|Year : 2020 | Volume
| Issue : 3 | Page : 325-327
Early-onset parkinsonism and halo sign: Beta-propeller protein-associated neurodegeneration
Debopam Samanta1, Raghu Ramakrishnaiah2
1 Child Neurology Division, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
2 Division of Neuroradiology and Pediatric Radiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
|Date of Submission||01-Apr-2020|
|Date of Decision||08-Jun-2020|
|Date of Acceptance||07-Jul-2020|
|Date of Web Publication||06-Nov-2020|
Dr. Debopam Samanta
1 Children’s Way, Little Rock, Arkansas, AR.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
A 13-year-old girl with infantile-onset self-resolving epilepsy and developmental delay had an unremarkable workup, including normal brain magnetic resonance imaging (MRI) and chromosomal microarray. During adolescence, she presented with features of early-onset parkinsonism: gait dyspraxia, freezing during walking, cogwheel rigidity in both upper extremities, and left arm dystonia. Repeat brain MRI showed iron deposition on the substantia nigra (SN) and basal ganglia, with hyperintense halo sign around a central linear hypointensity within the SN on the T1 imaging sequence. Whole-exome sequencing with trio revealed de novo heterozygote mutation in WDR45 to confirm the diagnosis of beta-propeller protein-associated neurodegeneration (BPAN). BPAN is a rare neurodegenerative with brain iron accumulation disorder with the pathognomonic halo sign. Preferential iron deposition over the SN compared to globus pallidus can distinguish this condition from other iron storage disorders. BPAN does not cause the radiologic eye of the tiger sign seen in other forms of iron storage disorders. Other types of childhood-onset parkinsonian disorders, such as PINK1-related Parkinson disease and Parkin-type Parkinson disease, do not have iron storage in the brain. This report describes a case of early-onset parkinsonism secondary to a mutation in WDR45. It underscores the importance of brain MRI to differentiate this condition from other childhood-onset parkinsonism and also other brain iron accumulation disorders. This report also shows iron deposition over the pituitary as a novel site of iron deposition in BPAN and emphasizes the presence of peri-dentate white matter volume loss and hyperintensity, which is another key radiologic abnormality associated with BPAN.
Keywords: Beta-propeller protein-associated neurodegeneration, halo sign, neurodegeneration with brain iron accumulation, parkinsonism, WD45
|How to cite this article:|
Samanta D, Ramakrishnaiah R. Early-onset parkinsonism and halo sign: Beta-propeller protein-associated neurodegeneration. J Pediatr Neurosci 2020;15:325-7
| Introduction|| |
Childhood-onset Parkinsonism More Details is an extremely rare condition. We report a 13-year-old with parkinsonism secondary to beta-propeller protein-associated neurodegeneration (BPAN), an ultrarare type of neurodegenerative disorder with brain iron accumulation (NBIA).
| Case Description|| |
A 13-year-old Caucasian female, with a history of intellectual impairment and epilepsy, presented with a 1-year history of motor and cognitive skills deterioration. She was born full-term after an uncomplicated pregnancy and delivery to non-consanguineous parents. Her birth weight was 3.2kg, length was 49 cm, and head circumference was 34.5 cm. She had early-onset global developmental delays and developed focal epilepsy with impaired awareness (frequent episodes of staring off and few episodes of tonic–clonic convulsions) since late infancy. Electroencephalography (EEG) showed mild background slowing and multifocal epileptiform discharges. However, her epilepsy was well controlled with oxcarbazepine monotherapy, which was successfully weaned off without recurrence of seizures during mid-childhood. She also had mild-to-moderate appendicular hypotonia. Brain magnetic resonance imaging (MRI) was reported normal at that time. Additional laboratory workup was unremarkable, including comprehensive metabolic panels, liver and renal functions, lactic acid, pyruvate, plasma amino acid, urine organic acid, biotinidase, carnitine and acylcarnitine profile, very long chain fatty acid, and chromosomal microarray.
She attained slow developmental and academic milestones until the age of 12 years when she started to show difficulty with walking. Physical examination showed gait dyspraxia, freezing during walking, and cogwheel rigidity in both upper extremities without any pyramidal signs or tremor. She was also noted to have left arm dystonia. With suspicion of a childhood-onset parkinsonian syndrome, brain MRI was repeated that showed iron deposition on the substantia nigra (SN) and basal ganglia. Besides the confirmation of a diagnosis of NBIA, neuroimaging also showed the characteristic halo sign in the form of the hyperintensity around a central linear hypointensity within the SN, characteristically present in BPAN. In addition, peri-dentate white matter volume loss and atrophy of the midline vermis were noted. A particularly rare finding of symmetric signal loss was noted in the pars lateralis of the pituitary due to mineral deposition [Figure 1]. Whole-exome sequencing with trio revealed de novo heterozygote mutation in WDR45 to confirm the diagnosis of BPAN. She responded dramatically to a low dose of levodopa–carbidopa combination with improvement in motor skills.
|Figure 1: Cropped oblique axial susceptibility weighted image (A) through basal ganglia and midbrain shows symmetric signal drop within the globus pallidus (arrowheads); SN (arrows) and within the red nucleus (curved arrow) cropped axial T1-weighted image through the midbrain (B) shows focal symmetric hyperintensity in the cerebral peduncle (positive halo sign). Coronal T2-weighted image of the cerebellum (C) shows peri-dentate white matter volume loss and hyperintensity (curved arrows) and atrophy of the midline vermis (black arrow). Coronal T2-weighted image through the sella turcica (D) shows symmetric signal loss (arrows) in the pars lateralis of the pituitary due to mineral deposition|
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| Discussion|| |
NBIA comprises several different rare genetic diseases with a combined prevalence of 1 in 1 million individuals.TP13A2, C19orf12, COASY, CP, DCAF17, FA2H, FTL, PANK2, PLA2G6, and WDR45 genes are associated with different types of NBIA. BPAN, only type of X-linked dominant subtype of NBIA, occurs secondary to WDR45 mutations, and it was first described in less than 10 years ago. Less than 70 cases of this ultrarare disorder had been reported, and less than 20 patients have been characterized in the pediatric literature. Being an X-linked dominant disorder, this disease affects females predominantly with usual lethality in males. Although sporadic de novo mutations are most commonly detected in affected patients, germ line pathogenic mutations with affected brother and sister duo have been reported. As expected in that scenario, males are more severely affected, and phenotypes in the females may be dependent on the skewed X-chromosome inactivation. Somatic mosaicism may also be responsible for less severity of the phenotypes. Disrupted protein–protein interaction and abnormal autophagic method to clear damaged cell components have been proposed as a primary mechanism of neurodegeneration in BPAN.
BPAN is characterized by early-onset seizures, developmental delay, particularly expressive language impairment, ataxia, incoordination, sleep dysfunction, autistic behavior, and presence of Rett syndrome–like stereotyped hand movements.,, Though childhood-onset seizures are usually easily controlled, infantile-onset developmental and epileptic encephalopathy with infantile spasms have been rarely reported in severely affected patients. Many patients with early-onset developmental delay present with cognitive deterioration, worsening spasticity, and the emergence of movement disorders such as dystonia and parkinsonism during the second or third decade of life.
BPAN has a pathognomonic neuroradiologic sign—hyperintense halo sign around a central linear hypointensity within the SN, evident on the T1 imaging sequence. T2-weighted and iron-sensitive sequence show hypointense signal in the SN and globus pallidus. BPAN does not cause the radiologic eye of the tiger sign seen in other forms of iron storage disorders, most classically associated with pantothenate kinase–associated neurodegeneration (PKAN). More iron deposition over the SN compared to globus pallidus can distinguish this condition from other iron storage disorders, such as COASY protein–associated neurodegeneration (CoPAN), fatty acid hydroxylase–associated neurodegeneration (FAHN), mitochondrial membrane protein–associated neurodegeneration (MPAN), PKAN, PLA2G6-associated neurodegeneration (PLAN), Kufor–Rakeb syndrome, neuroferritinopathy, aceruloplasminemia, and Woodhouse–Sakati syndrome. There are other nonspecific MRI findings seen in this condition, such as hypomyelination, thin corpus callosum, cerebellar, and cerebral atrophy. Other forms of childhood-onset parkinsonian disorders such as PINK1-related Parkinson disease and Parkin-type Parkinson disease do not have iron storage in the brain.
Effectiveness of the iron chelation therapy is currently unknown, but parkinsonian features may respond to levodopa–carbidopa combination as reported in this patient. However, close monitoring is needed for the emergence of functionally disabling motor fluctuations and dyskinesia. In patients with advanced disease, carbidopa–levodopa combination may be preferable to dopamine agonists as the former has a lower risk of adverse neuropsychiatric adverse effects. For the treatment of dystonia and spasticity, broad ranges of pharmacologic agents have been used, such as amantadine, benzodiazepines, baclofen, botulinum toxin injection, and trihexyphenidyl.
This report describes a case of early-onset parkinsonism secondary to a mutation in WDR45 and underscores the importance of brain MRI to differentiate this condition from other childhood-onset parkinsonism and also other brain iron accumulation disorders. This report also shows iron deposition over the pituitary as a novel site of iron deposition in BPAN and emphasizes the presence of peri-dentate white matter volume loss and hyperintensity, which is another key radiologic abnormality associated with BPAN.
All procedures performed in studies involving human participants were by the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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