Objective: To report a patient with Charcot-Marie-Tooth (CMT) type 2N (CMT2N) due to AARS gene mutation who developed early-onset Parkinson’s disease (PD).

Background: Aminoacyl tRNA synthetases (AARS) are a group of enzymes involved in attachment of amino acids to tRNA molecules in the cytoplasm and the mitochondria[1]. Beyond this function, they also have a role in several metabolic and signaling pathways important for cell viability. Because of their ubiquitous expression in brain, a growing body of evidence indicates that mutations in the AARSs genes can be associated with various neurodegenerative disorders[2].

Method: A 44-year-old, right-handed gentleman presented with a classic foot drop and distal limb weakness in his early thirties followed by action tremor in the left hemi body (upper > lower limb) at age 37. Family history was positive for CMT in the mother and an unspecified tremor in his grandmother. Genetic testing of the patient confirmed AARS heterozygous mutation (c.986G>A; p.R329H) consistent with CMT2N disease. His tremor was diagnosed as peripheral neuropathic tremor and treated with high doses of propranolol without improvement. Over time, he started noticing stiffness on his left side with the emergence of a classical rest tremor. A clinical diagnosis of tremor dominant PD was established with excellent response to levodopa. MRI of the brain was unremarkable, and a comprehensive PD genetic panel was negative. He then developed tremor in the right upper limb, peak dose dyskinesias and motor fluctuations. At age 44, he underwent bilateral STN DBS, with adequate control of his symptoms.

Results: Mutations in the AARSs genes have been implicated in abnormal chronic immune responses termed antisynthetase syndrome. Recent evidence points towards a link to neurodegeneration with mitochondrial dysregulation due to AARSs genes mutations proposed as the plausible mechanism[3].Tremor is often seen in patients with peripheral neuropathies and labeled as neuropathic tremor. In comparison, parkinsonism is rare, although it has been reported in CMT due to mutations in LRSAM1, FIG4 and SLC25A46 genes[4]. The mechanisms leading to substantia nigra pathology are unknown.

Conclusion: This is the first reported case of CMT2N, and PD associated with AARS mutation. Tremor in association with peripheral neuropathy should be investigated for underlying PD before accepting it as a neuropathic tremor.

References: [1] Rajendran V, Kalita P, Shukla H, Kumar A, Tripathi T. Aminoacyl-tRNA synthetases: Structure, function, and drug discovery. Int J Biol Macromol 2018;111:400–14. https://doi.org/10.1016/j.ijbiomac.2017.12.157.
[2] Ognjenović J, Simonović M. Human aminoacyl-tRNA synthetases in diseases of the nervous system. RNA Biol 2018;15:623–34. https://doi.org/10.1080/15476286.2017.1330245.
[3] González-Serrano LE, Chihade JW, Sissler M. When a common biological role does not imply common disease outcomes: Disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases. Journal of Biological Chemistry 2019;294:5309–20. https://doi.org/10.1074/jbc.REV118.002953.
[4] Gentile F, Bertini A, Priori A, Bocci T. Movement disorders and neuropathies: overlaps and mimics in clinical practice. J Neurol 2022;269:4646–62. https://doi.org/10.1007/s00415-022-11200-0.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-and-charcot-marie-tooth-type-2-coincidental-or-causal/