Neuropathologic Findings in a Patient With Juvenile-Onset Levodopa Responsive Parkinsonism Due to ATP13A2 Mutation
Objective:To describe the postmortem neuropathological findings of a patient with Kufor Rakeb Syndrome (KRS) due to ATP13A2 mutation. KRS is characterized by juvenile-onset, levodopa-responsive parkinsonism associated with pyramidal signs, supranuclear gaze palsy, and cognitive impairment.Methods:Detailed neuropathological analysis of the brain. The patient had a genetically confirmed ATP13A2 homozygous missense mutation and died at age 38, 26 years after the onset of his symptoms.Results:The main brain neuropathological findings were widespread neuronal and glial lipofuscin accumulation with no Lewy-body type inclusions and absence of 𝛼-synuclein-, tau-, 𝛽-amyloid-, and TDP-43-protein-positive pathologies. Sparse iron deposits were observed in several brain areas but no obvious axonal spheroids were identified.Discussion:This is to our knowledge the first KRS postmortem neuropathological description. Iron deposits were found but were not associated with increased axonal spheroids, as frequently observed in neurodegeneration with brain iron accumulation (NBIA). ATP13A2 mutations have been described in patients with neuronal ceroid lipofuscinosis (CLN). Moreover animal models with these mutations develop neurodegenerative disorders with CLN pathology. Therefore, our findings support that ATP13A2 mutations may be considered a genetic etiology of neuronal lipofuscinosis.