Objective: Here we report a patient with Charcot-Marie-Tooth (CMT) 4J disease (related to FIG4 mutations) who developed an early-onset Parkinson’s disease during evolution.

Background: FIG4 encodes a phosphatase that acts in the intracellular vesicle trafficking along the endosomal-lysosomal pathway. Several findings suggest that the expression of FIG4 is required for neural development and it is necessary to prevent neurodegeneration. In this regard, FIG4 inmunoreactivity has been found in Pick bodies, Lewy bodies, several types of intranuclear inclusions in different degenerative diseases, and Marinesco and Hirano bodies in elderly people. Mutations in FIG4 have been associated with CMT 4J, amyotrophic lateral sclerosis type 11, bilateral temporooccipital polymicrogyria and Yunis-Varon syndrome but FIG4 mutations have never been reported in Parkinson’s disease.

Method: Case report.

Results: A 51-year-old caucasian woman with progressive demyelinating motor and sensory polyneuropathy with pes cavus and scoliosis, started in childhood. She has severe muscle atrophy and distal weakness in upper and lower extremities, with severe functional impact requiring walking crutches. Motor conduction velocity in ulnar nerve was <10 m/sec. In her thirties, she began with rest tremor in the left upper extremity developing a severe bilateral hypokinetic-rigid syndrome in a few years. MRI was normal. [123I]FP-CIT Single-photon emission computed tomography (SPECT) showed asymmetric bilateral hypocaptation, right side worse than left side (concordant laterality). The response to antiparkinsonian drugs was always good. A next-generation sequencing of a targeted panel of CMT related genes was performed. We identified two mutations in FIG4 gene, c.122T>C (p.I41T) and c.1447C>T (p.R483*), both of them considered pathogenic even though the second one has not been previously described.

Conclusion: To our knowledge, this is the first reported case of association of CMT and Parkinson’s disease, with biallelic pathogenic mutations in FIG4. This fact reinforces the possible relation of FIG4 in prevention of neurodegeneration also in Parkinson’s disease. Nevertheless, we can not exclude a fortuitous association.

References: 1. Kon T, Mori F, Tanji K, et al. ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases. Neuropathology 2014;34:19-26. 2. Ikonomov OC, Sbrissa D, Compton LM, et al. The protein complex of neurodegeneration-related phosphoinositide phosphatase Sac3 and ArPIKfyve binds the Lewy body-associated synphilin-1, preventing its aggregation. J Biol Chem 2015;290:28515-29.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-charcot-marie-tooth-disease-parkinsons-disease-and-fig4-mutations/