β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation

Abstract

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Keywords: NBIA; Rett syndrome; autophagy; basal ganglia; iron.

Figure 1

MRI showing iron in BPAN. The globus pallidus is variably hypointense on axial T₂ (A and E) and more so on FLAIR sequence (B) and sequence (F). Substantia nigra (T₂, C and G; FLAIR, D; , H) shows even greater hypointensity, indicating high levels of iron in these structures.

Figure 2

The halo in the substantia nigra is unique to BPAN. On T₁-weighted axial imaging, substantia nigra shows a halo of hyperintense signal surrounding a thin linear region of hypointense signal on 1.5 T (A and sagittal view in B and C) and 3.0 T (D) field strength scanners.

Figure 3

Early MRI features of BPAN. (A–C) Axial diffusion-weighted images acquired with an echo planar sequence through the midbrain, cerebral peduncles and basal ganglia shows marked hypointensity resulting from the iron deposition in (A and B) substantia nigra and (C) globus pallidi (arrows). (D–F) Corresponding T₂-weighted slices reveals hypointense signal in the corresponding regions as well as vermian atrophy (arrow). (G) Coronal T₂-weighted demonstrates more global cerebellar atrophy. (H and I) Sagittal images (right and left) show hyperintensity of the substantia nigra on T₁-weighted imaging within the midbrain and cerebral peduncles (arrows).

Figure 4

MRI of the globus pallidus and substantia nigra in four main forms of NBIA. Axial T₂-weighted imaging of globus pallidus (top series) and substantia nigra (bottom series) in (A) BPAN; (B) phospholipase A2-associated neurodegeneration; (C) mitochondrial membrane protein-associated neurodegeneration; and (D) pantothenate kinase-associated neurodegeneration.

Figure 5

Pathological features of BPAN. The gross unstained substantia nigra demonstrating a homogenous grey/brown band (arrow) in (A); substantia nigra showing numerous large dystrophic axonal spheroids (arrow) and macrophages (arrowhead) full of haemosiderin (B, ×100, haematoxylin and eosin stain); same region with iron demonstrated by Prussian blue reaction (C, ×100); neurofibrillary tangles (arrows) in hypothalamus (D) the subiculum of the hippocampus (E, ×100, tau immunohistochemistry).