Authors :
Presenting Author: Takamasa Mitsumatsu, MD – Nagoya University Graduate School of Medicine
Hiroyuki Kidokoro, Lecturer – Nagoya University Graduate School of Medicine
Ayano Yanagisawa, MD – Nagoya University Graduate School of Medicine
Misa Hashimoto, MD – Nagoya University Graduate School of Medicine
Misae Yamada, MD – Nagoya University Graduate School of Medicine
Masahiro Kawaguchi, MD,PhD – Nagoya University Graduate School of Medicine
Yuji Ito, MD,PhD – Nagoya University Graduate School of Medicine
Tomohiko Nakata, MD,PhD – Nagoya University Graduate School of Medicine
Kazuhiro Muramatsu, Professor – Jichi Medical University
Jun Natsume, MD,PhD – Nagoya University Graduate School of Medicine
Rationale:
Pathogenic variants in the WDR45 gene, involved in autophagy, are associated with a spectrum of neurodevelopmental and neurodegenerative disorders, primarily causing beta-propeller protein-associated neurodegeneration (BPAN) and occasionally leading to developmental and epileptic encephalopathy (DEE). BPAN is the most common subtype of neurodegeneration with brain iron accumulation (NBIA). It typically presents in infancy or childhood with developmental delay, cognitive impairment, and seizures, following a relatively static course. In early adulthood, patients often experience rapid neurological deterioration with dystonia, parkinsonism, and dementia. Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is a neuroimaging technique that visualizes DAT distribution in the striatum and evaluates dopaminergic neuronal loss. However, the use of DAT-SPECT in BPAN has been limited, and its role in evaluating the disease process remains poorly understood.
Methods:
DAT-SPECT was performed in three female patients with genetically confirmed BPAN. Striatal radiotracer uptake was quantitatively assessed using specific binding ratios (SBRs).Results:
Patient 1 had developmental delay in infancy and walked independently at 1 year and 11 months. She had recurrent febrile seizures between ages 2 and 6, and developed epilepsy at age 33, characterized by episodes of impaired consciousness with upward eye deviation. At age 35, parkinsonian features, including bradykinesia and a shuffling gait, emerged, followed by rapid neurological decline. DAT-SPECT was performed at age 37. Patient 2 had developmental delay in infancy and recurrent febrile seizures between ages 1 and 6. She walked independently at age 2. At age 23, she developed gait instability and masked facies, followed by rapid deterioration. DAT-SPECT was performed at age 25. Patient 3 had more severe developmental delay and never achieved independent ambulation. EEG at 12 months showed excessive high-amplitude fast activity. She had a generalized tonic-clonic seizure at age 6 and was diagnosed with epilepsy. From early childhood, she exhibited stiffness in the hips and knees, bradykinesia, and tremulous movements of the left arm. DAT-SPECT was performed at age 14. At the time of DAT-SPECT, all three patients showed diffuse cerebral atrophy and bilateral T2-weighted hypointensity in the globus pallidus and substantia nigra on brain MRI. In Patients 1 and 2, DAT-SPECT revealed reduced bilateral striatal uptake, predominantly in the putamen, with asymmetric decreases in SBRs, resembling the pattern seen in Parkinson’s disease. In contrast, Patient 3 did not show a significant reduction in striatal uptake.Conclusions:
The asymmetrical reduction in striatal uptake on DAT-SPECT observed in two adult BPAN patients suggests underlying dopaminergic neuronal loss. Given that dopaminergic degeneration in Parkinson’s disease is known to progress during the prodromal phase, DAT-SPECT may serve as a valuable tool for elucidating BPAN pathophysiology and identifying opportunities for early therapeutic intervention.
Funding:
This research was not funded by any agency.