Skip to main content
SpringerLink
Log in

Aceruloplasminemia: a multimodal imaging study in an Italian family with a novel mutation

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Objective

Structural abnormalities in thalami and basal ganglia, in particular the globus pallidus (GP), are a neuroimaging hallmark of hereditary aceruloplasminemia (HA), yet few functional imaging data exit in HA carriers. This study investigated the iron-related structural and functional abnormalities in an Italian HA family.

Methods

Multimodal imaging was used including structural 3 T MRI, functional imaging (SPECT imaging with 123I-ioflupane (DAT-SPECT), cardiac 123I metaiodobenzylguanidine (123I-MIBG) scintigraphy, and 18F-fluorodeoxyglucose (18F-FDG)-PET imaging). In the proband, MRI and scintigraphic evaluations were performed at baseline, 2 and 4 years (structural imaging), and 2 years of follow-up period (functional imaging).

Results

We investigated two cousins carrying a novel splicing homozygous mutation in intron 6 (IVS6 + 1 G > A) of CP gene. Interestingly, MRI features in both subjects were characterized by marked iron accumulation in the thalami and basal ganglia nuclei, while GP was not affected. MRI performed in the proband at 2 and 4 years of follow-up confirmed progressive neurodegeneration of the thalami and basal ganglia without the involvement of GP. Functional imaging showed reduced putaminal DAT uptake in both cousins, whereas cardiac MIBG and FDG uptakes performed in the proband were normal. Longitudinal scintigraphic investigations did not show significant changes over the time.

Conclusions

For HA carriers, our findings demonstrate that GP was spared by iron accumulation over the time. The nigrostriatal presynaptic dopaminergic system was damaged while the cardiac sympathetic system remained longitudinally preserved, thus expanding the imaging features of this rare inherited disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Miyajima H, Nishimura Y, Mizoguchi K, Sakamoto N, Shimizu T, Honda N (1987) Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 37:761–767

    Article  CAS  Google Scholar 

  2. Yoshida K, Furihata K, Takeda S et al (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9:267–272

    Article  CAS  Google Scholar 

  3. Morita H, Ikeda S, Yamamoto K et al (1995) Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann Neurol 37:646–656

    Article  CAS  Google Scholar 

  4. McNeill A, Birchall D, Hayflick SJ et al (2008) T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 70(18):1614–1619

    Article  CAS  Google Scholar 

  5. Salsone M, Bagnato A, Novellino F et al (2009) Cardiac MIBG scintigraphy in primary progressive freezing gait. Parkinsonism Relat Disord 15(5):365–369

    Article  Google Scholar 

  6. Sammarra I, Barbagallo G, Labate A et al (2019) Value of multimodal imaging approach to diagnosis of neurosarcoidosis. Brain Sci 9(10):243

    Article  Google Scholar 

  7. Gelman N, Gorell JM, Barker PB et al (1999) MR imaging of human brain at 3.0 T: preliminary report on transverse relaxation rates and relation to estimated iron content. Radiology 210:759–767

    Article  CAS  Google Scholar 

  8. Stelten BML, van Ommen W, Keizer K (2019) Neurodegeneration with brain iron accumulation: a novel mutation in the ceruloplasmin gene. JAMA Neurol 76(2):229–230

    Article  Google Scholar 

  9. Zhou L, Chen Y, Li Y et al (2020) Intracranial iron distribution and quantification in aceruloplasminemia: a case study. Magn Reson Imaging 70:29–35

    Article  CAS  Google Scholar 

  10. Watanabe M, Ohyama K, Suzuki M et al (2018) Aceruloplasminemia with abnormal compound heterozygous mutations developed neurological dysfunction during phlebotomy therapy. Intern Med 57(18):2713–2718

    Article  CAS  Google Scholar 

  11. Kim HK, Ki CS, Kim YJ, Lee MS (2017) Radiological findings of two sisters with aceruloplasminemia presenting with chorea. Clin Neuroradiol 27(3):385–388

    Article  CAS  Google Scholar 

  12. Haemers I, Kono S, Goldman S, Gitlin JD, Pandolfo M (2003) Clinical, molecular, and PET study of a case of aceruloplasminemia presenting with focal cranial dyskinesia. J Neurol Neurosurg Psychiatry 75:334–337

    Article  Google Scholar 

  13. Suwijn SR, de Bruin K, de Bie RMA, Booij J (2014) The role of SPECT imaging of the dopaminergic system in translational research on Parkinson’s disease. Parkinsonism Relat Disord 20(Suppl 1):S184–S186

    Article  Google Scholar 

  14. Sakamoto F, Shiraishi S, Ogasawara K et al (2020) A diagnostic strategy for Lewy body disease using DAT-SPECT, MIBG and combined index. Ann Nucl Med 34(6):415–423

    Article  CAS  Google Scholar 

  15. Miyajima H, Takahashi Y, Kono S, Hishida A, Ishikawa K, Sakamoto M (2005) Frontal lobe dysfunction associated with glucose hypometabolism in aceruloplasminemia. J Neurol 252:996–997

    Article  Google Scholar 

  16. Miyajima H, Takahashi Y, Kono S et al (2002) Glucose and oxygen hypometabolism in aceruloplasminemia brains. Intern Med 41:186–190

    Article  CAS  Google Scholar 

  17. Fasano A, Colosimo C, Miyajima H, Tonali PA, Re TJ, Bentivoglio AR (2008) Aceruloplasminemia: a novel mutation in a family with marked phenotypic variability. Mov Disord 23(5):751–755

    Article  Google Scholar 

  18. Cuenca MC, Marchi G, Barqué A, Esteban-Jurado C, Marchetto A, Giorgetti A et al (2020) Genetic and clinical heterogeneity in thirteen new cases with aceruloplasminemia. Atypical anemia as a clue for an early diagnosis. Int J Mol Sci 21(7):2374

    Article  CAS  Google Scholar 

  19. Yazaki M, Yoshida K, Nakamura A et al (1998) A novel splicing mutation in the ceruloplasmin gene responsible for hereditary ceruloplasmin deficiency with hemosiderosis. J Neurol Sci 156(1):30–34

    Article  Google Scholar 

  20. Hatanaka Y, Okano T, Oda K, Yamamoto K, Yoshida K (2003) Aceruloplasminemia with juvenile-onset diabetes mellitus caused by exon skipping in the ceruloplasmin 1. Intern Med 42(7):599–604

    Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the two patients that kindly participated in the study.

Author information

Authors and Affiliations

  1. Institute of Molecular Bioimaging and Physiology, National Research Council, Rome, Italy

    Maria Salsone, Rita Nistico, Fabiana Novellino & Aldo Quattrone

  2. Sleep Disorders Center, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy

    Maria Salsone & Luigi Ferini-Strambi

  3. Institute of Neurology, University “Magna Graecia”, Catanzaro, Italy

    Gennarina Arabia & Andrea Quattrone

  4. Institute for Biomedical Research and Innovation, National Research Council, Mangone, CS, Italy

    Grazia Annesi & Monica Gagliardi

  5. Vita-Salute San Raffaele University, Milan, Italy

    Luigi Ferini-Strambi

  6. Neuroscience Center, University “Magna Graecia,” Germaneto, Catanzaro, Italy

    Aldo Quattrone

Authors
  1. Maria Salsone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gennarina Arabia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Grazia Annesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monica Gagliardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rita Nistico
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fabiana Novellino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luigi Ferini-Strambi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrea Quattrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Aldo Quattrone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aldo Quattrone.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

All procedures performed in the study involving human participant were in accordance with the ethical standards of the Institutional Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

Written informed consent was obtained from both participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salsone, M., Arabia, G., Annesi, G. et al. Aceruloplasminemia: a multimodal imaging study in an Italian family with a novel mutation. Neurol Sci 43, 1791–1797 (2022). https://doi.org/10.1007/s10072-021-05613-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-021-05613-4

Keywords

Search

Navigation