<scp> <i>FTH1</i> </scp> ‐Related Neuroferritinopathy: A Rare Form of Neurodegeneration with Brain Iron Accumulation Mimicking Pontocerebellar Hypoplasia

Childhood-onset neuroferritinopathy is an exceptionally rare neurodegeneration with brain iron accumulation (NBIA) disorder, caused by de novo heterozygous variants in ferritin heavy chain (FTH1) gene.1 We describe the movement disorder phenomenology in a young girl who was referred for the evaluation of developmental delay and dystonia. A 7.5-year-old European female, born to non-consanguineous parents, presented with global developmental delay, feeding difficulties, focal seizures, and intermittent dystonia of limbs. Perinatal history was notable for shoulder dystocia and microcephaly. At 7.5 years, she exhibited partial head control, reached for toys, reciprocative babbling, and recognized family members. Family history was non-contributory. Examination revealed a wheelchair-bound child with happy demeanor, intermittent esotropia, generalized dystonia, predominantly affecting lower limbs and face (Burke-Fahn-Marsden Dystonia Rating Scale-Motor score- 60.5/120), axial hypotonia, spasticity and brisk deep tendon reflexes with extensor plantars (Video 1). Exaggerated startle response was also noted. Sequential Brain MRIs (day 2 and 3 years) revealed cerebral atrophy, hypoplasia of brainstem and cerebellum and symmetric T1 hyperintensity in basal ganglia (Fig. 1A–H). Ophthalmology and hearing assessments were unremarkable. Serum iron studies were normal. While a genetic pontocerebellar hypoplasia (PCH) variant was considered, progressive dystonia alongside T1 basal ganglia hyperintensity were atypical findings. Trio whole exome sequencing revealed previously reported de novo pathogenic truncating variant c.512_513delTT (p.Phe171*) in exon 4 of FTH1 gene (NM_002032.2), confirming the diagnosis of FTH1-related neuroferritinopathy. Trihexyphenidyl provided limited benefit for dystonia, while prior baclofen worsened hypotonia. Disruption of iron homeostasis has been implicated in the pathogenesis of a minor subset of NBIAs, including neuroferritinopathy and aceruloplasminemia. Ferritin light chain (FTL1)-related neuroferritinopathy, is an adult-onset, autosomal dominant NBIA characterized by chorea, dystonia, infrequent Parkinsonism, psychiatric manifestations and later cognitive decline.2 On the contrary, FTH1-related neuroferritinopathy is a rare neurogenetic disorder, with reported cases seen in females aged 1.8–78 years, carrying C-terminal nonsense (c.512_513delTT, p.Phe171* and c.487_490dupGAAT, p.Ser164*) and frameshift (c.409_410del, p.H137Lfs*4) variants.1 Our patient, harboring the recurrent dinucleotide deletion c.512_513delTT, exemplifies the unique early neurodevelopmental phenotype that evolved into slowly progressive generalized dystonia, without any systemic features or biochemical evidence of iron overload. Other movement abnormalities reported include ataxia and athetosis; often accompanied by an exaggerated startle response and a cheerful affect, features that may serve as useful clinical clues.1 The blood–brain permeability and ferroxidase (catalytic) properties of the ferritin H protein, which facilitates iron uptake, may contribute to the early-onset and severe phenotype observed in FTH1-related neuroferritinopathy, contrary to the adult-onset, slowly progressive disease caused by FTL1 variants.1, 3 The MRI-based pattern recognition approach in NBIAs has consistently shown a robust correlation with underlying genetic variants. In FTH1-associated neuroferritinopathy, hallmark imaging features include prenatal-onset PCH and progressive cerebral atrophy and later iron deposition in deep gray matter structures; although abnormal mineralization has been documented as early as 9 months of age.1 COASY Protein-Associated Neurodegeneration, Fatty Acid Hydroxylase-Associated Neurodegeneration, and AMPD2-related PCH-9 remain the closest radiologic mimics of this entity.4, 5 Notably, our patient showed only prominent T1 basal ganglia hyperintensity (possibly reflecting abnormally bound iron complexes or proteinaceous ferritin aggregates), highlighting the need to consider this diagnosis even in the absence of classical susceptibility changes on MRI in younger children. In conclusion, this case characterizes the movement disorder phenotype of FTH1-related neuroferritinopathy, a remarkably unique NBIA subtype with distinct neuroimaging findings. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. S.R.C.: 1A, 1B, 1C, 1B, 2A, 2B, 3A. S.Y.: 1A, 1B, 1C, 2A, 2B, 2C, 3B. V.P.: 1B, 1C, 2A, 2B, 3A. A.L.: 2C, 3B. V.C.: 2C, 3B. R.M.L.: 2C, 3B. L.D.: 2C, 3B. C.G.: 1A, 1B, 1C, 2A, 2B, 2C, 3B. Ethical Compliance Statement: The authors confirm that the approval of an institutional review board/ patient consent was not required for this work. We also confirm that the patient has given written informed consent for the publication of his video. 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: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: CG received consulting fees from Medtronic Inc. and Ipsen and participated as an advisor at the advisory board meetings of Medtronic Inc. The rest of the authors declare that there are no additional disclosures to report. The data that support the findings of this study are available from the corresponding author upon reasonable request.