Red flags for neuronal ceroid lipofuscinosis type 2 disease
Venue: Developmental medicine and child neurology
Year: 2019

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative diseases caused by accumulation of lipofuscin in neurons and other tissues. A genetic cause has been identified in 13 of 14 forms, and the defective enzyme is also known for only three types (CLN1, CLN2, and CLN10) Symptomatic treatments are currently available for most NCLs, and enzyme replacement treatment (ERT) for CLN2 disease has been developed and approved for clinical use. Considering the (often rapid) neurodegenerative progression, early detection is important to gain the best results from treatment. To that end, Dozi eres Puyravel et al. described first symptoms in CLN2 disease, which is caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene, resulting in TPP1 enzyme deficiency and subsequent lysosomal storage. Epilepsy onset is between 2 and 4 years of age and this is usually the first symptom that brings the child to the attention of a paediatric neurologist. Different types of seizures (including febrile, generalized tonic clonic, absences, and focal motor and focal to bilateral tonic clonic) may occur before the typical myoclonic seizures. Rarely, ataxia is the presenting clinical manifestation. Delayed language acquisition frequently preceded the onset of more obvious symptoms, but in most cases language delay is under detected both by parents and general paediatricians. Recently language delay has been considered a forerunner of the disease as it was retrospectively identified in 83% of patients. Based on these data, the occurrence of a first seizure (any type) in a patient with a language delay may be considered a clinical red flag for the diagnosis of CLN2 disease. Photo paroxysmal response (PPR) on electroencephalography induced by low frequency photic stimulation was previously considered as highly suggestive of NCL disorders. Dozi eres Puyravel et al. found a lower rate of PPR than previous studies (33% vs 69 78% Such variability might be due to lack of a standardized procedure of photic stimulation, and it might be influenced by antiepileptic drugs. Different photic stimulators have also been reported to induce different results. Other investigations, such as brain magnetic resonance imaging (MRI) visual evoked potential (VEP) and electroretinogram (ERG) have a low specificity at onset. MRI findings, particularly cerebellar atrophy and posterior periventricular white matter signal, are present in almost all patients at onset, but they have a low specificity as they can be found in other neurological diseases. Although VEP could show prolonged P100 latency and giant potential at onset, ERG is often normal initially, becoming impaired only later in the course of the disease. In sum, early diagnosis of CLN2 disease is based mainly on the first clinical symptoms. The occurrence of a first seizure in a child aged between 2 and 4 years with a language delay should raise the suspicion for CLN2 disease. Enzyme activity on dried blood spot or gene sequencing should then be performed in order to make an early diagnosis and start ERT. Although the authors found a low rate of PPR at low frequency photostimulation, our own experience suggests that this can still be considered as a neurophysiological hallmark of progressive myoclonic epilepsies and CLN2 disease, and its absence does not exclude the diagnosis.