Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview

Abstract

The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.

Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

“…Cognitive decline in young children occurs rapidly, while adolescents and adults show a much slower rate, allowing for normal life and education. Cognitive decline occurs as a two-phase problem [ 139 ]. Early in the disease, children’s developmental trajectory slows; they acquire new learning more slowly than their peers but often remain within the normal range for some time [ 139 ].…”

“…Cognitive decline occurs as a two-phase problem [ 139 ]. Early in the disease, children’s developmental trajectory slows; they acquire new learning more slowly than their peers but often remain within the normal range for some time [ 139 ]. They go on to plateau and then begin to lose the cognitive competences they have acquired during the earliest months and/or years of their lives [ 139 ].…”

“…This is often the time at which the diagnostic investigations are triggered. In CLN2 disease, however, many children show a delayed acquisition of cognitive skills at a very early stage; their profiles are characteristically uneven, with delays being more evident in the domain of expressive language, compared with motor skills [ 139 ]. In CLN3, the rate of disease progression is commonly slow, and children can attend school, with support for the intellectual, visual, and, sometimes, behavioral difficulties.…”

“…In CLN3, the rate of disease progression is commonly slow, and children can attend school, with support for the intellectual, visual, and, sometimes, behavioral difficulties. There is no evidence, to date, of an uneven developmental profile early in life and before the onset of progressive vision loss [ 139 ].…”

“…This is the case with CLN3, where cardiac involvement is often described in adolescent and adult patients [ 84 , 140 ]. This problem is amenable to treatment by implanting a pacemaker, when the patient’s psychomotor performance has improved [ 3 , 139 ].…”