Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies

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.

Missense Variation in <em>TPP1</em> Gene causes Neuronal Ceroid Lipofuscinosis Type 2 in a Family from Jammu and Kashmir-India

“…A precise diagnosis of CLN2 is quite challenging during early stages of its precipitation and is often delayed until its significant progression in severity, leading to complex diagnostic odyssey characterized by several misdiagnoses in a clinical set up [23]. Delayed diagnosis or misdiagnosis of a disease usually results in disjointed care and treatment delay for the patients.…”

“…The clinical management of CLN2 is complex, which primarily encompasses supportive and palliative care, pharmacological treatment of symptoms presented in CLN2 paediatric cases, enzyme replacement therapy (ERT) and gene therapy [20][21][22][23]. Antiepileptic drugs, including benzodiazepines (clobazam/clonazepam, lamotrigine, levetiracetum and valproate, are the common first-line therapeutics used for the management of epileptic as well as non-epileptic seizures and myoclonus [22].…”

“…It was disheartening to find out upon genetic screening of the family that the younger, year old asymptomatic kid is also harbouring the same variation in a homozygous manner. With new developments in place for the pharmacological treatment of symptoms presented in CLN2 paediatric cases as well as enzyme replacement therapy (ERT) and gene therapy [20][21][22][23], it is anticipated if interventions are provided at this juncture too, may help the family extensively and the affected kids (in particular) in leading a better life.…”

Treatable inherited metabolic epilepsies

“…It typically manifests between 2 and 4 years of age with seizures, language delay/arrest, and rapid psychomotor regression. 15,28 Seizures are usually polymorphic, including multiple types of seizures, and resistant to anti-seizures drugs. EEG with low-frequency (1-3 Hz) intermittent photic stimulation shows a characteristic photoparoxysmal response.…”

“…Intracerebroventricular administration of cerliponase alfa (rhTPP1 enzyme) stabilizes neuronal ceroid lipofuscinosis type 2 progression, adding this disease to the list of potentially treatable disorders requiring prompt diagnosis. 28 Approach to treatable inherited metabolic epilepsies. The presence of any of sign and symptom highlighted in Table 2 should raise suspicion for an underlying metabolic etiology of epilepsy.…”