A New Phenotype–Genotype Correlation for FIG4 and Parkinson's Disease

We read with great interest the report of Georgiades et al., describing a patient with rapid‐onset dystonia parkinsonism associated with homozygosity in the pathogenic variant p.Ile41Thr (I41T) in the FIG4 gene. ¹ Their case broadens the phenotypic spectrum of FIG4 and highlights a rare, yet potentially significant, genetic contributor to parkinsonism. In this context, we present a distinctly different parkinsonian phenotype in a patient homozygous for the same variant, who developed early‐onset Parkinson's disease (PD) without peripheral neuropathy over nearly 15 years of follow‐up.

The patient is a 58‐year‐old woman of Cretan descent, born to nonconsanguineous parents with negative family history for neurological diseases. At the age of 44, she presented with hypomimia and left‐side parkinsonian signs, including resting tremor, bradykinesia, and a “striatal hand” deformity (Hoehn & Yahr [H&Y] = 1). Atypical features included asymmetric hyperreflexia with occasional clonus, and painless dystonic posture of the left foot, more pronounced with exertion. Muscle strength was normal without gait/balance/speech impairment or cerebellar/sensory deficits.

Brain and cervical spine magnetic resonance imaging (MRI) was insignificant at baseline and 5 years after symptom onset. A 3‐T brain MRI with susceptibility‐weighted imaging, conducted 12 years into the disease course, revealed symmetrical bilateral hypointensities in the globus pallidus and absence of the normal hyperintensity within the substantia nigra (absence of “swallow tail” sign) (Fig. 1). Dopamine transporter imaging, performed 5 years after symptom onset due to the patient's initial refusal, demonstrated significant reduction in tracer uptake in the right striatum, consistent with the clinical asymmetry at that time. Neurophysiology testing during the same period, including nerve conduction studies, electromyography, and motor evoked potentials, revealed corticospinal tract dysfunction, predominantly on the left, with no evidence of sensorimotor neuropathy or motor neuron disease; follow‐up studies over time yielded similar results.

FIG. 1.

The clinical course of disease progression, DaTscan (dopamine transporter scan) imaging and MRI (magnetic resonance imaging). Brain MRI with (A, B) T2 ‐weighted Turbo Spin Echo, (C, F) three‐dimensional T1 MPRAGE (magnetization‐prepared rapid acquisition gradient echo) with mild symmetrical frontoparietal atrophy, and (D, E) SWI (susceptibility‐weighted imaging) with absence of “swallow tail sign.” RBD (rapid eye movement sleep behavior disorder) was confirmed using polysomnography.

Dopaminergic therapy elicited a partial, albeit clear improvement in her bradykinesia, whereas resting tremor was more effectively controlled with biperiden. Within 5 years of symptom onset and shortly after levodopa (l‐dopa) initiation (levodopa equivalent daily dose: 200), she developed left‐sided stereotypic, peak‐dose hemidystonic spasms involving primarily the face and upper extremity. An apomorphine (5 mg) trial 6 years after symptom onset was discontinued due to severe nausea/vomiting and troublesome dyskinesia, further highlighting her sensitivity to dopaminergic medication. Parkinsonian signs spread at the contralateral side 8 years after disease onset (H&Y = 2). By year 11, the patient developed impairment of postural reflexes and rare falls (H&Y = 3). Currently, she remains functionally independent with bilateral, though still significant asymmetric, parkinsonism, mild motor fluctuations, and the same dyskinesia profile without freezing of gait.

No prodromal symptoms were reported. Six years after disease onset, the patient developed a major depressive episode and anxiety disorder, leading to significant disruption in antiparkinsonian treatment. Mood and anxiety symptoms persisted with fluctuating severity, requiring long‐term high‐dose antidepressants. No hallucinations or cognitive decline has ever been observed. She reports no pain or sensory complaints but has experienced photosensitivity, seborrheic dermatitis, and rosacea over the past 5 years.

A diagnosis of clinically established PD was made. ² Whole‐exome sequencing identified homozygous FIG4 I41T, with no pathogenic variants in other PD‐related genes.

This case stands in contrast to the patient reported by Georgiades et al., who developed rapidly progressive dystonia parkinsonism, marked by severe dysarthria, early postural instability, unresponsiveness to l‐dopa, and progressive sensorimotor neuropathy. Both individuals exhibited an early‐onset asymmetric parkinsonian phenotype with pronounced dystonic features. However, our patient exhibited a relatively benign disease course with slow progression, l‐dopa responsiveness, emergence of drug‐induced dyskinesia at low l‐dopa dose, and nigrostriatal degeneration, clinical hallmarks more consistent with idiopathic PD than atypical parkinsonism. Importantly, our patient exhibited no signs of neuropathy or motor neuron disease despite the presence of the I41T variant, which has otherwise been associated with Charcot–Marie–Tooth disease type 4J (CMT4J) or amyotrophic lateral sclerosis type 11. ³ , ⁴ In a recent literature review, ⁵ 5 I41T homozygous cases were detected, presenting with CMT4J and no concurrent parkinsonism. Moreover, 12 cases of FIG4‐related parkinsonism were identified, all of whom were compound heterozygous for the I41T variant and a loss‐of‐function allele. On all occasions, parkinsonism manifested either concurrently with or after neuropathy, and with variable response to l‐dopa. Particularly, 2 sisters demonstrated a sensitivity to low l‐dopa doses and easy emergence of dyskinesia, ⁶ similar to our patient and other cases of genetic PD. ⁷ This characteristic may point toward mechanisms beyond classic striatal dysfunction, such as the frontal cortex, ⁸ particularly due to the brain atrophy observed in these cases and our patient. Moreover, the shared genotype and dopaminergic sensitivity among the siblings may suggest that additional genetic modifiers affected the phenotypic expression of FIG4‐related parkinsonism, similar to the presence of polymorphisms in the promoter region of the PMP22 gene modulating gene expression in CMT1A. ⁹

Our case enriches the phenotypic heterogeneity of FIG4‐related disorders and, to the best of our knowledge, represents the first report of PD in a homozygous carrier of I41T without concomitant neuropathy. The comprehensive clinical description and the prolonged follow‐up highlight key features that align with other autosomal recessive forms of PD, adding FIG4 to the long list of PD‐related genes. Due to its critical function in phosphoinositide metabolism and endolysosomal trafficking, ¹⁰ pathways already implicated in PD pathogenesis, FIG4 emerges as a potential contributor to parkinsonian syndromes, though additional genetic or environmental modifiers may influence its clinical expression. Our case challenges current knowledge that I41T homozygosity leads primarily to polyneuropathy and underscores the multifaceted role of FIG4 in neurodegeneration. Considering these factors, we suggest that FIG4 variants, though rare, should be considered in early‐onset or atypical parkinsonism/PD cases, particularly when pyramidal signs, polyneuropathy of unknown origin, or l‐dopa sensitivity is present.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique.

I.B.: 1B, 3A, 3B

P.M.: 1C, 3B

S.E.: 1C, 3B

E.P.: 1C, 3B

C.S.: 1A, 1B, 3A, 3B

Disclosures

Ethical Compliance Statement: This work did not require ethics committee approval. The patient provided written informed consent. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This study was carried out within the framework of the Action ‘Flagship Research Projects in challenging interdisciplinary sectors with practical applications in Greek industry’, implemented through the National Recovery and Resilience Plan Greece 2.0 and funded by the European Union – NextGenerationEU (project code: TAEDR‐0535850), and within the framework of the Project Changing – Connected Hubs in Ageing: Healthy Living to Protect Cerebrovascular Function, funded by the European Union’s Horizon Europe Program (Excellence Hubs Call – Horizon‐WIDERA‐2022‐ACCESS‐04‐01 under grant agreement No 101087071). The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: I.B. has received research funding from the European Union’s Horizon Europe Program (Excellence Hubs Call – Horizon‐WIDERA‐2022‐ACCESS‐04‐01 under grant agreement No 101087071), and the European Union‐NextGeneration EU (project code: TAEDR‐0535850), as well as honoraria for educational and travel grants from AbbVie. P.M. has received research funding from the Hellenic Precision Medicine Network, the European Union Horizon 2020 research innovation program under the Marie Sklodowska‐Curie grant agreement No 101007926 and the European Union’s Horizon Europe Program (Excellence Hubs Call – Horizon‐WIDERA‐2022‐ACCESS‐04‐01 under grant agreement No 101087071). S.E. has no additional disclosures to report. E.P. has no additional disclosures to report. C.S. has received research funding from the Greek National Precision Medicine Network, the European Union’s Horizon 2020 research innovation program under the Marie Sklodowska‐Curie grant agreement No 101007926, the European Union‐NextGeneration EU (project code: TAEDR‐0535850), and the European Union’s Horizon Europe Program (Excellence Hubs Call – Horizon‐WIDERA‐2022‐ACCESS‐04‐01 under grant agreement No 101087071), as well as honoraria for lecturing, advisory fees, educational grants, and travel grants from ITF Hellas, Innovis, Merck Serono, AbbVie, CSL Behring, Roche and Teva.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.