A 39‐year‐old male, born of nonconsanguineous parents, presented with 1‐year hand tremor and gait difficulties. He had pes cavus and hammertoes since childhood, and on neurological examination, there was facial hypomimia, left predominant rest/re‐emergent postural tremor, cogwheel rigidity, bradykinesia, and bilaterally decreased arm swing (UPDRS‐III:19). Additionally, decreased vibration on the halluces and difficulties in walking on heels. Brain MRI disclosed pallidal hypointensities, CT scan was normal, and [123I] FP‐CIT SPECT showed bilateral presynaptic dopaminergic deficit (Fig. 1). Electromyography revealed a sensory‐motor polyneuropathy with distal‐to‐proximal gradient and some demyelinating features. A WES‐based panel identified two heterozygous variants in FIG 4 [(NM_014845.5)‐c.122 T > C(p.(Ile41Thr)) and (NM_014845.5)‐c.1519dup(p.(Tyr507Leufs*10))] (confirmed to be in trans). He was treated with levodopa and later rotigotine, with clinical improvement (2 years follow‐up UPDRS‐III in OFF:29 and ON:14).
Fig. 1.
(A) Axial T2‐weighted image, disclosing pallidal hypointensities; (B) SWI‐weighted sequence, being more evident pallidal hypointensities; (C) Normal brain CT scan, excluding calcium deposits; (D–F) [123I] FP‐CIT SPECT disclosing marked bilateral presynaptic dopaminergic deficit, with right predominance.
FIG 4 is a phosphatase, functioning in a trimolecular complex with PIKFYVE (PI3P kinase) and VAC14 (scaffold protein), regulating the levels of PI(3,5)P2 in the endolysosomal membrane. 1 VAC14 has already been associated with NBIA, 2 and given that FIG 4 pathogenic variants also lead to dysfunction of PI(3,5)P2, we hypothesize the same underlying mechanism would be responsible for the iron deposits observed in our patient.
To our knowledge, this is the sixth case of young‐onset Parkinsonism and Charcot–Marie‐Tooth‐4 J features associated with FIG 4. 3 For the first time, pallidal hypointensities suggestive of iron deposition are described, further expanding the phenotypic‐imaging spectra of FIG 4‐related disorders.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
L.S.: 1A, 1B, 1C, 2A, 2B, 3A.
J.P.F.: 2C, 3B.
A.F.B.: 2C, 3B.
M.C.: 2B, 2C, 3B.
J.D.: 1A, 1B, 2A, 2C, 3B.
All co‐authors have been substantially involved in the study and/or preparation of the manuscript and have read and approved the submitted manuscript.
Disclosures
Ethical Compliance Statement: Informed consent (verbal and written) was obtained from the patient in a face‐to‐face consultation. The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Approval by the ethics committee of Centro Hospitalar Universitário de Santo António was not necessary for this work.
Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: L.S.: No conflicts of interest to report. Employment: Centro Hospitalar de Santo António, Porto, Portugal. João Parente Freixo—No conflicts of interest to report. Employment: Institute for Molecular and Cell Biology. A.F.B.: No conflicts of interest to report. Employment: Institute for Molecular and Cell Biology. M.C.: No conflicts of interest to report. Employment: Centro Hospitalar de Santo António, Porto, Portugal. J.D.: No conflicts of interest to report. Advisory Boards: Abbvie. Honoraria: Bial. Grants: Bolsa para Trabalhos Académicos Inseridos em Teses de Doutoramento, Departamento de Ensino, Formação e Investigação, Centro Hospitalar de Santo António, Porto. Employment: Centro Hospitalar de Santo António, Porto, Portugal.
References
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