Skip to main content

Advertisement

Log in

Evolution of the retinal function by flash-ERG in one child suffering from neuronal ceroid lipofuscinosis CLN2 treated with cerliponase alpha: case report

  • Clinical Case Report
  • Published:
Documenta Ophthalmologica Aims and scope Submit manuscript

Abstract

Introduction

Neuronal ceroid lipofuscinoses (CLN) are neurodegenerative disorders among the most frequent, inherited as an autosomal recessive trait. Affected patients can present with progressive decline in cognitive and motor functions, seizures, a shortened life span and visual deficiency. CLN2 is one of the rare CLN that benefits from treatment by cerliponase alpha an enzyme replacement therapy. Preliminary results on treated animal models have shown delayed neurological signs and prolonged life span. However, cerliponase alpha did not prevent vision loss or retinal degeneration in those animal models. Cerliponase alpha has currently been delivered to a few CLN2-affected patients. We report the case of one patient suffering from CLN2 treated with intracerebroventricular infusions of cerliponase alpha 300 mg every two weeks. Evolution of his retinal function was assessed by three successive flash-ERG and flash-VEP recordings throughout his treatment over a 4-year period.

Results

Before treatment at the age of 4 years 5 months, patient’s retinas were normal (normal fundi and normal flash-ERG). After 29 infusions at the age of 6 years 10 months, a-wave combined response was absent, while cone and flicker responses were normal. After 80 infusions at the age of 8 years 9 months, a-wave cone response was absent with b-wave peak time increased, and no combined response.

Comments

Despite treatment, our patient’s retinas showed a progressive abnormal and inhomogeneous function. Rods function was altered first, then the scotopic system and afterward, the cones. This result differs from those recorded in animal models. The relative preservation of cone functioning for a while could not be unequivocally attributed to enzyme replacement therapy as we lack comparison with the evolution of flash-ERGs recorded in untreated subjects.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

cd:

Candela

cd/m2 :

Candela per meter square

cd.s/m2 :

Candela.second per meter square

CLN:

Neuronal ceroid lipofuscinoses

CLN2:

Late infantile neuronal ceroid lipofuscinosis (Jansky–Bielschowsky)

CLN2 :

CLN2 Gene

ERG:

Electroretinogram

VEP:

Visual evoked potential

References

  1. Menache CC., Haenggeli Ch-A., and Safran AB., (2004) Affections du métabolisme général à expression neuro-ophtalmologique., in Neuro-Ophtalmologie - Rapport de la Société Française d'Ophtalmologie, Safran AB., Editor Masson: Paris. p. 425–454

  2. Mukherjee AB et al (2019) Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses. Mol Neurodegener 14(1):4

    Article  Google Scholar 

  3. Saudubray JM, Van den Berghe G, Walters JH (2012) Inborn metabolic diseases. Diagnosis and treatment, 5th edn. Springer-Verlag, Heidelberg

    Book  Google Scholar 

  4. Nelvagal HR et al (2019) Pathomechanisms in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta Mol Basis Dis 9:165570

    Google Scholar 

  5. Perez-Poyato MS et al (2013) Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. J Child Neurol 28(4):470–478

    Article  Google Scholar 

  6. Nickel M et al (2018) Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health 2(8):582–590

    Article  Google Scholar 

  7. Williams RE et al (2017) Management strategies for CLN2 disease. Pediatr Neurol 69:102–112

    Article  Google Scholar 

  8. Sima N et al (2018) Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses. Orphanet J Rare Dis 13(1):54

    Article  Google Scholar 

  9. Mole SE et al (2019) Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis. Lancet Neurol 18(1):107–116

    Article  Google Scholar 

  10. Kohlschutter A et al (2019) Current and emerging treatment strategies for neuronal ceroid lipofuscinoses. CNS Drugs 33(4):315–325

    Article  Google Scholar 

  11. Markham A (2017) Cerliponase alfa: first global approval. Drugs 77(11):1247–1249

    Article  CAS  Google Scholar 

  12. Katz ML et al (2014) Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). J Neurosci Res 92(11):1591–1598

    Article  CAS  Google Scholar 

  13. Sanders DN et al (2011) A reversal learning task detects cognitive deficits in a Dachshund model of late-infantile neuronal ceroid lipofuscinosis. Genes Brain Behav 10(7):798–804

    Article  CAS  Google Scholar 

  14. Cherukuri A et al (2018) Immunogenicity to cerliponase alfa intracerebroventricular enzyme replacement therapy for CLN2 disease: results from a phase 1/2 study. Clin Immunol 197:68–76

    Article  CAS  Google Scholar 

  15. Vuillemenot BR et al (2014) Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: safety, pharmacokinetics, and distribution. Toxicol Appl Pharmacol 277(1):49–57

    Article  CAS  Google Scholar 

  16. Whiting RE et al (2016) Intracerebroventricular gene therapy that delays neurological disease progression is associated with selective preservation of retinal ganglion cells in a canine model of CLN2 disease. Exp Eye Res 146:276–282

    Article  CAS  Google Scholar 

  17. Schulz A et al (2018) Study of intraventricular cerliponase Alfa for CLN2 disease. N Engl J Med 378(20):1898–1907

    Article  CAS  Google Scholar 

  18. Kohlschutter A, Schulz A (2016) CLN2 disease (classic late infantile neuronal ceroid lipofuscinosis). Pediatr Endocrinol Rev 13(Suppl 1):682–688

    PubMed  Google Scholar 

  19. Specchio N, Pietrafusa N, Trivisano M (2020) Changing times for CLN2 disease: the era of enzyme replacement therapy. Ther Clin Risk Manag 16:213–222

    Article  CAS  Google Scholar 

  20. Lau JC et al (2018) Image-guided Ommaya reservoir insertion for intraventricular chemotherapy: a retrospective series. Acta Neurochir (Wien) 160(3):539–544

    Article  Google Scholar 

  21. Wang A et al (2019) Placement of ommaya reservoirs using electromagnetic neuronavigation and neuroendoscopy: a retrospective study with cost-benefit analysis. World Neurosurg 122:e723–e728

    Article  Google Scholar 

  22. Fulton AB, Hartmann EE, Hansen RM (1989) Electrophysiologic testing techniques for children. Doc Ophthalmol 71(4):341–354

    Article  CAS  Google Scholar 

  23. Bradshaw K, Hansen R, Fulton A (2004) Comparison of ERGs recorded with skin and corneal-contact electrodes in normal children and adults. Doc Ophthalmol 109(1):43–55

    Article  Google Scholar 

  24. Hamilton R, Graham K (2016) Effect of shorter dark adaptation on ISCEV standard DA 0.01 and DA 3 skin ERGs in healthy adults. Doc Ophthalmol 133(1):11–9

    Article  CAS  Google Scholar 

  25. Bach M, Meroni C, Heinrich SP (2020) ERG shrinks by 10% when reducing dark adaptation time to 10 min, but only for weak flashes. Doc Ophthalmol 141(1):57–64

    Article  Google Scholar 

  26. Odom JV et al (2016) ISCEV standard for clinical visual evoked potentials: (2016 update). Doc Ophthalmol 133(1):1–9

    Article  Google Scholar 

  27. Weleber RG (1998) The dystrophic retina in multisystem disorders: the electroretinogram in neuronal ceroid lipofuscinoses. Eye (Lond) 12(Pt 3b):580–590

    Article  Google Scholar 

  28. Quagliato E et al (2017) Retinal function in patients with the neuronal ceroid lipofuscinosis phenotype. Arq Bras Oftalmol 80(4):215–219

    Article  Google Scholar 

  29. Dozieres-Puyravel B et al (2020) Paediatric-onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis. Dev Med Child Neurol 62(4):528–530

    Article  Google Scholar 

  30. Mohand-Said S et al (2001) Rod-cone interactions: developmental and clinical significance. Prog Retin Eye Res 20(4):451–467

    Article  CAS  Google Scholar 

  31. Yang Y et al (2009) Functional cone rescue by RdCVF protein in a dominant model of retinitis pigmentosa. Mol Ther 17(5):787–795

    Article  CAS  Google Scholar 

  32. Le Gargasson JF et al (1990) Visual electrophysiology in 101 children with encephalopathy. J Fr Ophtalmol 13(8–9):441–448

    PubMed  Google Scholar 

  33. Specchio N et al (2017) Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease. Epilepsia 58(8):1380–1388

    Article  CAS  Google Scholar 

  34. Whiting RE et al (2014) Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis. Exp Eye Res 125:164–172

    Article  CAS  Google Scholar 

  35. Mowat FM et al (2008) Topographical characterization of cone photoreceptors and the area centralis of the canine retina. Mol Vis 14:2518–2527

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Florence Rigaudière.

Ethics declarations

Statement of human rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Statement on the welfare of animals

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflicts of interest

None.

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

Rigaudière, F., Nasser, H., Pichard-Oumlil, S. et al. Evolution of the retinal function by flash-ERG in one child suffering from neuronal ceroid lipofuscinosis CLN2 treated with cerliponase alpha: case report. Doc Ophthalmol 143, 99–106 (2021). https://doi.org/10.1007/s10633-021-09825-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10633-021-09825-z

Keywords

Navigation