Beta‐propeller protein‐associated neurodegeneration: a case report and review of the literature

Key Clinical Message Beta‐propeller protein‐associated neurodegeneration (BPAN) is a rare disorder, which is increasingly recognized thanks to next‐generation sequencing. Due to a highly variable phenotype, patients may present to pediatrics, neurology, psychiatry, or internal medicine. It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition.


Introduction
Beta-propeller protein-associated neurodegeneration (BPAN) was first described by Haack et al. in 2012 [1]. Before the elucidation of its genetic etiology, the disorder was termed static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). This term reflected the disorder 0 s typical clinical course, comprising static psychomotor retardation in childhood followed by progressive deterioration in adolescence or young adulthood with progressive dystonia, parkinsonism, and dementia. After the discovery of pathogenic mutations in the WDR45 gene, the disorder was renamed BPAN in keeping with the naming conventions of other forms of neurodegeneration with brain iron accumulation (NBIA).
Beta-propeller protein-associated neurodegeneration is a rare disease. NBIA disorders have a prevalence of 1/ A 33-year-old woman of Norwegian descent was referred for neurological evaluation due to rapid motor deterioration. Her parents and two brothers were healthy (Fig. 1). She had been born after a normal pregnancy and delivery and had an uncomplicated neonatal and early development until the age of 6 months, when she was admitted due to episodic cyanosis and eye-rolling/deviation raising suspicion about epileptic seizures. The parents reported persistent crying and intermittent fever during the weeks prior to admittance. Electroencephalography (EEG) showed high-voltage activity with bursts of spike and wave activity, similar to that seen in children with infantile spasms. Suspicion of viral encephalitis was raised, but CSF examination was unremarkable. After discharge, the patient continued having complex partial seizures, characterized by automatisms in the form of lip-smacking and swallowing, which later converted to short pure consciousness lapses, similar to absence seizures. Interictal EEG continued to show epileptic activity of variable localization. Computed tomography (CT) of the brain showed generalized cerebral atrophy.
Her early motor development was normal. She walked at 13 months and was able to climb as a child. At 18 months, it was noted that her language and cognitive development were delayed. At 2.5 years of age, she lost her speech with the exception of a few words and communicated mostly by inarticulate sounds. Intermittent strabismus was described during her school years, and occlusion therapy was attempted but was unsuccessful due to poor compliance. Her hearing developed normally. She was treated with salivary gland surgery at the age of seven due to drooling. Concentration difficulties, anxiety, and phobias were also reported.
The patient 0 s epilepsy responded to treatment with phenobarbital, but due to side effects, she was switched to carbamazepine and finally valproic acid, which was well tolerated and provided optimal long-term seizure control. Her antiepileptic therapy was discontinued at the age of 12, as she had become seizure free. At the age of 17, she developed myoclonic jerks, particularly in her upper extremities, which improved after initiation of clonazepam. Magnetic resonance imaging (MRI) showed signs of metal accumulation in the basal ganglia with conspicuously low T2 signal in the basal ganglia. Susceptibilityweighted imaging (SWI) was not performed.
At the age of 32, her motor function began deteriorating. She developed flexion of her left elbow, wrist, and fingers. This was followed by rapid worsening of general locomotion and gait with frequent falls. Her cognitive and language skills also declined further, and she developed urinary and fecal incontinence. On clinical examination, she was obese, short in stature, but with a generally "happy demeanor" and had severe intellectual disability and poor language skills. She had pronounced dystonic posturing and rigidity in all extremities, bradykinesia, freezing of gait, and stooped posture. Tendon reflexes were normal. She communicated mainly through inarticulate sounds and gestures. Dysmorphic features were noted in the form of short distal phalanx of the thumbs, enlarged gap between the upper teeth, and strabismus. MRI showed a hyperintense "halo" surrounding a band of central hypointensity in the substantia nigra and cerebral peduncles on T1-weighted images and hypointensity in the substantia nigra and globus pallidus (mostly pronounced in substantia nigra) on T2-weighted images. SWI showed prominent hypointensity consistent with metal deposition in the areas mentioned above. There was also marked cerebral atrophy and slight atrophy of vermis (Fig. 2).
Whole-exome sequencing (WES) was performed using the SeqCap EZ MedExome Target Enrichment System (Roche) and Illumina NextSeq 500 platform with NextSeq 500/550 High Output v2 kit (2 9 75 cycles). Data analysis was performed as previously described [4]. Variant filtering was carried out in the NGS module of Cartagenia. WES identified a heterozygous frameshift mutation in the    WDR45 gene: c.1007_1008del, p.Y336Cfs*5. This mutation has been previously reported in two patients with BPAN and is known to be pathogenic. The patient's parents tested negative for the mutation consistent with a de novo origin. Based on these findings, the patient was diagnosed with BPAN. Treatment with levodopa/carbidopa (100/25 mg qid) led to substantial improvement in motor function (in particular, improvement of the bradykinesia), language skills (slight improvement of vocabulary), and her general condition.

Literature Review Demographics and clinical spectrum of BPAN
A total of 64 patients were included in the analysis, comprising 55 women (85.9%) and nine men (14.1%) ( Tables 1 and 2) [1,. Mean age at diagnosis was 27.6 AE 14 years (range 1-52), and mean age at deterioration was 27.2 AE 5.7 (range 13-39). The origin of the mutations was assessed in 47 patients and found to be de novo in 43 (91.5%) and inherited in four (8.5%). All patients had delayed psychomotor development and intellectual disability manifesting from infancy or early childhood characterized by pronounced loss of expressive language skills. In addition, 44 of 59 patients (74.6%) developed progressive cognitive decline upon reaching adolescence or early adulthood. The majority had epileptic seizures (42/62, 67.7%) and movement disorders including dystonia (44/60, 73.3%) and parkinsonism (35/ 58, 60.3%). Epileptic seizures started in early childhood and showed a spectrum ranging from focal to generalized seizures and epileptic spasms. Multiple seizure types were commonly seen in the same individuals [6,16,20]. The epilepsy was generally most severe in childhood and improved with advancing age [3]. Dystonia and parkinsonism developed in adolescence or early adulthood when the motor function started deteriorating and caused severe motor disability with many patients becoming wheelchair-dependent or bedridden.
Rett-like features, including developmental regression, loss of purposeful hand skills, stereotypic hand movements, and bruxism, were seen in 14 patients (14/50, 28%). All but one of these [23] had atypical Rett syndrome or Rett-like features, meaning that they did not fulfill all formal diagnostic criteria for Rett syndrome.

Imaging findings
The vast majority of patients with BPAN (55/61, 90.2%) had MRI findings consistent with iron deposition in the basal ganglia. The two most typical findings were as follows: • Hypointense signal in the substantia nigra and globus pallidus on T2-weighted or iron-sensitive sequences such as SWI. This finding was more prominent in older individuals. The T2 hypointensity was generally more pronounced in the substantia nigra compared to the globus pallidus, a feature that may help distinguish BPAN from other forms of NBIA.
• Hyperintense "halo" surrounding a band of central hypointensity in the substantia nigra and cerebral peduncles on T1-weighted images. This finding is generally regarded as pathognomonic for BPAN.

Treatment
Treatment with oral levodopa leads to clinical improvement in 20 of 21 (95.2%) of BPAN patients with parkinsonism. Positive effects included amelioration of rigidity and bradykinesia, improved affect, appetite, and interest in activities [14,18,21,22]. Slight improvement of expressive language was seen in one case [14]. The majority of patients (15/20, 75%) also had treatment side effects, however, in the form of motor fluctuation and dyskinesias [18]. Clinical improvement was reported in two cases without parkinsonism. One of these experienced amelioration of dystonia, whereas the nature of improvement is not specified in the other. As seen in Table 2, several BPAN patients with parkinsonism (14/35, 40%) were either not treated with levodopa or no information was given on treatment effect.

Pathophysiology
BPAN is caused by mutations in the WDR45 gene. WDR45 encodes WIPI-4 (WD repeat domain phosphoinositide-interacting protein 4), which is part of the WD40 repeat protein family. This group of proteins facilitates the assembly of multiprotein complexes and is important in many essential biological processes, such as signal transduction, cell cycle progression, gene regulation, and apoptosis [33,34]. WD40 domaincontaining proteins assume a symmetric, seven-bladed, beta-propeller platform structure that supports proteinprotein interactions. WIPI-4 is phylogenetically related to two yeast proteins (ATG18 and ATG21) that are part of a recycling system involved in transferring and recycling components from the isolation membrane (also known as phagophore) to the growing autophagosome [35,36]. Available evidence suggests that human WIPI4 protein is involved in autophagy and interacts with the known autophagy factors ATG2A and ATG2B [3,35,36].
Patients with WDR45 mutations have lower autophagic activity and accumulation of aberrant early autophagic structures in lymphoblastoid cell lines (LCLs) [19]. These findings established a direct link between autophagy dysfunction and neurodegeneration in humans [19]. Research into the pathophysiology of BPAN could provide us with new insight into the role of autophagy in iron metabolism [37], and thus further increase our knowledge of pathophysiology of NBIA disorders as a whole. Currently, the primary pathophysiological process leading to NBIA disorders is still not fully understood. Whether abnormal iron deposition is a final common pathway causing disturbed neuronal dysfunction or a "biomarker" of NBIA remains to be determined [38].

Inheritance and Gender
Beta-propeller protein-associated neurodegeneration is inherited in an X-linked dominant manner, but the vast majority of cases (91.5% of the reported cases) are singletons due to de novo mutations. Most affected individuals are female, suggesting reduced survival of male embryos carrying pathogenic WDR45 mutations [18,38]. The broad phenotypic variability in females can be at least partly explained by mosaicism due to skewed X chromosome inactivation. Disease severity in females ranges from pronounced and early disability to asymptomatic carriers. Therefore, cases should not be assumed to be de novo in the absence of clinical signs in the mother [27]. A few male patients have been described, and most seem to have similar but more severe disease [6,16,20,27]. Evidence suggestive of somatic mosaicism (i.e., uneven distribution in different cells and tissues) was reported in one male patient [1] offering a potential explanation for the highly variable involvement and disease severity also seen in males. In conclusion, the broad spectrum of clinical features and severity of BPAN is believed to be due to a combination of one or more of the following: the severity of the mutation, skewed X chromosome inactivation in females, and somatic mosaicism in both sexes.

Conclusion
We have reviewed data from 68 published cases of BPAN. Our analyses show that the clinical spectrum of BPAN is highly heterogeneous. Next-generation, broadspectrum genetic analyses, such as whole-exome sequencing, have enabled early detection of BPAN also in individuals with atypical phenotypes, rendering this disorder highly relevant for both pediatric and adult neurologists. Early diagnosis and regular clinical followup of patients with BPAN are essential in order to offer proper genetic counseling to the affected families, anticipate the deterioration that occurs later in the course of the disease, and provide symptomatic therapy for the movement disorder, when appropriate. The molecular pathophysiology of BPAN is only starting to become unraveled and provides an intriguing novel link between neurodegeneration and impaired autophagy. Increased insight into the molecular mechanisms underlying BPAN will enable the design of tailored therapies for this debilitating disorder and may also provide novel understanding into the role of autophagy in brain aging and neurodegeneration.