Download Novel WDR45 Mutation and Pathognomonic BPAN Imaging in a

Novel WDR45 Mutation and
Pathognomonic BPAN Imaging in a
Young Female With Mild Cognitive
Delay
Michelle Long, MDa, Nishard Abdeen, MD, FRCPCb, Michael T. Geraghty, MD, FRCPCc, Penelope Hogarth, MD, FRCPCd,
Susan Hayflick, MD, FRCPCd, Sunita Venkateswaran, MD, FRCPCe
b-propeller protein-associated neurodegeneration (BPAN) is a recently identified
X-linked dominant form of neurodegeneration with brain iron accumulation
caused by mutations in the WDR45 gene. BPAN commonly presents as global
developmental delay in childhood with rapid onset of parkinsonism and dementia
in early adulthood and associated pathognomonic changes seen on brain MRI. In
this case report, we present a pediatric patient with mild cognitive delay and
pathognomonic MRI changes indicative of BPAN preceding neurologic
deterioration who is found to have a novel de novo mutation in the WDR45 gene.
Neurodegeneration with brain iron
accumulation (NBIA) is a genetically and
clinically heterogeneous group of
disorders with the common feature of
iron deposition in the basal ganglia and
substantia nigra. b-propeller proteinassociated neurodegeneration (BPAN) is
a recently identified, X-linked dominant
form of NBIA characterized by 2 phases
of disease: intellectual disability and
global developmental delay in childhood
with rapid progressive onset of
parkinsonism, dystonia, and dementia
in early adulthood.1 Previously referred
to as static encephalopathy of childhood
with neurodegeneration, BPAN involves
de novo mutations in the WDR45 gene,
which plays a critical role in autophagy
through a WD40 repeat protein with
a b-propeller platform structure.2 In
this case report, we present a young
woman with MRI changes preceding
clinical progression who possesses
a novel, heterozygous mutation in
WDR45: c.251A.G (p.Asp84Gly).
PATIENT PRESENTATION
We report an 18-year old young
woman born from nonconsanguineous
PEDIATRICS Volume 136, number 3, September 2015
parents who was referred for
neurologic assessment at age 17 for
a long-standing history of mild speech
development issues and cognitive
difficulties. Before the publication of
this case report, fully informed written
consent was provided by the family.
Pregnancy and birth history were
unremarkable. Gross and fine motor
developmental milestones were
achieved at appropriate times during
childhood; however, her mother
reported a long-standing history of
expressive and receptive language
difficulties requiring speech language
therapy until grade 8. She continued to
struggle with sentence structure,
grammar, and articulation at the time
of assessment. Cognitive difficulties
were first identified at age 6, and she
was subsequently placed into a special
education program. Previous
psychoeducational testing results were
unavailable. Her mother reported no
history of developmental regression
but did feel her language skills
plateaued at age 14. At age 17, she was
completely independent in her
activities of daily living and was
abstract
a
Division of Emergency Medicine, bDepartment of Medical
Imaging, cDepartment of Pediatrics, Metabolic Unit, and
e
Division of Neurology, Children’s Hospital of Eastern
Ontario, University of Ottawa, Ottawa, Canada; and
d
Departments of Molecular and Medical Genetics and
Neurology, Oregon Health & Science University, Portland,
Oregon
Dr Long was involved in patient care and drafted
and revised the initial manuscript; Dr Abdeen
interpreted the key images that lead to the
diagnosis, provided the images and interpretation of
images, and reviewed the manuscript; Dr Geraghty
was involved in conception and design of the
manuscript and revised it critically for content; Drs
Hogarth and Hayflick made substantial
contributions to the analysis and interpretation of
the data and critically revised the manuscript for
the intellectual content; Dr Venkateswaran
conceptualized and designed the report, and
critically reviewed and revised the manuscript; and
all authors have approved the final manuscript as
submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-0750
DOI: 10.1542/peds.2015-0750
Accepted for publication May 19, 2015
Address correspondence to Sunita Venkateswaran,
Division of Neurology, Children’s Hospital of Eastern
Ontario, 401 Smyth Rd, Ottawa, ON, K1H 8L1 Canada.
E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2015 by the American Academy of
Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated
they have no financial relationships relevant to this
article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have
indicated they have no potential conflicts of interest
to disclose.
CASE REPORT
functioning in a basic stream in her
age-appropriate school grade.
There was no history of seizures,
headaches, or visual disturbances.
There were also no reported autistic
features or other neurologic
abnormalities. She was described as
a restless sleeper. Sleep evaluation
was normal. At age 16, she was
referred to a metabolic clinic for
hypercholesterolemia on routine
blood testing, which was thought to
be exacerbated by isotretinoin for
acne treatment.
Family history included maternal
history of polycystic kidney disease
and paternal history of
hypercholesterolemia and possible
learning disorder. Maternal ethnicity
was Welsh and French, and paternal
ethnicity was unknown. There was no
history of neurologic disease in the
family.
Physical examination revealed a welllooking female with no dysmorphic
features. Her demeanor was pleasant
and affect appropriate. She had
articulation difficulties but was able
to convey her thoughts. Growth
parameters included weight 52.7 kg
(.10th centile), height 150.5 cm (3rd
centile), and BMI 23 (.50th centile).
Head circumference was 53.3 cm
(25th centile). Neurologic
examination was completely
unremarkable with no clear
dysarthria, spasticity, dystonia, or
parkinsonian features.
Given her long-standing history of
intellectual and language difficulties
without concrete neurologic findings,
initial testing consisted of fragile X
testing and comparative genomic
hybridization microarray, which were
normal. Electroencephalography was
normal. The patient received her first
brain MRI at this point, which
demonstrated bilateral prominent T2
hypointensity in both the globus
pallidus and substantia nigra, with
relatively increased hypointensity in the
substantia nigra (Fig 1). Furthermore,
on sagittal T1, there were mildly
2
FIGURE 1
A and B, Susceptibility-weighted angiography demonstrating striking hypointensity in bilateral
globus pallidi and substantia nigra. C and D, Axial T2-weighted images with globus pallidi only
minimally more hypointense to white matter. E, Coronal gradient echo image demonstrating subtle
T1 hyperintensity in the substantia nigra (arrows), the “halo sign.”
increased streaks of hyperintensity in
these areas. There was no cortical
atrophy observed on imaging.
On the basis of her clinical features
and the findings on brain MRI, BPAN
was suspected, and a WDR45 gene
LONG et al
analysis was performed, revealing
a heterozygous mutation (c.251A.G;
p.Asp84Gly). Her mother did not have
this mutation, and her father was
unavailable for genetic testing. The
findings were discussed with the
patient and her family, and the
prognosis provided regarding
possible future neurodegeneration
was guarded given the limited data
available in the literature.
DISCUSSION
This is the first patient reported with
the previously mentioned WDR45
gene mutation. She presented with
only mild cognitive and language
difficulties and pathognomonic MRI
findings preceding
neurodegeneration in the context of
a BPAN diagnosis. This report further
expands the WDR45 phenotype. The
diagnosis was suggested by typical
brain MRI findings in a female child
with cognitive delay and no other
clinical features and emphasizes the
need to consider WDR45 gene
sequencing in pediatric patients
(especially females) with history of
cognitive delay and such MRI
findings, regardless of severity.
The gene responsible for BPAN was
recently identified in 2012, and there
are currently only 29 cases described
in the literature including this
report.3–5 WDR45 belongs to the family
of WD40 proteins that are crucial to
protein-protein interactions in
autophagy, a process thought to be
defective in many neurodegenerative
conditions.6 The exact mechanism
through which WDR45 mutations
cause clinical features is currently
unknown. There have been a few
reported cases of males with the same
condition, but in general BPAN is
thought to be lethal in males.1
Neuroimaging in BPAN patients reveal
striking basal ganglia and substantia
nigra pathology with the distinguishing
feature of a bright halo on T1-weighted
imaging in the cerebral peduncles and
substantia nigra due to iron deposition
in these areas.3
PEDIATRICS Volume 136, number 3, September 2015
In a report of 23 patients with BPAN,
Hayflick et al found that all subjects
were diagnosed with global
developmental delay in early
childhood and severe limitations in
expressive language skills.3 For our
patient, it is interesting to note that
her long-standing cognitive and
language difficulties were classified
as mild on multiple medical
assessments, and there was no
history of delay in attaining social and
gross and fine motor developmental
milestones. In fact, her mother faced
significant challenges in obtaining
a neurologic assessment for her
daughter given the lack of severity of
her symptoms. Furthermore, Haack
et al found that some patients with
BPAN exhibited spasticity, disordered
sleep, ocular defects, epilepsy, and
ataxia, and Ohba et al presented
a case report of a BPAN patient with
clinical findings of Rett syndrome
(regression, loss of acquired
purposeful hand movements, gait
abnormalities).5,6 These features
were all absent in our patient. She did
have a history of
hypercholesterolemia, but there have
been no reports in the literature to
date linking lipid metabolism and
BPAN; thus, this finding was felt to be
secondary to her acne medication.
In previous case reports, brain MRI
that resulted in the subsequent
diagnosis of BPAN was triggered by
neurologic deterioration and the
development of dysarthria, dystonia,
and Parkinsonism in affected
patients.7 These MRI findings were
consistent with evidence of increased
iron accumulation in the substantia
nigra and globus pallidus and
occasional generalized cerebral
atrophy at the time of neurologic
degeneration. The youngest patient
reported with these MRI findings is
a 6-year-old girl with Rett
syndrome–like features diagnosed by
whole exome sequencing.8 In
contrast, although our patient
underwent her first brain MRI as part
of a diagnostic workup for cognitive
delay at age 17, which revealed
striking findings consistent with
BPAN, she did not display any signs
or symptoms of neurologic or
psychiatric degeneration seen in
previously reported subjects with the
same MRI findings.
Currently, there is no known
effective prevention or treatment of
neurologic decline in BPAN. In
previous reports, medical therapy
with levodopa resulted initially in
significant improvements in patients’
motor function and affect; however,
these benefits were short-lived with
early recurrence of dystonia and
development of disabling
dyskinesias.1 Continued
deterioration of motor and language
skills with subsequent severe,
progressive dementia are common
features in previous case reports of
patients with BPAN, leading to early
death in the third through fifth
decade of life due to secondary
complications from dysphagia and
severe parkinsonism.
As authors of previous BPAN case
reports have suggested, we
recommend that the diagnosis of
BPAN should be considered in all
children with global developmental
disabilities, especially when
accompanied by seizures, disordered
sleep, or Rett syndrome–like
symptoms. However, as demonstrated
through our case, BPAN deficiency
can present as nonspecific cognitive
delays, making the diagnosis difficult
to ascertain unless a brain MRI or
gene sequencing is performed. We
recommend that WDR45 testing
should also be considered in cases of
isolated cognitive and language
delays, regardless of severity if MRI
findings are suggestive. Early
diagnosis of BPAN is of utmost
importance, providing families with
a direction for possible management
and prognosis and preventing further
unnecessary diagnostic testing. In
addition, early identification of
WDR45 mutation may lead to a better
understanding of the pathophysiology
of BPAN and result in the
3
development of novel therapeutic
interventions for preventing or
delaying the onset of
neurodegeneration for pediatric
patients. Finally, gaining insight into
the role of autophagy dysfunction in
the development of BPAN will likely
advance our understanding of
common disorders thought also to be
related to autophagy dysregulation,
such as Huntington disease,
Alzheimer disease, and Parkinson
disease.
ABBREVIATIONS
BPAN: b-propeller proteinassociated
neurodegeneration
NBIA: neurodegeneration with
brain iron accumulation
4
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LONG et al