Objective: To present a patient with clinical and radiological features of neurodegeneration with brain iron accumulation (NBIA) due to a novel variant mutation in adaptor protein complex 4 (AP4M1). We present this patient to expand on the literature regarding the association between AP4M1 mutation and NBIA.

Background: AP4-deficiency typically produces complex hereditary spastic paraplegias (HSP) but has recently been described in patients with NBIA. We present a 22-year-old man with history of migraines, six-month history of tremor at rest and with action, causing difficulty with typing and writing. There is family history of tremor in his maternal uncle and maternal grandfather. On examination, he had asymmetric resting tremor, rigidity, bradykinesia, lower extremity hyperreflexia without weakness and reduced arm swing while walking.

Method: Investigation included blood work to check copper, ceruloplasmin, inflammatory and autoimmune markers, MRI Brain using T2 -weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging sequences (SWI), Dopamine transporter scan (DAT scan) and whole exome sequencing.

Results: Blood work was normal. MRI showed subtle hyperintensities in the center of bilateral globus pallidi with hypointense periphery and bilateral SWI hypo intensity in the basal ganglia, presumably from iron accumulation. DaTScan showed bilateral diffuse decrease in striatal uptake on quantitative analysis. Whole exome sequencing showed an unspecified variant (c1128C>T) in AP4M1 gene.

Conclusion: With clinical evidence of parkinsonism in a young adult with evidence of dopaminergic deficiency on DaTScan and MRI imaging supporting NBIA, we believe that the mutation identified in AP4M1 is pathogenic and associated with clinical-radiological phenotype of NBIA spectrum disorder.

References: Roubertie A, Hieu N, Roux CJ, et al. AP4 deficiency: A novel form of neurodegeneration with brain iron accumulation?. Neurol Genet. 2018;4(1):e217. Published 2018 Jan 24. doi:10.1212/NXG.0000000000000217

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-case-of-neurodegeneration-with-brain-iron-accumulation-with-novel-adaptor-protein-4-m1-subunit-mutation/