To date, a total of 160 WDR45-related cases have been described, including 21 males [2]. The most common presenting initial symptom, in both genders, is usually developmental delay followed by epilepsy [2, 9]. Other frequent findings in males include movement disorders (50%), cognitive deterioration (around 30%), and cerebellar dysfunction (around 40%) as seen in our proband [2].
Variable MRI findings are associated with this disorder.[9]. Initial nonspecific findings include T2-weighted hyperintensities and swelling of dentate, globi pallidi and substantia nigra,optic nerve thinning, cerebral and cerebellar atrophy [3, 9, 10]. Although deep grey matter swelling was previously considered transient and related to triggering events (e.g. pyrexia and seizures) [11], recent data confirm that, similar to our report, swelling often persists over time [3]. Brain iron accumulation is usually evident by the age of 5 years. Rare cases of later presentation, as seen in our proband, have been reported [3]. Thus, the absence of iron accumulation in young children does not exclude the diagnosis of a WDR45-related NDDs and a close MRI follow with, iron-sensitive sequences must be established.
In our patient we detected a cI deficiency both in muscle and fibroblasts and a cII deficiency in muscle only. Oxidative phosphorylation (OXPHOS) system deficiencies have never been reported in WDR45 patients to date, but mitochondrial abnormalities have been reported in several NBIA subtypes [4]. Furthermore, mitochondrial morphological changes, including accumulation of abnormal mitochondrial proteins, enlarged mitochondria, decreased mitochondrial membrane potential and reduced ATP production have been proven in WDR45 −/− deficient mice, HeLa cells, WDR45 mutant fibroblasts and induced pluripotent stem cell-derived neurons [5–7, 12]. Additionally, a CI deficiency was recently demonstrated in the brain of WDR45 −/− deficient mice [7]. The interplay between autophagy and mitochondrial dysfunction is to date not yet fully understood. Mitochondrial dysfunction could be autophagy-independent or could be a consequence of impaired autophagy. In support of the latter, findings on mammalian fibroblasts have shown that inhibition of autophagy led to an increase of mitochondrial mass function of WDR45 [6].
The autophagy analysis carried out in our patient suggests that WIPI4 encoded by WDR45 contributes to the early activation of autophagy by regulating p62. However, compensatory mechanisms likely intervene to ensure autophagy progression, at least in non-neuronal cells, such as the patient’s fibroblasts, as indicated by the normal response of autophagy marker LC3 to the autophagy flux.
These results are in line with recent findings indicating that the autophagic flux is unaffected or only mildly reduced upon individual deletion of WIPI3 (encoded by WDR45B) and WIPI4 (encoded by WDR45) or upon introduction of specific missense mutations in WDR45, thus suggesting that neurodegeneration in BPAN may be related to non-autophagic functions of WIPI4 [13].
Functional evidence from our patient seems to indicate that the p. (Ser250del) in WIPI4 also has a mild effect on autophagy, but significantly affects the assembly and enzymatic activity of cI, similar to recent data in mouse model of BPAN [7]
Our report suggests that WDR45-associated diseases, especially in males, can mimic MDs from a clinical, biochemical and neuroradiological standpoint, and thus should be considered in the differential diagnosis of these disorders. Future additional studies are needed to fully understand the molecular mechanisms underlying this mitochondrial dysfunction.
In conclusion, our study confirms, for the first time, a mitochondrial impairment in humans and strengthens the role of mitochondria in the pathogenesis of WDR45-related NDDs, paving the way for novel therapeutic approaches in BPAN patients.