Chapter 9 - Neurodegeneration with brain iron accumulation
Section snippets
Introduction and overview
Neurodegenerative disorders associated with high brain iron accumulation (NBIA) were first recognized by the German neuropathologists Julius Hallervorden and Hugo Spatz in 1922. Until recently all patients with high brain iron were given a diagnosis of Hallervorden–Spatz syndrome, despite the obvious clinical heterogeneity of the individual patients. However, Hallervorden and Spatz were involved in active euthanasia under the Nazi regime, so patients should be given a diagnostic label according
Clinical features
The phenotype and natural history of neuroferritinopathy caused by the 460insA mutation in exon four of the FTL gene (Curtis et al., 2001) have been well defined by a large cohort study (Chinnery et al., 2007). Neuroferritinopathy due to the 460insA mutation is predominantly an adult-onset disorder with a mean age at onset of 39 years (range 13–63 years) and which is inherited in an autosomal-dominant manner. The predominant clinical phenotype is an extrapyramidal disorder in the absence of
Clinical features
The phenotype and natural history of aceruloplasminemia have been defined by reviewing published case reports (McNeill et al., 2008b). Aceruloplasminemia is caused by mutations in the ceruloplasmin gene; homozygotes and heterozygotes have distinctive phenotypes (McNeill et al., 2008b, Miyajima et al., 1995, Miyajima et al., 2001a). Homozygous aceruloplasminemia, in which most patients are compound heterozygotes, presents at a mean age of 51 (range 16–72 years) with no gender predominance. The
Clinical features
The phenotype of PKAN (Zhou et al., 2001) has been defined by multicenter studies in North America and western Europe (Hayflick et al., 2003, Hartig et al., 2006). The clinical features described here are based upon reports of patients with confirmed PANK2 mutations only. Hayflick and colleagues (2003) delineated the phenotypes of both classical and atypical PKAN. Classical PKAN has a homogeneous clinical presentation, with 88% of cases presenting before age 6 (range 6 months to 12 years). The
Clinical features
INAD is a severe psychomotor disorder with progressive hypotonia, hyperreflexia, and tetraparesis (Gregory et al., 2008, Kurian et al., 2008). The phenotype of INAD has been defined by the multinational study of Gregory and colleagues (2008). The majority (79%) of INAD cases in this series had a mutation in the PLA2G6 gene. A classical and an atypical INAD phenotype were recognized. In classical INAD the mean age at onset was 1 year (range 5 months to 2.5 years), with a presentation of
Idiopathic NBIA
Idiopathic NBIA is an umbrella term used to describe all cases where imaging or autopsy shows high brain iron but in which a mutation in one of the known genes is not identified. There is evidence that idiopathic NBIA has both genetic and acquired etiologies. A general description of inherited idiopathic NBIA can be deduced from case series of PKAN (Hayflick et al., 2003) and INAD (Gregory et al., 2008). In cases of idiopathic NBIA from within a cohort investigated for PLA2G6 mutations, average
A clinical approach to suspected NBIA
The presentation of both adult and pediatric NBIA is nonspecific, with phenotypes which overlap significantly with more common neurological and metabolic conditions. Table 9.1 summarizes the characteristics of the NBIA subtypes. Neuroferritinopathy is part of the differential diagnosis of adult-onset chorea, dystonia, or parkinsonism which is inherited in a dominant manner, whilst aceruloplasminemia should be considered when these movement disorders are inherited in a recessive manner and are
Acknowledgments
We thank Dr. SJ Hayflick and Professor Hiroaki Miyajima for helpful correspondence regarding INAD and aceruloplasminemia, respectively, and Dr. E Ohta for providing imaging data for the c.469_484dup16nt neuroferritinopathy family.
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Cited by (33)
Metal Imaging in the Brain
2017, Biometals in Neurodegenerative Diseases: Mechanisms and TherapeuticsA combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload
2016, NeuroscienceCitation Excerpt :Iron-overload condition has commonly known to induce cellular toxicity by damaging the cellular compartments, such as DNA and mitochondria, as well as cause the membrane lipid peroxidation (Eaton and Qian, 2002). Moreover, the excessive amounts of iron in the brain have been shown to be associated with neurodegeneration (McNeill and Chinnery, 2011). A previous study demonstrated that the cognitive impairment following chronic iron-overload condition occurred by causing the breakdown of blood–brain barrier (BBB), impairing brain mitochondrial function leading to brain apoptosis (Sripetchwandee et al., 2014a).
Neuroferritinopathy
2012, Parkinsonism and Related DisordersCitation Excerpt :Antidepressants and antiepileptics had no beneficial effect [25,28]. Deep brain stimulation has been tried in one case but was not effective [1]. Therapeutic options for neuroferritinopathy remain unsatisfactory.
Association between PLA2G6 gene polymorphisms and Parkinson's disease in the Chinese Han population
2012, Parkinsonism and Related DisordersCitation Excerpt :PLA2G6, at the PARK14 locus, was also reported to be the causative gene for a form of autosomal recessive early-onset dystonia-parkinsonism [2]. Moreover, mutations of the PLA2G6 gene have also been identified in patients diagnosed with infantile neuroaxonal dystrophy (INAD), PANK2 mutation-negative neurodegeneration associated with brain iron accumulation (NBIA), and Karak syndrome [3]. The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2, also known as calcium-independent phospholipase A2 beta (iPLA2β), which catalyzes the hydrolysis of glycerophospholipids at the sn-2 position; this leads to the generation of a free fatty acid, preferentially docosahexaenoic acid (DHA, C22:6n-3), and a lysophospholipid [4].
Brain, blood, and iron: Perspectives on the roles of erythrocytes and iron in neurodegeneration
2012, Neurobiology of DiseaseCitation Excerpt :Loss of function mutations in Cp destabilize ferroportin proteins, resulting in decreased iron transport towards the plasma and increased storage of intercellular iron (De Domenico et al., 2007). These data explain how mutations in Cp can lead to iron depositions, what the exact mechanisms remains to be elucidated (McNeill and Chinnery, 2011; Texel et al., 2008. Iron deposition has been detected in astrocytes and neurons in the basal ganglia, thalamus and cerebral and cerebellar cortices of ACP affected individuals (Kono and Miyajima, 2006).
Iron dysregulation in movement disorders
2012, Neurobiology of DiseaseCitation Excerpt :Gene mutations (Table 2) or other dysregulation of proteins involved in iron metabolic pathway may ultimately lead to iron accumulation in certain brain regions (Table 3) and cause their dysfunction. A large group of heterogeneous neurologic disorders with markedly excessive, regional brain iron stores, far surpassing the levels observed during normal aging, have been labeled as NBIA (for review see Gregory and Hayflick, 2011; Kurian et al., 2011; McNeill and Chinnery, 2011; Schneider et al., 2011). A distinctive feature of NBIAs is a prominent accumulation of iron recognizable on routine MRI, usually as a decreased signal on T2WI.