Beta-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.

Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient

“…It has been hypothesized that the gender bias was due to WDR45 variants lethality in males. 3 Along the same line, somatic mosaicism would explain the similar phenotype between the few affected males and female patients. Indeed, Haack et al 2 have confirmed the presence of somatic mosaicism in a male patient.…”

“…2 WDR45 variants associated with BPAN syndrome have been almost exclusively found in females and only three male cases have been described to date. 3 This low incidence of male cases has been attributed to male lethality and the existence of a few male carriers to somatic mosaicism. 2 Among published cases, 70% of patients suffered from epileptic seizures beginning after 3 months of age.…”

“…2 Among published cases, 70% of patients suffered from epileptic seizures beginning after 3 months of age. 3,4 Early-onset epileptic encephalopathies (EOEE) form a group of severe epilepsies occurring in the first 3 months of life. Clinical signs include stormy seizures associated with an altered interictal electroencephalographic (EEG) pattern and abnormal neurological development.…”

Autophagy and human diseases

“…It is unclear, however, whether hemizygous mutations in male patients are lethal. Hayflick's group reported three male SENDA patients with similar phenotypes [12,26]; all three may have had somatic mosaicism. These studies provided the first direct evidence that the deficiency of a core autophagy factor is indeed a contributing factor to human neurodegenerative diseases.…”

Niemann-Pick’s disease type B and brain iron accumulation

“…Besides PKAN caused by mutations in the PANK2 gene, [1,2] the best characterized subtypes include MPAN with mutations/deletions in the c19orf12 gene, [7][8][9] the PLA2G6 Associated Neurodegeneration (PLAN) with mutations in the PLA2G6 gene, [10] the Coasy Protein Associated Neurodegeneration (CoPAN) with mutations in the Coasy gene, [11] and the Beta-Propeller Protein Associated Neurodegeneration (BPAN) with mutations in the WDR45 gene. [12] A shared feature of these diseases is brain iron accumulation that is likely secondary to abnormalities in lipid metabolism and autophagy. [3,4] Figure 2.…”