Objective: We present a patient with atypical Parkinson’s disease (PD), carrying a homozygous missense mutation of FIG4.

Background: FIG4 is involved in endosomal-lysosomal trafficking and autophagy. Mutations of this gene have been associated with several disorders, including Yunis-Varon syndrome, Charcot-Marie-Tooth polyneuropathy type 4J (CMT4J), motor neuron disease (MND) and parkinsonism.

Method: A 42-year-old female patient presented with unilateral rest/postural tremor and bradykinesia of the left upper extremity. Pyramidal signs and dystonia of the left limbs were also detected. Brain and cervical spine MRI findings were unremarkable, while DaTscan imaging revealed right-sided asymmetrically reduced striatal tracer uptake, leading to diagnosis of PD. Response to dopaminergic therapy was suboptimal. Neurophysiology testing including magnetic stimulation indicated pyramidal tract dysfunction on the left side. There were no polyneuropathy or MND findings. Five years into the disease course the patient developed peak-dose non-troublesome dyskinesias with a left hemidystonia pattern, involving the face, neck, and upper limb. Symptoms remained strictly unilateral for ten years before parkinsonian signs, including tremor, progressed to the right upper extremity. Impairment of postural reflexes was noticed 15 years after symptoms onset.

Results: Whole exome sequencing genetic testing identified a homozygous c.122T>C (p.Ile41Thr) FIG4 mutation. Heterozygous state of this missense mutation is associated with slowly progressive MND, while compound heterozygosity with a null mutation is the most frequently encountered genotype in CMT4J. Few CMT4J cases are reported with comorbid parkinsonism/PD and various responses to dopaminergic treatment. Experimental models of homozygous c.122T>C FIG4 mutation predicted an association with early-onset and severe polyneuropathy, which was subsequently confirmed by very few published cases of patients carrying this genotype.

Conclusion: This is the first case of PD patient with a subjacent homozygous c.122T>C FIG4 mutation without polyneuropathy or MND. The clinical presentation challenges current knowledge that a homozygous state of this mutation leads to early-onset, severe polyneuropathy suggesting that additional genetic or other factors may alter the clinical expression of this variant. FIG4 gene is added to the long list of PD-related genes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-new-phenotype-genotype-correlation-for-fig4-gene-and-parkinsons-disease/