Objective: To describe a phenotypic variant of FIG4-related diseases resulting in parkinsonism.

Background: The FIG4 gene codes for P1(3,5)P₂ phosphatase that plays an important role in preventing neurodegeneration. Mutations in FIG4 have been associated with both CMT4J and Yunis-Varon syndrome (YVS).

Method: For the past 7 years, a 61-year-old male had an exam demonstrating intermittent rest tremor in the right hand and left leg, bradykinesia with finger taps and foot stomps bilaterally, significant scoliosis, truncal and cervical dystonia, and mild cognitive impairment. He received botulinum toxin injections for sialorrhea and cervical dystonia. He presented with worsening fatigue, numbness in his feet, gait instability, and falls. His examination was significant for right>left decreased sensation to pinprick, vibration, and proprioception in a length-dependent distribution and diminished reflexes, high feet arches, and hammer toes. EMG/NCS revealed conduction blocks and temporal dispersion in the peroneal and tibial nerves consistent with a severe demyelinating neuropathy. MRI Brain and C-spine were unrevealing. Lumbar puncture demonstrated 1 nucleated cell, 36 red blood cells, and elevated protein of 98 mg/dL. Treatment with intravenous immunoglobulin provided no benefit. Additional family history revealed that the patient’s father also had mild parkinsonian features and then developed arm weakness and numbness in the 6^th decade of life.

Results: Genetic testing revealed two pathogenic variants in the FIG4 gene (c.122T>C(p.Ile41Thr) and c.2459+1G>A(splice donor)), both of which are associated with CMT4J. Classically, mutations on the FIG4 gene have been associated with either an isolated peripheral or central nervous system process. CMT4J is a peripheral process causing neuropathy, gait difficulties, and atrophy and weakness of muscles. YVS is a central process resulting in global developmental delay, swallowing difficulties, hearing loss, spasticity, and dysmorphism.

Conclusion: This case expands the phenotypic spectrum of FIG4-related diseases, demonstrating a continuum between CMT4J and YVS manifesting as mild cognitive impairment, peripheral neuropathy, foot deformities, scoliosis, dystonia, and parkinsonism. In patients presenting with parkinsonism and demyelinating polyneuropathy, FIG4-related diseases should be considered in the differential.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/adding-parkinsonism-to-the-phenotypic-spectrum-of-fig4-related-diseases/