Brain iron takes off: a new propeller protein links neurodegeneration with autophagy.

‘Neurodegeneration with brain iron accumulation’ (NBIA) is a clinically and genetically heterogeneous group of disorders presenting with progressive extrapyramidal dysfunction, and as a common feature, with brain iron deposition in the basal ganglia, particularly in the globus pallidus and substantia nigra (Gregory and Hayflick, 2013a). Over recent years an increasing number of mutations in novel disease genes have been identified in NBIA, facilitated by new genetic technologies. Mutations in nine different genes have been shown to cause NBIA to date, with a spectrum of overlapping clinical phenotypes (Fig. 1, Gregory and Hayflick, 2013a). The identification of novel disease genes has improved our understanding of major disease mechanisms leading to iron deposition as a potential common pathway, although the direct link between iron accumulation and clinical presentation requires further work. The clinical ‘hallmarks’ of NBIA are progressive dystonia, dysarthria, spasticity and parkinsonism. Optic atrophy, retinal degeneration and peripheral neuropathy may be associated features in a number of NBIA syndromes. Characteristic MRI findings may be helpful in the diagnosis, but they may appear only later in the disease course. However some specific signs on MRI may facilitate the diagnosis (Fig. 1). The age of manifestation (childhood–adulthood) and the inheritance pattern (autosomal recessive in seven forms; autosomal dominant in neuroferritinopathy; and X-linked in WDR45 deficiency) may be helpful in the differential diagnosis of NBIA (Fig. 1). In a large proportion of cases ( 40%), the underlying genetic basis of NBIA has yet to be defined, suggesting further genetic heterogeneity (Gregory and Hayflick, 2013a). The first identified and most common form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN, MIM 234200; formerly known as Hallervorden-Spatz disease), caused by mutations in PANK2 (Gregory and Hayflick, 2013b). PKAN typically presents with dystonia before 10 years-of-age associated with dysarthria, rigidity and pigmentary retinopathy. Infantile neuroaxonal dystrophy (MIM 256600) is a recessive early childhoodonset disorder with hypotonia, psychomotor retardation and pyramidal signs due to PLA2G6 mutations (Morgan et al., 2006). The third most common NBIA is mitochondrial membrane protein-associated neurodegeneration (MPAN, MIM 614298) due to mutations in C19orf12 (Hartig et al., 2011). The onset is in childhood or early adulthood, the spasticity may be more prominent than the dystonia, and typical features include optic atrophy and motor neuropathy with increased creatine kinase (Horvath et al., 2012). Neuroferritinopathy (MIM 604290, FTL1 gene) is more common in the UK ( 75 reported cases: McNeil and Chinnery, 2012). Rare forms of NBIA are fatty acid hydroxylase-associated neurodegeneration (FAHN, MIM 612443), KuforRakeb disease (PARK9, MIM 606693), aceruloplasminemia (MIM 604290) and Woodhouse-Sakati syndrome, caused by mutations in the FA2H, ATP13A2, aCP and DCAF17 genes, respectively (Gregory and Hayflick, 2013a). In this issue of Brain, Susan Hayflick’s group—in collaboration with several international investigators—reports a large cohort of 23 patients with a recently identified form of NBIA, carrying mutations in the X-chromosomal WDR45 gene encoding a betapropeller protein, postulated to play a role in autophagy (Hayflick et al., 2013). While two papers reported recently on the identification of WDR45 as a novel NBIA gene (Haack et al., 2012; Saitsu et al., 2013), the paper by Hayflick and colleagues (2013) provides an excellent overview on the clinical presentation. Before the identification of WDR45, the original description of some patients with this form of NBIA referred to a distinct clinical syndrome called static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). The new study expands the clinical phenotype and suggests that WDR45 deficiency should be named as ‘beta-propeller protein-associated neurodegeneration’ (BPAN). BPAN is a clinically recognizable disorder with a two-stage disease progression and most likely represents a common type of NBIA (Haack et al., 2012; Saitsu et al., 2013). Despite a high number of different mutations and variable ethnic background, the natural history of the disease is remarkably uniform and recognizable by its distinct pattern of clinical and MRI features. The first stage of the disease is global developmental delay with intellectual disability in infancy or early childhood. Most children are described as clumsy; spasticity and epilepsy—including focal, atonic, absence, generalized tonic-clonic or myoclonic seizures—are frequently reported. A second phase of the disease affects all patients and manifests in adolescent or young adult life ( 25 years) with progressive dystonia, cognitive decline, speech difficulties and parkinsonism characterized by bradykinesia and rigidity, usually without tremor. The severity of parkinsonian features in some patients prompted the authors to suggest that BPAN may be also classified as a genetic form of Brain 2013: 136; 1687–1691 | 1687