurodegeneration with brain iron accumulation (NBIA) is a collective term to indicate a group of neurodegenerative diseases presenting accumulation of iron in the basal ganglia. These disorders can result in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Onset age ranges from infancy to late adulthood and the rate of progression is very variable. So far, the genetic bases of nine types of NBIA have been identified, pantothenate-kinase-associated neurodegeneration (PKAN) being the most frequent type. The brain MRI “eye-of-the-tiger” sign, T2-weighted hypointense signal in theglobus palliduswith a central region of hyperintensity, has been considered virtually pathognomonic for PKAN but recently several reports have denied this. A significant percentage of individuals with clinical and radiographic evidence of NBIA do not have an alternate diagnosis or mutation of one of the nine known NBIA-associated genes (idiopathic NBIA). Here we present an adult-onset case of “undiagnosed” NBIA with the brain MRI “eye-of-the-tiger” sign, and with psychotic symptoms which were successfully treated with antipsychotic and mood stabilizer medications. Here, the term “undiagnosed” is used because the patient has not been screened for all known NBIA genes, but only for two of them.

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Neurodegeneration with brain iron accumulation type 4 by mutation in the C19orf12 gene: first time found in adolescent of Russian origin

Neuropediatrics ◽

10.1055/s-0033-1337851 ◽

2013 ◽

Vol 44 (02) ◽

Author(s):

E Giagkou ◽

S Lutz ◽

U Schara ◽

K Becker ◽

C Möller-Hartmann

Keyword(s):

Iron Accumulation ◽

Brain Iron ◽

First Time

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Psychotic Disorder in Neurodegeneration with Brain Iron Accumulation

Clinical Schizophrenia & Related Psychoses ◽

10.3371/1935-1232.10.3.178 ◽

2016 ◽

Vol 10 (3) ◽

pp. 178-180

Author(s):

Menekse Sila Yazar ◽

Nurhan Fistikci ◽

Ozlem Devrim Balaban ◽

Nezih Eradamlar ◽

Latif Alpkan

Keyword(s):

Psychotic Disorder ◽

Iron Accumulation ◽

Brain Iron

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Faculty Opinions recommendation of T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120518.576728 ◽

2008 ◽

Author(s):

Cynthia Comella

Keyword(s):

Iron Accumulation ◽

Brain Iron

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Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-201080 ◽

2021 ◽

pp. 1-9

Author(s):

Janice L. Atkins ◽

Luke C. Pilling ◽

Christine J. Heales ◽

Sharon Savage ◽

Chia-Ling Kuo ◽

...

Keyword(s):

Iron Reduction ◽

Brain Mri ◽

European Ancestry ◽

Uk Biobank ◽

Brain Iron ◽

Mri Features ◽

Incident Dementia ◽

Hfe Mutations ◽

The Uk

Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2 * measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2 * measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.

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Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson’s disease with brain iron accumulation through pseudo-exon activation

Neurogenetics ◽

10.1007/s10048-021-00667-0 ◽

2021 ◽

Author(s):

Chiara Cavestro ◽

Celeste Panteghini ◽

Chiara Reale ◽

Alessia Nasca ◽

Silvia Fenu ◽

...

Keyword(s):

Early Onset ◽

Cerebellar Atrophy ◽

Iron Accumulation ◽

Brain Iron ◽

Causative Gene ◽

Coding Regions ◽

Aberrant Transcript ◽

Pathogenic Variants ◽

Intronic Mutation ◽

Mrna Analysis

AbstractPLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

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