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

Abstract

‘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, 2013 a ). 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, 2013 a ). 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. Figure 1 Summary of the distinguishing features in different types of NBIA. Different coloured arrows represent the primary pathomechanisms. aCP = aceruloplasminemia; BPAN = beta-propeller protein-associated neurodegeneration; FAHN = fatty acid hydroxylase-associated neurodegeneration; INAD = infantile neuroaxonal dystrophy; KRD = Kufor-Rakeb disease; MPAN = mitochondrial membrane protein-associated neurodegeneration; PKAN = pantothenate kinase associated neurodegeneration; WSS = Woodhouse-Sakati syndrome. 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, …