Language Delay in Patients with CLN2 Disease: Could It Support Earlier Diagnosis?

Abstract

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric disorder associated with rapid neurodegeneration, and premature death in adolescence. An effective enzyme replacement therapy (cerliponase alfa) has been approved that can reduce this predictable neurological decline. The nonspecific early symptoms of CLN2 disease frequently delay diagnosis and appropriate management. Seizures are generally recognized as the first presenting symptom of CLN2 disease, but emerging data show that language delay may precede this. An improved understanding of language deficits in the earliest stage of CLN2 disease may support the early identification of patients. In this article, CLN2 disease experts examine how language development is affected by CLN2 disease in their clinical practices. The authors' experiences highlighted the timings of first words and first use of sentences, and language stagnation as key features of language deficits in CLN2 disease, and how deficits in language may be an earlier sign of the disease than seizures. Potential challenges in identifying early language deficits include assessing patients with other complex needs, and recognizing that a child's language abilities are not within normal parameters given the variability of language development in young children. CLN2 disease should be considered in children presenting with language delay and/or seizures to facilitate earlier diagnosis and access to treatment that can significantly reduce morbidity.

Keywords

CLN2 disease - neuronal ceroid lipofuscinosis - language development - enzyme replacement therapy - cerliponase alfa

Publication History

Received: 13 January 2023

Accepted: 26 April 2023

Article published online:
17 June 2023

• References

• 1 Mole SE, Schulz A, Badoe E. et al. Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients. Orphanet J Rare Dis 2021; 16 (01) 185
• 2 Nickel M, Simonati A, Jacoby D. et al. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health 2018; 2 (08) 582-590
• 3 Chang M, Cooper JD, Davidson BL. et al. CLN2. In: Mole S, Williams R, Goebel H. eds. The Neuronal Ceroid Lipofuscinoses (Batten Disease). Oxford: Oxford University Press; 2011: 80-109
• 4 Kohlschütter A, Schulz A. CLN2 disease (classic late infantile neuronal ceroid lipofuscinosis). Pediatr Endocrinol Rev 2016; 13 (Suppl. 01) 682-688
• 5 Pérez-Poyato MS, Marfa MP, Abizanda IF. et al. Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. J Child Neurol 2013; 28 (04) 470-478
• 6 Specchio N, Pietrafusa N, Trivisano M. Changing times for CLN2 disease: the era of enzyme replacement therapy. Ther Clin Risk Manag 2020; 16: 213-222
• 7 Worgall S, Kekatpure MV, Heier L. et al. Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. Neurology 2007; 69 (06) 521-535
• 8 Johnson AM, Mandelstam S, Andrews I. et al. Neuronal ceroid lipofuscinosis type 2: an Australian case series. J Paediatr Child Health 2020; 56 (08) 1210-1218
• 9 Fietz M, AlSayed M, Burke D. et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab 2016; 119 (1–2): 160-167
• 10 Schulz A, Ajayi T, Specchio N. et al; CLN2 Study Group. Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med 2018; 378 (20) 1898-1907
• 11 BioMarin International Ltd. Brineura 150 mg Solution for Infusion: Summary of Product Characteristics. Cork, Ireland: BioMarin International Ltd; 2017
• 12 Wyrwich KW, Schulz A, Nickel M. et al. An adapted clinical measurement tool for the key symptoms of CLN2 disease. J Inborn Errors Metab Screen 2018; 6: 1-7
• 13 Feldman HM. How young children learn language and speech: implications of theory and evidence for clinical pediatric practice. Pediatr Rev 2019; 40 (08) 398-411
• 14 Scherr JF. Comparing developmental outcomes of children with CLN2 disease receiving cerliponase alfa to a natural history cohort. Poster presented at: 7th Annual WORLDSymposium; February 8–12, 2021
• 15 Žigman T, Petković Ramadža D, Šimić G, Barić I. Inborn errors of metabolism associated with autism spectrum disorders: approaches to intervention. Front Neurosci 2021; 15: 673600
• 16 Pacheva I, Ivanov I, Yordanova R. et al. Epilepsy in children with autistic spectrum disorder. Children (Basel) 2019; 6 (02) 15
• 17 Vogindroukas I, Stankova M, Chelas EN, Proedrou A. Language and speech characteristics in autism. Neuropsychiatr Dis Treat 2022; 18: 2367-2377
• 18 Specchio N, Bellusci M, Pietrafusa N, Trivisano M, de Palma L, Vigevano F. Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease. Epilepsia 2017; 58 (08) 1380-1388
• 19 Ho M-L, Wirrel EC, Petropoulou K. et al. Role of electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings in early recognition and diagnosis of neuronal ceroid lipofuscinosis type 2 disease. J Child Neurol 2022; 37 (12–14): 984-991
• 20 Aydın K, Havali C, Kartal A, Serdaroğlu A, Haspolat Ş. MRI in CLN2 disease patients: subtle features that support an early diagnosis. Eur J Paediatr Neurol 2020; 28: 228-236