https://orcid.org/0000-0002-9405-5066
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ABSTRACT
Introduction
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric neurodegenerative condition, which is usually fatal by mid-adolescence. Seizures are one of the most common early symptoms of CLN2 disease, but patients often experience language deficits, movement disorders, and behavioral problems. Diagnosis of CLN2 disease is challenging (particularly when differentiating between early-onset developmental, metabolic, or epileptic syndromes), and diagnostic delays often overlap with rapid disease progression. An enzyme replacement therapy (cerliponase alfa) is now available, adding CLN2 disease to the list of potentially treatable disorders requiring a prompt diagnosis.
Areas covered
Although advances in enzymatic activity testing and genetic testing have facilitated diagnoses of CLN2 disease, our review highlights the presenting symptoms that are vital in directing clinicians to perform appropriate tests or seek expert opinion. We also describe common diagnostic challenges and some potential misdiagnoses that may occur during differential diagnosis.
Expert opinion
An awareness of CLN2 disease as a potentially treatable disorder and increased understanding of the key presenting symptoms can support selection of appropriate tests and prompt diagnosis. The available enzyme replacement therapy heralds an even greater imperative for early diagnosis, and for clinicians to direct patients to appropriate diagnostic pathways.
Article highlights
CLN2 disease is a rare pediatric disease associated with seizures, language deficits, and progressive neurological decline.
CLN2 disease is usually fatal by mid-adolescence, although an enzyme replacement therapy that slows disease progression is now available.
Early diagnosis is key to accessing treatment, but diagnosis is challenging because of similarities with other disorders and limited awareness of CLN2 disease because of its rarity.
Seizures are one of the most common presenting symptoms, although patients may also present with language deficits, movement disorders and behavioral issues.
The results of clinical tests, such as electroencephalography (EEG) and magnetic resonance imaging (MRI), may also provide clues that can raise suspicion of CLN2 disease.
Although enzyme activity testing and genetic testing have advanced, a range of tests are now available, and selection must be guided by an understanding of the diseases that each test can diagnose.
An awareness of key presenting symptoms is of vital importance in directing clinicians to seek expert advice or appropriate tests that can confirm a diagnosis and providing patients with opportunities to access treatment at an early disease stage.
We ask that clinicians consider CLN2 disease as a treatable disorder for which diagnosis should be prioritized.
Abbreviations
| AED | = | Antiepileptic drug |
| AGAT | = | L-Arginine:glycine amidinotransferase |
| CLN2 | = | Neuronal ceroid lipofuscinosis type 2 |
| CSF | = | Cerebrospinal fluid |
| CT1 | = | Creatine transporter 1 |
| DBS | = | Dried blood spot |
| EEG | = | Electroencephalography |
| ERG | = | Electroretinogram/electroretinography |
| ERT | = | Enzyme replacement therapy |
| GAMT | = | Guanidinoacetate methyltransferase |
| GLUT1 | = | Glucose transporter 1 |
| HCP | = | Healthcare professional |
| IPS | = | Intermittent photic stimulation |
| MAE | = | Myoclonic astatic epilepsy |
| MRI | = | Magnetic resonance imaging |
| NCL | = | Neuronal ceroid lipofuscinosis |
| PDE | = | Pyridoxine-dependent epilepsy |
| PPR | = | Photoparoxysmal response |
| TPP1 | = | Tripeptidyl peptidase 1 |
| VEP | = | Visual evoked potential |
Acknowledgments
This manuscript was developed after discussions at a meeting of experts organized and supported by BioMarin Europe Ltd. Writing support was provided by Emma Conran, Porterhouse Medical, Reading, UK, and funded by BioMarin Europe Ltd.
Declaration of interest
All authors received an honorarium from BioMarin Europe Ltd for their contributions to an expert meeting at which it was agreed that this manuscript should be developed. In addition, H Huidekoper reports institutional reimbursement from BioMarin Europe Ltd, outside of the submitted work. M Mazurkiewicz-Bełdzińska reports personal fees from Biogen; personal fees from Roche; personal fees from BioMarin Europe Ltd; and personal fees from Novartis, outside of the submitted work. C Mühlhausen reports personal fees from PTC Therapeutics Germany GmbH, outside of the submitted work. I Prpić reports non-financial support from Dravet Syndrome Association Croatia; grants, personal fees and non-financial support from BioMarin Europe Ltd; non-financial support from Merck; non-financial support from Belupo d.d.; personal fees and non-financial support from Makpharm d.o.o.; personal fees and non-financial support from Pliva d.o.o.; non-financial support from Academy for Child Neurodevelopment; personal fees from Medis d.o.o.; non-financial support from the organizer of ‘New Challenges in Paediatrics’ Symposium, Croatia, March 2020; and personal fees and non-financial support from BioMarin Pharmaceutical Inc., outside of the submitted work. P Striano reports personal fees from Zogenix; personal fees from GW Pharmaceuticals; personal fees from Enecta BV; and personal fees from Proveca during the conduct of the study. S Auvin reports personal fees and non-financial support from BioMarin, outside of the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.