Objective: ATP6AP2 mutation, previously described in literature to cause early onset Parkinson’s disease (PD) with atypical signs, evolved into frontotemporal lobar degeneration in a 7year followup which begs the question if this mutation causes α-synucleinopathy (PD) or tauopathy (Frontotemporal dementia)

Background: We previously described a case of atypical PD with spasticity having ATP6AP2 mutation on Whole Exome Sequencing (WES)[1][table1] treated with baclofen showing significant improvement in 2018, on further followup, patient showed progressive worsening of motor symptoms (FOG, axial imbalance, and rigidity, frequent backward falls, unrestricted sitting, progression of muscle wasting without fasciculation in all four limbs without any clear predisposing factor, aphasia) and of non-motor symptoms of (RBD, autonomic dysfunction, aggressive behavior with visual hallucinations, apathy)[table2]

With just one other family reported[2], we wish to discuss what pathology this mutation entails: an α- synucleinopathy explained by parkinsonism features or taupathy explained by frontotemporal lobar degeneration

Method: Serial noncontrast CT (NCCT)[figure2] scans of patient 7years apart were compared which showed progressive degeneration of frontal and temporal lobes (MRI not done due to aneurysmal clipping) and NCV was done to evaluate significant muscle wasting[figure1]. With shortening of ON period and increased dyskinesia to levodopa-carbidopa over the years patient was managed with daily titrations.

Results: NCCT findings of atrophy in medial frontal cortex correspond temporally with violent behavior, aphasia and subsequent severe apathy showing more frequent episodes of delirium and overall deteriorating cognition. With progression in motor symptoms and wasting atrophy in all four limbs, NCV revealed normal latency and amplitude.

Use of testosterone injections helped patient regain some muscle mass and marginally improve the postural instability.

Conclusion: This case study shows that rare mutations can have varied and overlapping pathophysiology which shows the importance of genetic studies along with long follow-up to observe disease progression to understand the overall syndrome and help in better diagnosis of other undiagnosed cases with similar symptomatology by offering genetic evaluation or use of Tau-specific ligands in PET scans in case of complex syndromic presentation to delineate the underlying pathology.

[Table 1]

[table2]

[figure1]

[figure2]

References: [1] K. Shukla, N. Sawal. First case of sporadic ATP6AP2 Mutation reported in Asia in a Parkinson’s Disease patient [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/first-case-of-sporadic-atp6ap2-mutation-reported-in-asia-in-a-parkinsons-disease-patient/. Accessed March 16, 2024.

[2] Korvatska O, Strand NS, Berndt JD, Strovas T, Chen DH, Leverenz JB, Kiianitsa K, Mata IF, Karakoc E, Greenup JL, Bonkowski E, Chuang J, Moon RT, Eichler EE, Nickerson DA, Zabetian CP, Kraemer BC, Bird TD, Raskind WH. Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum Mol Genet. 2013 Aug 15;22(16):3259-68. doi: 10.1093/hmg/ddt180. Epub 2013 Apr 16. PMID: 23595882; PMCID: PMC3723311.

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