Cerebellar dentate nuclei swelling: a new and early magnetic resonance imaging finding of beta-propeller protein–associated neurodegeneration

Abstract

To the Editor Beta-propeller protein–associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA), caused by mutations in the WD repeat domain 45 (WDR45) gene on chromosomeX that has a key role in the autophagy pathway [1]. Clinically, BPAN is characterized by global developmental delay and epilepsy in early childhood followed by sudden-onset severe dystonia, parkinsonism and progressive dementia in early adulthood. With increasing age, the abnormal progressive iron accumulation causes typical brain MRI hypointensity of the globus pallidus (GP) and substantia nigra (SN) on both T2-weighted images (T2WI) and susceptibility-weighted imaging (SWI), while a SN hyperintense appearance with a central band of low signal, called “halo sign”, can be observed on T1-weighted images (T1WI). The diagnosis of BPAN may be challenging in childhood because of the non-specificity of the symptoms and the initial lack of iron detection on MRI. Other previously described MRI findings in children include cerebral and cerebellar atrophy, thinning of the corpus callosum, and delayedmyelination [2, 3]. To date, there are no effective treatments for BPAN; however, an early diagnosis is crucial to define the natural history of disease and to trial future therapeutic strategies. To our knowledge, we describe for the first time a paediatric patient with mild intellectual disability and generalized epilepsy carrying a pathogenic mutation in WDR45 in whom a first brainMRI showed a severe bilateral swelling of dentate nuclei (DN) in the absence of brain iron deposition on T2WI. The patient was born by healthy non-consanguineous parents by caesarean delivery after 38 weeks of normal pregnancy. Her birth weight was 2800 kg (25th centile). She had a normal acquisition of developmental milestones (first words at 8 months, walking at 12 months). At 16 months, she presented the first complex febrile seizure (focal and lasting about 15 min). A first EEG was normal. She had other three febrile seizures with the same semeiology until 4 years of age. At this age, she started to experience several daily episodes of behavioural arrest. EEG showed generalized epileptic discharges so therapy with valproic acid was introduced. At this age, a global developmental delay, especially concerning language skills, was evident and a rehabilitation program characterized by psychomotor and speech therapy was started. At 6 years of age because of the increase in absences’ frequency, ethosuximide was added in combination with valproic acid, reaching a seizure freedom. Brain MRI showed bilateral enlargement (more than double the normal) of DN, which appeared also slightly hyperintense on T2WI and hypointense on T1WI (hypointense to grey matter) (Fig. 1a–b). Bilateral swelling of SN, corpus callosum thinning (Fig. 1c–f), and cerebral subarachnoid spaces’ slight enlargement were also present in our patient. To investigate the aetiology of mild intellectual disability and epilepsy, we performed a comparative genomic hybridization-array, resulting normal. Next-generation sequencing (NGS) of a panel of 149 genes responsible for epilepsies was performed in the proband. Target enrichment and library preparation was performed using a custom-designed SureSelect assay (Agilent, Santa Clara, USA) and sequencing was performed on an Illumina NextSeq 550 (Illumina, San Diego, CA, USA) with a 2 × 150 bp paired end protocol. Variants were annotated and filtered using the ANNOVAR tool. The NGS analysis revealed a de novo heterozygous non-sense pathogenic variant in the WDR45 gene (c.343_344+2del). The variant was confirmed by Sanger sequencing. At the last evaluation at 7 years, the neurological evaluation showed a mild intention * Gaetano Terrone [email protected]