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Cerebral Iron Accumulation Is Not a Major Feature of FA2H/SPG35.

ABSTRACT: Mutations in the fatty-acid 2-hydroxylase (FA2H) gene cause an autosomal recessive spastic paraplegia (SPG35), often associating with cerebellar ataxia; cerebral MRI may show iron accumulation in the basal ganglia, leading to the inclusion of SPG35 among the causes of neurodegeneration with brain iron accumulation. This finding was initially considered strongly relevant for diagnosis, although its frequency is not yet established. We found 5 novel patients (from two families) with mutations in the FA2H gene: none of them showed cerebral iron accumulation (T2-weighted images performed in all; T2 gradient-echo in 2); notably, in 1 case, iron accumulation was absent even after 18 years from disease onset on both T2 gradient-echo and susceptibility-weight MRI sequences. Cerebral iron accumulation is not a prominent feature in SPG35 and is not always dependent on disease duration; its absence should not discourage from evoking this diagnosis.

SUBMITTER: Marelli C

PROVIDER: S-EPMC6353525 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Cerebral Iron Accumulation Is Not a Major Feature of <i>FA2H</i>/SPG35.

Marelli Cecilia C Salih Mustafa A MA Nguyen Karine K Mallaret Martial M Leboucq Nicolas N Hassan Hamdy H HH Drouot Nathalie N Labauge Pierre P Koenig Michel M

Movement disorders clinical practice 20150218 1

Mutations in the fatty-acid 2-hydroxylase (<i>FA2H</i>) gene cause an autosomal recessive spastic paraplegia (SPG35), often associating with cerebellar ataxia; cerebral MRI may show iron accumulation in the basal ganglia, leading to the inclusion of SPG35 among the causes of neurodegeneration with brain iron accumulation. This finding was initially considered strongly relevant for diagnosis, although its frequency is not yet established. We found 5 novel patients (from two families) with mutatio ...[more]

PMID: 30713878

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Project description: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.

Dataset Information

Cerebral Iron Accumulation Is Not a Major Feature of FA2H/SPG35.

Publications

Cerebral Iron Accumulation Is Not a Major Feature of <i>FA2H</i>/SPG35.

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