Discussion

We describe a case of a 50‐year‐old Emirati male with ACP who initially presented with diabetes mellitus, followed by psychiatric symptoms and subsequent neurological deterioration. The distinctive aspect of this case was the early presentation of psychiatric symptoms, including paranoia, delusions, and hallucinations, preceding neurological manifestations, which resulted in the delay of identifying the underlying metabolic disorder. The combination of diabetes mellitus and abnormal iron deposition on brain MRI should prompt measurement of serum ceruloplasmin. Low ceruloplasmin levels, characteristic MRI findings, and confirmation of a homozygous CP gene mutation (c.2426‐1G>A) established the diagnosis of ACP. ACP is an extremely rare autosomal recessive disorder of iron metabolism, with an estimated prevalence of approximately 1 in 2,000,000 individuals [1]. Due to its rarity and protean manifestations, ACP is often underdiagnosed or misdiagnosed, resulting in significant diagnostic delays [2]. However, if we increased clinical awareness, especially in cases with low or absent serum ceruloplasmin. This may facilitate earlier recognition and appropriate intervention [3].

Neurologic features typically emerge in mid‐adulthood and may include extrapyramidal signs (tremors, parkinsonism, chorea), cerebellar ataxia, cognitive impairment, and psychiatric disturbances [2, 5]. These usually follow systemic manifestations such as diabetes mellitus, microcytic anemia, and retinal degeneration. However, there is considerable phenotypic heterogeneity in ACP [2, 6]. While most cases have been reported in Japanese or Italian cohorts [6, 7], our patient, an Emirati male, illustrates the broader ethnic distribution of ACP.

Importantly, this case adds to the growing literature that highlights atypical neurologic presentations in ACP. The earliest manifestation in this patient was diabetes mellitus, consistent with the typical disease course [8]. Although less common, psychosis is a recognized feature of ACP, particularly in cases with neurologic onset [2]. Additionally, we highlight the findings of Ketata et al. [9], who observed that male patients with homozygous CP mutations often develop diabetes first, with neuropsychiatric symptoms developing later, mirroring the pattern observed in our patient. Hence, this case broadens the recognized neuropsychiatric spectrum and underscores the importance of considering ACP in middle‐aged individuals with unexplained psychiatric symptoms in the setting of metabolic disturbances.

Genotypically, more than 70 CP gene mutations have been reported [2]. The splice‐site mutation in our case (c.2426‐1G>A) appears to be novel, as it is absent from both ClinVar and gnomAD databases, and to our knowledge has not been previously published. Such mutations expand the known allelic heterogeneity and suggest possible genotype–phenotype correlations. Notably, Ketata et al. [9] also reported a novel CP mutation (c.988A>T) associated with atypical neurologic onset in Tunisian siblings.

In silico prediction tools support the pathogenicity of this variant. SpliceAI, a deep learning model for splicing prediction developed by the Broad Institute, generates Δ scores ranging from 0 to 1, where higher values indicate greater confidence in splice site disruption. Using the SpliceAI lookup tool, our analysis of the patient's variant (c.2426‐1G>A) yielded a Δ score of 0.99 for splice acceptor loss, strongly predicting loss of the canonical splice acceptor site and a high likelihood of exon skipping or intron retention. Pangolin similarly predicted splice site loss with a score of 0.79. Together, these findings suggest that the variant disrupts normal mRNA processing and likely results in a nonfunctional ceruloplasmin protein. SpliceAI results were obtained using the online lookup interface (https://spliceailookup.broadinstitute.org) [10].

Laboratory findings in ACP often include absent ceruloplasmin, low serum copper and iron, and elevated ferritin, consistent with our patient's results [3]. In some cases, ceruloplasmin ferroxidase activity is measured and is typically absent, though this was not assessed in our case. Systemic features, particularly diabetes mellitus (seen in ~68.5% of ACP cases) and microcytic anemia (~80%–86%), are often the earliest clinical clues [6, 8]. Ophthalmologic evaluation revealed central scotomas due to diabetic retinopathy, not retinal degeneration associated with ACP. This distinction is important because retinal pigmentary changes and vision loss have been frequently reported in ACP cohorts, especially in Japanese patients [7], but were absent in this case. Therefore, we focus our discussion on the psychiatric and neurological manifestations that dominated the clinical course.

Our patient's MRI demonstrated typical ACP‐related iron deposition in the basal ganglia, thalami, substantia nigra, and dentate nuclei, consistent with previously reported patterns [11]. This distinguishes ACP from other NBIA disorders, which show more localized or heterogeneous distributions. Although rare cases of ACP with normal MRI findings have been reported [9], the clear radiological iron deposition in our patient supported the clinical and genetic diagnosis.

Treatment of ACP is not standardized and is guided primarily by case reports. Iron chelation remains the mainstay of therapy, with agents such as deferoxamine, deferasirox, and deferiprone commonly used [2]. In our patient, deferasirox was initially administered at 20 mg/kg/day and later reduced without adverse effects. Although deferasirox can reduce hepatic iron, its efficacy in reducing brain iron remains limited [12]. Phlebotomy, attempted in our case, is controversial. Literature suggests that it offers little benefit and may exacerbate anemia or neurologic symptoms due to impaired tissue iron mobilization [2, 9].

Other therapies include fresh‐frozen plasma, which supplies exogenous ceruloplasmin, and zinc or vitamin E to mitigate oxidative stress. Zinc therapy has shown some benefit in symptomatic heterozygous ACP carriers, but evidence remains limited [13].

In summary, this case illustrates an atypical presentation of ACP with prominent neuropsychiatric features and a novel CP mutation. It reinforces key teaching points: (1) MRI typically demonstrates characteristic iron deposition; (2) phlebotomy may not always be beneficial; and (3) resistant psychiatric symptoms in middle age warrant metabolic and genetic evaluation when accompanied by abnormal iron indices.