Chapter 9 - Neurodegeneration with brain iron accumulation

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Abstract

Neurodegenerative disorders with brain iron accumulation (NBIA) are a clinically and genetically heterogeneous group of conditions in which there is neurodegeneration accompanied by elevated levels of brain iron. NBIA is frequently of genetic etiology, but may be secondary to an acquired systemic or neurological disease. Mutations in the ferritin light chain cause an adult-onset autosomal-dominant choreiform movement disorder termed neuroferritinopathy. Homozygous mutations in the ceruloplasmin gene cause aceruloplasminemia, which is characterized by the triad of diabetes, retinopathy, and a neurological disorder in mid adulthood. Mutations in pantothenate kinase 2 (PANK2) and phospholipase A2 (PLA2G6) cause recessive, childhood-onset extrapyramidal disorders termed pantothenate kinase-associated neurodegeneration (PKAN) and infantile neuroaxonal dystrophy (INAD), respectively. There is considerable phenotypic overlap between these conditions. The most useful investigation in suspected NBIA is brain magnetic resonance imaging, which can identify pathological iron deposition and distinguish between genotypes. Iron depletion therapy has been demonstrated to be successful in aceruloplasminemia, but not neuroferritinopathy, PKAN, or INAD. The presentation of NBIA overlaps with the more common adult movement disorders and pediatric neurometabolic conditions, and a high index of suspicion is required to make a correct diagnosis.

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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