Brain iron takes off: a new propeller protein links neurodegeneration with autophagy
Dr Rita Horvath
+ Author Affiliations
Institute of Genetic Medicine, Newcastle University, UK E-mail: Rita.Horvath@ncl.ac.uk
‘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).
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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 beta-propeller 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).
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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 parkinsonism.
[...] Additional symptoms are sleep disturbance (abnormal REM, hypo- or hypersomnolence), ocular features (patchy loss of papillary ruff, coloboma, myopia) and Rett-like hand movement stereotypesin; in seven patients this led to an original diagnosis of atypical Rett syndrome (Hayflick et al., 2013). [...]
Prominent iron accumulation has been detected in the substantia nigra in the early phase of the disease. While nigral iron is evident in these patients, the pallidum may not appear hypointense on regular T2-weighted images, only on gradient-echo or T2* sequences. T1-weighted signal hyperintensity with a central band of hypointensity in the substantia nigra seems to be a specific finding in BPAN. Generalized cerebral atrophy is also reported in 19 out of 23 patients, whereas cerebellar atrophy is a less common feature only being present in six individuals (Hayflick et al., 2013).
One of the most puzzling features of WDR45 deficiency is its inheritance pattern. Although WDR45 is located on the X chromosome, clinical features of the disease do not follow the pattern typical for an X-linked disorder. All affected individuals to date are sporadic cases with no family history of NBIA and most WDR45 variants are nonsense mutations, each arising de novo (Hayflick et al., 2013). Although the significant gender bias (20 females versus three males) suggests that WDR45 mutations are lethal in most males, the phenotypes of the three affected male patients carrying nonsense mutations is clinically indistinguishable from the clinical presentation in females (Gregory and Hayflick, 2013). After excluding sex-chromosome aneuploidy, the most likely explanation is that the mutations are post-zygotic, leading to somatic mosaicism in males, and possibly in females. This mechanism could explain the similarities between genders and also the detection of exclusively de novo mutations in females; and suggests that genetic analysis of multiple tissues may be necessary to screen for WDR45 mutations in mildly affected individuals (Haack et al., 2012). A similar inheritance pattern has been observed in Rett syndrome (MIM 312750), another X-linked dominant disease (Christodoulou and Ho, 2012).
