We report on a patient with a distinct clinical and neuroradiologic phenotype and a de novo variant in the FTH1 gene. The patient was a 25-year-old woman with developmental delay and pontocerebellar hypoplasia, who after years of stable condition visited our hospital at age 20 years because of clinical deterioration. With consent from the patients' family, we obtained clinical, imaging, and genetic data from the patient's medical record. Neurologic examination demonstrated a new hypertonia, ataxia, dystonia, dysarthria, and apathy. Cerebral MRI revealed new bilateral symmetrical signal abnormalities of the basal nuclei, thalamus, cerebral peduncles, and hippocampus, indicating iron accumulation. Exome sequencing revealed a de novo monoallelic variant in the FTH1 gene, c.510_511delTC. Similar de novo FTH1 gene variants were reported in a case series of 5 patients with a similar, distinctive phenotype. Because this is a recently discovered cause of prenatal-onset cerebellar atrophy with later-onset neuroferritinopathy, our case adds to the literature to learn more about this distinct disease.

COASY protein associated neurodegeneration is a rare, progressive autosomal recessive neuroferritinopathy due to pathogenic mutations in the COASY gene, coding for the mitochondrial located coenzyme A synthase. Clinical manifestations include seizures, progressive spasticity, dystonia, neuropathy, cognitive decline and neuropsychiatric abnormalities. Both foetal and childhood onset phenotypes are described. We report three patients with COASY protein associated neurodegeneration who were identified on newborn screening with a dried bloodspot acylcarnitine pattern consistent with carnitine palmitoyltransferase 1a deficiency, that is, an elevated ratio of free carnitine (C0) to the sum of palmitoylcarnitine (C16) and octanoylcarnitine (C18):[C0/(C16+C18)]. Two siblings, who died in infancy, displayed neurological features from birth, with magnetic resonance imaging of the brain displaying immature cortical sulcation, parenchymal atrophy and pontocerebellar hypoplasia. The third patient presented with global developmental delay, pyramidal signs and seizures with brain magnetic resonance imaging at age 15 months demonstrating a thin corpus callosum, symmetric diffusion restriction throughout the basal ganglia and evidence of deposition in the globus pallidus. This report demonstrates that phenotypes of COASY protein associated neurodegeneration should be included in the differential diagnosis of dried blood spot acylcarnitine pattern suggestive of carnitine palmitoyltransferase 1a deficiency and may represent new potential for early diagnosis.

Ferritins are symmetrical, hollow nanocaged iron storage proteins, which sequester and concentrate iron as a hydrated ferric oxyhydroxide (ferrihydrite) biomineral. Spontaneous self-assembly of 24 subunits in eukaryotic ferritins leads to the formation of symmetrical pores, i.e., eight hydrophilic 3-fold pores and six hydrophobic 4-fold pores. However, unlike the relatively wider 3-fold pores, which drive Fe2+ inside, the functions of narrow 4-fold pores are relatively understudied. The current work investigates the role of 4-fold pores by gradual alterations of specific amino acids using site-directed mutagenesis, structural analysis by X-ray crystallography, and solution-based kinetic studies. Increasing the negative charge in ferritin 4-fold pore retained the cage integrity and iron-loading capability despite altering the pore structure/size/electrostatics. As additional substitutions accumulated within the same channel, the aperture widens further and the electrostatic environment became progressively more acidic around the pore lining. These gradual alterations resulted in an enhanced rate of iron mobilization (up to ∼10-fold), possibly due to remodeling of the 4-fold (C4) pore, leading to a progressive increase in 4-fold pore diameter. Moreover, these modifications decreased cage stability, both thermally (∼5 °C) and chemically (∼3-4 folds), and increased iron-induced ferritin precipitation, similar to the case of neuroferritinopathy.

Increased iron levels, common in neurodegenerative diseases, correlate with disease severity, suggesting a role in the pathological process. Recently, efforts have been made to understand the role of iron in cerebral inflammatory processes. Employing astrocyte cell models of genetic neurodegenerative pathologies characterized by iron imbalance, such as the neurodegeneration with brain iron accumulation disorders, can provide valuable insights into astrocytes reactivity, a pivotal process in brain inflammation. Specifically, we employed human-induced pluripotent stem cell-derived astrocytes from Neuroferritinopathy, where iron accumulation is primary. After confirming iron accumulation and the deregulation of proteins involved in iron management, we observed that at 35 days since the beginning of differentiation, the elevated iron levels not only trigger ferroptosis but also place the astrocytes in a reactive state. This is evident in the higher extracellular concentrations of IL-6, IL-1β, and glutamate, along with changes in morphology, genes, and proteins involved in astrocyte reactivity. Interestingly, by day 60, IL-6 and IL-1β levels drop below those of the controls, and we observe a reversal in most of the factors considered. Moreover, at day 60, it is possible to observe not only increased senescence but also ferroptosis. These findings demonstrate that iron plays a primary role in inducing astrocyte reactivity.