Aceruloplasminemia Initiating with Neurologic Symptoms: Two Cases Featuring a Novel Mutation and Literature Review

Dear Editor, Aceruloplasminemia (ACP) is an inherited autosomal recessive disease resulting from a genetic mutation in the ceruloplasmin (CP) gene.[1] ACP typically emerges during adulthood and is diagnosed late in life.[1] ACP initiating with neurologic symptoms (NS) is less common than with systemic signs (SS).[2] Microcytic anemia and elevated blood sugar typically characterize most biological features.[1] Brain iron overload (BIO) is considered a hallmark of ACP, and previous studies associated NS with BIO.[2] In this report, we describe two siblings with unique NS, caused by a new homozygous missense mutation. The two brothers were born to Tunisian parents who were nonconsanguineous, after uneventful pregnancies. The first sibling (II2) was a 37-year-old male who achieved normal developmental milestones [Figure 1a]. At age 36 years, he presented to our department with a history of recurring seizures. Both focal motor seizures (hypertonia of the left lower limb) with secondary generalization and generalized tonic–clonic seizures started at age 3 years. The seizures occurred once every 3 months. After 22 years, he was diagnosed with having subclinical hypothyroidism (SH) and received levothyroxine treatment. A neurologic examination was normal, except for the presence of rigidity in the right upper limb. The biological assessment showed SH (thyroid-stimulating hormone: 6.49 mUI/L, with normal free thyroxine) and macrocytosis (mean corpuscular volume: 112.6 fl) with normal hemoglobin and Vitamin B12 levels. His blood glucose level was normal. His CP level was 0.02 g/L. The iron level was low (21 μg/dL), but the ferritin level was high (1420 ng/mL). Abdominal ultrasound showed multiple gallstones but no hepatic iron overload. Thyroid ultrasound revealed subacute thyroiditis and testicular ultrasound indicated orchitis. An examination was performed by an ophthalmologist, and no retinal degeneration was observed. The sequences used for detecting BIO were sagittal and axial sequences T1, T2, Flair, coronal T2 sequences, and three-dimensional fast spoiled gradient echo sequences with reconstruction in all three planes. Brain magnetic resonance imaging (MRI) was unremarkable. Despite taking three antiepileptic drugs (carbamazepine, clobazam, and levetiracetam), he still experienced seizures. His video-electroencephalogram showed a normal background with left diffuse spikes and waves, without seizure recording [Figure 1b]. Activation methods such as light stimulation and hyperpnea revealed no additional abnormalities.Figure 1: (a) Genealogical chart, (b) The electroencephalogram of the first patient shows a normal background with left diffuse spikes and waves. (c) PolyPhen-2 database assessment yields a score of 1000, indicating a likely damaging variant, (d) Polyphen-2 database shows the impact of the mutation on ceruloplasmin protein functionThe second brother (II5) [Figure 1a] presented to our department at age 31 years; his childhood development was typically normal. At age 20 years, he experienced recurring focal nonmotor (behavior arrest) and generalized tonic–clonic seizures; thus, he began phenobarbital treatment. Despite adding clobazam due to ongoing seizures, the therapy proved ineffective. After 10 years, he was diagnosed with having SH. His neurologic examination was normal. An electroencephalogram with activations methods showed no abnormalities. His biological assay indicated macrocytosis (mean corpuscular volume: 100.4 fL). His hemoglobin and Vitamin B12 levels were normal. The CP concentration was low at 0.01 g/L (1 mg/dL). His ferritin was high (1350 ng/mL), but his serum iron level was low (18 μg/dL). An ophthalmologic evaluation was conducted, revealing no evidence of retinal degeneration. Brain MRI and abdominal ultrasound showed no signs of iron overload. Despite administering three antiepileptic drugs (levetiracetam, clobazam, and carbamazepine), he continued to experience seizures. In one sibling (II5), exome sequencing revealed a novel homozygous missense mutation (c.988A>T, [p. Asn330Tyr]) in the CP gene. The PolyPhen-2 database predicted that this missense mutation was expected to be deleterious and have a negative impact on the CP protein function [Figure 1c and d]. In addition, the genetic test results do not indicate the existence of continuous deletion gene syndrome. Accordingly, we can suggest that the atypical phenotypic observed in our cases could be related to the novel variant (c.988A>T). Symptom initiation with epilepsy is unique and distinct, a classic feature of ACP. The interesting aspect of our case report is the initiation of the two cases with epilepsy without subsequent development of other NS apart from the rigidity of the right upper extremity in the first sibling. Another intriguing discovery is the disparity in the age of epilepsy onset between the two brothers. Other factors that may account for this variation include environmental factors, potential genetic modifiers, or epigenetic factors, which have been investigated in ACP.[3] In addition, it is noteworthy that the onset of epilepsy in both brothers occurred at an earlier age compared with the onset of NS mentioned in a meta-analysis with a mean onset at 51 years.[3] This raises intriguing questions regarding the diverse clinical presentation and progression of the disease. Further research is essential to uncover the underlying mechanisms responsible for such variability in disease onset and progression. On the other hand, both siblings also presented with diabetes or anemia, which is commonly associated with endocrine pathologies in ACP. They subsequently developed SH, orchitis, and multiple gallstones. A recent meta-analysis demonstrated that NS was present at disease onset in only 20% of patients with ACP.[3] Similarly, our literature review found that among 108 patients with ACP, 14 started ACP with NS (15.7%) [Table 1].[1,2,4-11] Among these 14 patients, ACP was more prevalent in males.[1,2,4-11] The average age for NS onset was 51.64 ± 2.4 years, which was notably older than the two brothers we documented.[1,2,4-11] In our sibling patients, the time from NS onset to diagnosis was significantly longer compared with the average duration reported in the literature (6.37 ± 1.2 years).[1,2,4-11] Initiating ACP with epilepsy was a particular feature in our cases. Indeed, neither our literature review nor the recent meta-analysis revealed any instances of the condition beginning under these circumstances.[3] Epilepsy has been documented in patients whose ACP onset began with SS, but this was linked to a metabolic disorder, consistent with observations from the meta-analysis.[3] On the other hand, our literature review showed that ataxia was the most common initial symptom among patients who began with NS (10/14 cases).[1,2,4-11] These findings underscore the importance of considering ACP in young patients when ataxia, abnormal movements, or resistant epilepsy are present, even if the symptoms are isolated. In our two cases, neither anemia nor diabetes was present. Among the 14 cases found in our literature review, diabetes developed in four patients,[1,2,8,9] and anemia developed in five patients[4-6,9,10] Interestingly, a recent meta-analysis showed that the onset of the disease with NS was negatively correlated with the development of SS.[3] This might explain our observation. Nevertheless, our notable finding was identifying SH as an SS. Although SH was not previously reported, hypothyroidism was observed in two cases in which ACP was initiated with diabetes and anemia.[12,13]Table 1: Characteristics of included studiesBiologically, our patients showed macrocytosis, differing from the typical microcytic anemia or isolated microcytosis seen in ACP.[4-6,9,10] This macrocytosis is probably due to SH. In the second brother, the iron level was low and the ferritin level was high. Low iron levels and high ferritin levels are characteristic features of ACP.[3] This was also reported in previous case reports.[3] However, normal levels of ferritin and iron have also been described in certain cases. Miyajima et al. observed normal levels of ferritin and iron in three cases that started with NS, and Hines et al. demonstrated normal ferritin levels in one case and normal iron levels in two cases.[2,11] In addition, CP was low in the second brother. In a recent meta-analysis, 99% of patients had low CP levels.[3] A further unique finding is that both brothers had normal brain MRIs. In our literature review, brain MRIs showed BIO in 8/14 of included cases and were normal in 5/14 cases.[1,4,6-10] In a meta-analysis, investigators showed that 6.2% of patients with ACP had normal brain MRIs regardless of the symptoms of onset.[3] Moreover, in this meta-analysis, the onset of ACP with NS and male sex was negatively correlated with BIO (OR = 0.1, 95% CI: [0.03–0.35]; P < 0.001).[3] This could potentially clarify why we did not detect BIO in our cases, both of whom were male and presented with ACP alongside NS initiation. In our cases, we identified a novel missense mutation (c.988A>T, [p. Asn330Tyr]), which was observed to be pathogenic according to Polyphen-2. Among 11 patients with available genetic assessments, the missense mutation was the most reported (8/11) [Table 1]. According to the recent meta-analysis,[3] our two cases may have experienced incomplete penetrance or could be influenced by a modifier gene. This may explain the manifestation of the disease with NS. The genetic test confirmed the diagnosis of ACP in our cases. We report the first instance of epilepsy onset during infancy in ACP with normal brain MRI. Diagnosing ACP based on resistant epilepsy might be very challenging for physicians. This case report provides a novel perspective on ACP, suggesting that it should be considered even when brain MRI results are normal. These features can be related to a novel missense mutation. Genetic testing is the conclusive method for reaching the final diagnosis. Contribution details Concept: I.K, E.E., Design: I.K, E.E., Definition of intellectual content: I.K, E.E., Literature search: I.K, R.M., Clinical studies: I.K, E.E.,R.M., Experimental studies: E.E.,R.M., Data acquisition: I.K, R.M., Data analysis: I.K, Statistical Analysis: I.K, Manuscript preparation: I.K,R.M., Manuscript editing: E.E., Manuscript review: E.E., Gurantor: I.K, E.E., R.M. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.