Management of CLN1 Disease: International Clinical Consensus

Augustine, Erika F.; Adams, Heather; Reyes, Emily de los; Drago, Kristen; Frazier, Margie; Guelbert, Norberto; Lainé, Muriel; Levin, Tanya; Mink, Jonathan W.; Nickel, Miriam; Peifer, Danielle; Schulz, Angela; Simonati, Alessandro; Topçu, Meral; Turunen, Joni A.; Williams, Ruth; Wirrell, Elaine; King, Serina

doi:10.1016/j.pediatrneurol.2021.04.002

Cited by 16 publications

(14 citation statements)

References 103 publications

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“…Sleep disturbances are common in all NCL types. There are few studies on this issue ( 105 – 107 ) but the importance of sleep management has been outlined in two recent consensus papers ( 108 , 109 ). Poor sleep quality and sleep pattern disturbance will impact adversely on the quality of life of affected children and their families directly and indirectly through worsening of seizure control and behavior.…”

Section: Selected Clinical Featuresmentioning

confidence: 99%

“…Medical care should follow internationally agreed standards and guidelines for individual symptoms and organ systems (for example epilepsy, respiratory, orthopedic and gut) and be delivered in line with the holistic values of palliative care. These approaches with particular reference to the NCLs have been described in a number of publications in recent years ( 108 , 109 , 120 ). Experts in rare diseases should be cognisant of advances in these areas or at least be able to signpost families and carers to appropriate expertise.…”

Section: Treatment: the State Of Artmentioning

confidence: 99%

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

Simonati

Williams

2022

Front. Neurol.

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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.

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Section: Selected Clinical Featuresmentioning

confidence: 99%

Section: Treatment: the State Of Artmentioning

confidence: 99%

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

Simonati

Williams

2022

Front. Neurol.

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“…The age at epilepsy onset may differ according to the NCLs variant, starting from the first months of life to adulthood; both focal and generalized seizures can be seen at onset (5). Epilepsy may represent the presenting symptom, as it happens in CLN2 and CLN6 diseases, or appear after visual loss or cognitive and motor decline, as in CLN3 and CLN5 diseases (20).…”

Section: Neurophysiological Studies Electroencephalogrammentioning

confidence: 99%

“…Additional phenotypes have been observed with late infantile, juvenile, and adult onset. In the latter cases, epilepsy typically begins several years after the initial symptom of visual impairment, following developmental regression and behavioral changes (20). Few data are available on EEG features in CLN1 disease (21,22).…”

Section: Neurophysiological Studies Electroencephalogrammentioning

confidence: 99%

Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses

et al. 2022

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Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative diseases, characterized by progressive cerebral atrophy due to lysosomal storage disorder. Common clinical features include epileptic seizures, progressive cognitive and motor decline, and visual failure, which occur over different time courses according to subtypes. During the latest years, many advances have been done in the field of targeted treatments, and in the next future, gene therapies and enzyme replacement treatments may be available for several NCL variants. Considering that there is rapid disease progression in NCLs, an early diagnosis is crucial, and neurophysiological features might have a key role for this purpose. Across the different subtypes of NCLs, electroencephalogram (EEG) is characterized by a progressive deterioration of cerebral activity with slowing of background activity and disappearance of spindles during sleep. Some types of heterogeneous abnormalities, diffuse or focal, prevalent over temporal and occipital regions, are described in many NCL variants. Photoparoxysmal response to low-frequency intermittent photic stimulation (IPS) is a typical EEG finding, mostly described in CLN2, CLN5, and CLN6 diseases. Visual evoked potentials (VEPs) allow to monitor the visual functions, and the lack of response at electroretinogram (ERG) reflects retinal neurodegeneration. Taken together, EEG, VEPs, and ERG may represent essential tools toward an early diagnosis of NCLs.

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“…However, some mutations in this gene result in more delayed presentations according to the precise mutation ( 8 , 9 ). Its clinical manifestations include sensory and motor deficits, visual impairment leading to blindness, and epileptic seizures ( 10 ). Because there is currently no effective therapy, all cases are fatal ( 11 , 12 ), with a life expectancy of 9 to 12 years ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep

Nelvagal¹,

Eaton²,

Wang³

et al. 2022

Journal of Clinical Investigation

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CLN1 disease is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by delivering monthly infusions of recombinant human PPT1 (rhPPT1) in PPT1-deficient mice (Cln1 −/− ), and CLN1 R151X sheep to assess scale up for translation. In Cln1 −/− mice, intracerebroventricular rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1 treated-mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1 R151X sheep, intracerebroventricular infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural magnetic resonance imaging and neuropathology. These findings demonstrate the feasibility and therapeutic efficacy of intracerebroventricular rhPPT1 enzyme replacement therapy. This represents a key step towards clinical testing of ERT in children with CLN1 disease and highlights the importance of a cross-species approach to developing a successful treatment strategy.

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Management of CLN1 Disease: International Clinical Consensus

Cited by 16 publications

References 103 publications

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

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

Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses

Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep

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