A Rare Case of CLN3-associated Isolated Retinal Degeneration with Macular Oedema

Introduction

The neuronal ceroid lipofuscinoses (NCLs) comprise a set of hereditary neurodegenerative disorders involving lysosomal storage, and up to this point, they have been linked to 13 genes. Prevalence is one in every 100,000 live births [1]. Historically, the ailment was categorised into various types based on the onset of the disease. Given considerable variations in disease onset and progression, a conclusive diagnosis often necessitates genetic testing and confirmation of the specific sequence variant responsible. As a result, a novel gene-centred nomenclature has been implemented to simplify the classification of the disease. The classic CLN3 disease characterized by an early onset in adolescence, previously termed “juvenile neuronal ceroid lipofuscinosis” (JNCL) and commonly known as “Batten disease,” is a variant of NCL caused by sequence variations in the CLN3 gene (Ceroid Lipofuscinosis, Neuronal, 3; Online Mendelian Inheritance in Man: 204 200). This gene is responsible for encoding a transmembrane protein with an unidentified function [2]. The prevalent sequence variant in CLN3 is a homozygous 1 kb deletion constituting around 85% of JNCL cases [3]. This deletion spans exons 7 to 8, leading to the production of a truncated and non-functional protein. However, other mutations in CLN3 may give rise to isolated adult-onset retinal degeneration [4]. Confirmation of JNCL diagnosis may involve the identification of vacuolated lymphocytes and lysosomal (fingerprint) inclusions on a blood film in addition to molecular genetic testing [2], [5]. Symptoms commonly manifest in early childhood, including vision loss between 4 and 10 years, behavioural and cognitive issues between 7 and 10 years, and progressive motor deterioration and seizures between 10 and 13 years. Ultimately, these complications lead to premature death in the second or third decade of life [6], [7]. This case illustrates that CLN3 mutations can manifest as an isolated retinal phenotype with cystoid macular oedema and should be considered in atypical cases of this condition.

Publication History

Received: 16 September 2024

Accepted: 31 March 2025

Article published online:
03 June 2025

• References

• 1 Johnson TB, Cain JT, White KA. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol 2019; 15: 161-178
• 2 Licchetta L, Bisulli F, Fietz M. A novel mutation of Cln3 associated with delayed-classic juvenile ceroid lipofuscinois and autophagic vacuolar myopathy. Eur J Med Genet 2015; 58: 540-544
• 3 Mink JW, Augustine EF, Adams HR. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol 2013; 28: 1101-1105
• 4 Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 2005; 6: 107-126
• 5 Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat 2012; 33: 42-63
• 6 Ku CA, Hull S, Arno G. Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration. JAMA Ophthalmol 2017; 135: 749-760
• 7 Weisschuh N, Mayer AK, Strom TM. et al. Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing. PLoS One 2016; 11: e0145951
• 8 Mole SE, Anderson G, Band HA. Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis. Lancet Neurol 2019; 18: 107-116
• 9 Pichi F, Abboud EB, Ghazi NG. et al. Fundus autofluorescence imaging in hereditary retinal diseases. Acta Ophthalmol 2018; 96: e561-e561
• 10 Smirnov VM, Nassisi M, Solis Hernandez C. et al. Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort. JAMA Ophthalmol 2021; 139: 278-291
• 11 Schulz A, Ajayi T, Specchio N. Study of intraventricular Cerliponase Alfa for CLN2 disease. N Engl J Med 2018; 378: 1898-1907
• 12 Dulz S, Schwering C, Wildner J. et al. Ongoing retinal degeneration despite intraventricular enzyme replacement therapy with cerliponase alfa in late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2 disease). Br J Ophthalmol 2023; 107: 1478-1483
• 13 Collins J, Holder GE, Herbert H. et al. Batten disease: features to facilitate early diagnosis. Br J Ophthalmol 2006; 90: 1119-1124