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.

No abstract

Gross external findings were determined at necropsy and the brains then fixed whole by suspension in 10% formalin for three to six weeks before slicing. In the 47 cases collected prospectively the brain stem and cerebellum were detached and the cerebrum sliced coronally at one cm intervals. Any grossly obvious lesions were sampled for histological examination. Routinely, blocks were also taken from frontal, temporal, parietal and occipital lobes, hippocampus, basal ganglia, thalamus, cerebellum and medulla. The pons was carefully examined for evidence of CPM and blocks taken at mid-pontine level. In cases where the clincal history suggested pontine disease or where there was evidence of CPM in the first block, additional blocks were taken to include rostral and caudal pons. In three cases only single random blocks of pons were available for study.The tissue was processed to paraffin wax using a standard technique and sections were cut and stained with haematoxylin and eosin and luxol fast blue. In cases where initial sections were suspect for CPM, immunohistochemical stains for glial fibrillary acidic protein (GFAP) and neurofilament protein were prepared using an indirect immunoperoxidase technique,30 and further blocks of tissue were stained with oil red 0 to detect neutral fat.All clinical records were carefully scrutinised and particular note was made of neurological features and serum sodium changes in both the periods before and after transplantation.

No abstract