Among the neurodegeneration with brain iron accumulation disorder spectrum, aceruloplasminemia is a rare, adult‐onset, autosomal recessive disease caused by mutations in the ceruloplasmin gene that result in ceruloplasmin absence and cellular iron accumulation. Neurological manifestations characteristically appear in adulthood, typically after the fourth decade, and include cerebellar symptoms and hyperkinesias. 1 , 2 , 3 Anemia, liver disease, diabetes mellitus, and retinopathy are other characteristic findings. Here we report a patient with markedly asymmetric involuntary movements diagnosed with aceruloplasminemia.
Case Report
A 60‐year‐old male was admitted to our hospital with predominantly right‐sided involuntary movements. The patient was the product of a consanguineous marriage and had diabetes mellitus and hypertension. The neurologic exam revealed generalized chorea more marked on the right side, gait ataxia, and areflexia. This was accompanied by occasional dystonic posturing and retrocollis (Video S1, segment A). The Mini‐Mental State Examination score was normal (29/30), as was the Beck Depression Inventory score (5/63). Laboratory findings showed severe anemia (hemoglobin, 8.3 mg/dL). His ferritin level was 1212 ng/mL (23–336 ng/mL), and the ceruloplasmin was <0.002 g/L (0.22–0.58 g/L). The fluid attenuation inversion recovery sequences of brain magnetic resonance imaging (MRI) revealed white matter hyperintensities in the anterior temporal cortex and middle cerebellar peduncle, and susceptibility‐weighted imaging and T2 sequences revealed paramagnetic material deposition in the bilateral basal ganglia and cerebellum (Fig. 1). Kayser Fleischer rings and retinal degeneration were not observed.
FIG. 1.
Initial cranial magnetic resonance imaging (A–D). (A) Fluid attenuation inversion recovery hyperintensities in the anterior temporal cortex and middle cerebellar peduncle (B). Paramagnetic material deposition in the bilateral basal ganglia in susceptibility‐weighted imaging sequences (C). Paramagnetic material deposition in the basal ganglia and cortical regions in T2 sequences (D) paramagnetic material deposition in the basal ganglia and thalamus in coronal T2 sequences. Patient's cranial magnetic resonance imaging performed 15 months later (E–H). (E) Fluid attenuation inversion recovery sequences of follow‐up brain magnetic resonance imaging without anterior temporal cortex and middle cerebellar peduncle hyperintensities. (F) Paramagnetic material deposition in the cerebral cortex, bilateral basal ganglia, and thalamus in susceptibility‐weighted imaging sequences, (G) paramagnetic material deposition in the bilateral dentate nuclei in susceptibility‐weighted imaging sequences, and (H) an area of central hyperintensity surrounded by hypointensity of the lentiform nuclei in coronal T2 sequences.
Next‐generation sequencing (MiSeq; Illumina Inc., San Diego, CA) revealed a novel homozygous mutation in the ceruloplasmin gene (NM_000096.3:c.1173delC [p.D391Efs*17]); this mutation causes a frameshift and an early stop codon. All coding exons of the ceruloplasmin gene and their flanking splice site junctions were sequenced by MiSeq (Illumina Inc.) according to the manufacturer's recommendations. The sequences were aligned to the hg19 genome in MiSeq Reporter software (Illumina Inc.). Visualization of the data was performed with Integrative Genomics Viewer 2.3 (Broad Institute, Cambridge, MA) software. The relevant sequence analysis is presented in Figure 2.
FIG. 2.
Frameshift mutation at the 391st amino acid in exome 6 of the ceruloplasmin gene (NM_000096.3:c.1173delC [p.D391Efs*17]). The variant position is covered by 1000 reads.
The patient was prescribed 75 mg/day tetrabenazine for symptomatic treatment of chorea and zinc sulfate 50 mg/day to reduce iron absorption. Iron chelation therapy with deferasirox (500 mg/day) was delayed for impaired renal function and finally added 5 months later. The patient's ferritin concentration decreased during the follow‐up period; however, the patient progressed clinically and radiologically. His most recent MRI scan, 15 months after the initial scan, showed an increase in iron accumulation (Fig. 1).
Discussion
Here we present a case of aceruloplasminemia with generalized but markedly asymmetric chorea as the predominant manifestation related to a novel mutation of the ceruloplasmin gene. Disease‐related mutations in the ceruloplasmin gene are usually unique to each family and lead to an absence of or severe reduction in ceruloplasmin. The NM_000096.3:c.1173delC (p.D391EfsTer8) variant was not found through exome sequencing of 1500 of our clinic patients; neither had it been reported in large online databases (Gnomad, ExAC, Bravo, and Kaviar). Mutation tester software predicted this variant as a disease‐causing mutation (probability: 1). Furthermore, as this mutation generates a null variant, it is also predicted as a disease‐causing mutation based on the American College of Medical Genetics criteria. We identified 17 cases previously reported with a frameshift mutation in the ceruloplasmin gene. 4
Movement disorders are common in aceruloplasminemia. Nevertheless, our case presented with the unusual feature of asymmetric involuntary movements, which, to the best of our knowledge, has not been previously reported. Asymmetric presentation of movement disorders, including chorea, is typically associated with contralateral brain lesions; however, they have also been documented in hematologic conditions. 5 , 6
As with other neurodegenerations with brain iron accumulations, characteristic MRI features are crucial in suggesting a diagnosis. 7 , 8 Our patient's brain MRI showed extensive iron deposition in the basal ganglia, thalamus, dentate nuclei, and cerebral cortex with T2 hyperintensities and susceptibility‐weighted imaging hypointensities. Furthermore, the follow‐up MRI revealed an area of central hyperintensity surrounded by hypointensity of the lentiform nuclei in T2 coronal sequences. Although hyperintensity in the putamen in neurodegeneration with brain iron accumulations suggestive of additional necrosis is far more typical of neuroferritinopathy, the combination of hyperintense and hypointense abnormalities of the basal ganglia has not been reported previously in aceruloplasminemia. This MRI pattern could be the result of different stages of pathologic processes in different brain regions. 8
Despite a thorough literature search, we did not identify any case report that focused on findings of fluid attenuation inversion recovery sequences in aceruloplasminemia. However, the change seen in the fluid attenuation inversion recovery sequences in our case was remarkable. Somewhat unexpectedly, a follow‐up brain MRI did not replicate the middle cerebellar peduncle and anterior temporal hyperintensities, which we believe could be attributed to the initiation of chelation therapy. Iron chelation was not initiated at admission because of the patient's impaired renal function; however, it was added later because of the patient's ongoing high ferritin level. Recent data regarding the effects of current therapies on brain iron deposition and neurological manifestations are controversial. 9 Although our patient's ferritin levels were reduced from 1212 ng/mL to 432 ng/mL with chelation therapy at the 15‐month follow‐up, his neurological condition further deteriorated (Video S1, segment B).
Author Roles
(1) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
S.T.A.: 1A
O.B.: 1A
S.C.: 1B
M.C.A.: 1A, 1B
Disclosures
Ethical Compliance Statement
The Institutional Review Board of Ankara University School of Medicine does not require approval for case reports. All procedures performed in this case were in accordance with the ethical standards of 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the patient. 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
The authors declare that there are no conflicts of interest relevant to this work, and the authors received no specific funding for this work.
Financial Disclosures for Previous 12 Months
M.C.A. receives honoraria from Abbott, Abdi Ibrahim, Allergan, Bohringer Ingelheim, Gen Ilac, Generica, Glaxo Smith Kline, Medtronic, Lundbeck, Novartis, Ilko, and SantaFarma and a project promotion bonus from The Scientific and Technological Research Council of Turkey as an additional conflict of interest.
Supporting information
Video S1. Segment A: recorded in August 2017. Notice right hemi‐chorea including face and mild left‐sided bradykinesia. Infrequent dystonic posturing and choreiform movements present all body parts, gait ataxia, and cerebellar dysarthria. Segment B: recorded in September 2019. The patient now has mild chorea of the feet bilaterally, moderate bradykinesia prominent on the right side and accompanied by retrocollis, and wide‐based gait. Ataxia and parkinsonism are worse when compared with segment A.
Acknowledgments
We acknowledge Prof Mehmet Yörübulut's comments on radiological findings of the patients.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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Supplementary Materials
Video S1. Segment A: recorded in August 2017. Notice right hemi‐chorea including face and mild left‐sided bradykinesia. Infrequent dystonic posturing and choreiform movements present all body parts, gait ataxia, and cerebellar dysarthria. Segment B: recorded in September 2019. The patient now has mild chorea of the feet bilaterally, moderate bradykinesia prominent on the right side and accompanied by retrocollis, and wide‐based gait. Ataxia and parkinsonism are worse when compared with segment A.