Methods

Investigations

Laboratory investigations revealed microcytic anemia (Hb 9.5 g/dL, MCV 76.8 fL) with low serum iron (37 μg/dL), low transferrin (1.99 g/L), and elevated ferritin (2482 ng/mL). Ceruloplasmin and serum copper were markedly reduced (< 0.03 g/L and 20.2 μg/dL, respectively). The patient also had poorly controlled diabetes (HbA1c 12.5%) and dyslipidemia. Liver function tests were largely unremarkable aside from a mild ALT elevation (58 U/L). A peripheral smear showed mild microcytosis and hypochromia; platelets and WBCs were normal.

CSF analysis demonstrated elevated protein (140 mg/dL) and IgG (15.9 mg/dL), with normal glucose (194 mg/dL, consistent with serum hyperglycemia) and no pleocytosis. CSF infectious and autoimmune panels were negative. Thyroid function (TSH and T4) was normal.

Neuroimaging supported the diagnosis: non‐contrast CT revealed diffuse atrophy with hyperdensities in deep gray matter structures. MRI with T2 and SWI sequences showed hypointensities indicating iron deposition in basal ganglia, thalami, substantia nigra, and cerebellar nuclei, with white matter hyperintensities and brain atrophy (Figure 1). Abdominal MRI demonstrated hepatic and pancreatic iron overload (Figure 2). Although rare cases of ACP with normal MRI findings have been reported in the literature, our patient demonstrated typical iron deposition across brain and systemic imaging, supporting the clinical and genetic diagnosis.

FIGURE 1: CT and MRI of the brain showed iron deposition in basal ganglia and dentate nuclei. CT brain (axial) showing a hyperdense signal (yellow arrow) in the dentate nuclei (top left). MRI brain FLAIR sequence showing a white matter hyperintensity along the corticospinal pathway extending to the pons (red arrow) and a hypointense signal in the dentate nuclei (yellow arrows) (top right). MRI brain Fluid Attenuated Inversion Recovery (FLAIR) shows hypointense signals in the bilateral thalami, caudate, and lentiform nuclei, as well as a hyperintense signal in the posterior limb of the internal capsule (bottom left). MRI brain SWI confirming iron deposits (bottom right).

FIGURE 2: MRI of the abdomen showed iron deposition in the liver. Liver T2* showed liver iron loading was 1.5 ms, corresponding to 8–15 mg/g, which indicates severe liver iron overload [4].

A liver biopsy confirmed hepatocellular siderosis with minimal fibrosis and focal copper accumulation. Hepatocyte nuclei also showed glycogenation. Genetic analysis identified a homozygous pathogenic variant in the CP gene (c.2426‐1G>A), unreported in ClinVar or gnomAD, confirming the diagnosis of aceruloplasminemia.

Differential Diagnosis

The combination of diabetes, microcytic anemia, and neurological symptoms raised suspicion for ACP. However, other inherited metabolic and neurodegenerative disorders were initially considered, including Friedreich's ataxia, mitochondrial syndromes such as MELAS, pantothenate kinase–associated neurodegeneration (PKAN), hereditary hemochromatosis, and multiple sclerosis. Given the patient's movement disorder and psychiatric features, Wilson's disease, Huntington's disease, and autoimmune limbic encephalitis were also part of the differential.

The laboratory profile of microcytic anemia with high ferritin, low serum copper, and absent ceruloplasmin excluded most alternative diagnoses. Neuroferritinopathy was briefly considered but was unlikely given the presence of diabetes, retinopathy, and absent ceruloplasmin. Ultimately, confirmation of a homozygous CP gene mutation (c.2426‐1G>A) established the diagnosis of ACP.

Treatment

Management required a multidisciplinary approach. Carbidopa‐levodopa provided partial symptomatic relief of parkinsonism. Iron chelation with deferasirox was initiated but interrupted due to psychiatric and medical complications. Phlebotomy was attempted but subsequently discontinued, and iron chelation was resumed.