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Background: Recurrent non-epileptic episodes of frightened facial and body expression occur in more than half of post-adolescent patients with juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3 disease). Clinically, the episodes look similar to the attacks of paroxysmal sympathetic hyperactivity (PSH) commonly seen following traumatic brain injury (TBI). The episodes occur when the patients are exposed to separation, hear loud sounds or are otherwise bothered by discomfort and as in PSH following TBI, the attacks are difficult to prevent and/or treat. Aim and methods: Based on present knowledge of triggering factors, the neural anxiety/fear circuit, its afferent and efferent pathways and documented CLN3 disease-impact on these tracks, the current study discusses a rational approach how to prevent and/or treat the attacks. Results: Patients with JNCL have a disturbed somatosensory modulation leading to a reduced threshold of pain; a degeneration within the neural anxiety/fear circuit leading to an imbalance of central network inhibition and excitation pathways; and finally, an, with advancing age, increasing autonomic imbalance leading to a significant dominance of the sympathetic neural system. Discussion: Theoretically, there are three points of attack how to prevent or treat the episodes: (1) increase in threshold of discomfort impact; (2) modulation of imbalance of central network inhibition and excitation, and (3) restoring the balance between the sympathetic and parasympathetic neural systems prompted by a parasympathetic withdrawal. As to (1) and (2), prevention should have the greatest priority. As regards (3), research of transcutaneous vagal stimulation treatment in JNCL is warranted. [ABSTRACT FROM AUTHOR]

BackgroundRecurrent non-epileptic episodes of frightened facial and body expression occur in more than half of post-adolescent patients with juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3 disease). Clinically, the episodes look similar to the attacks of paroxysmal sympathetic hyperactivity (PSH) commonly seen following traumatic brain injury (TBI). The episodes occur when the patients are exposed to separation, hear loud sounds or are otherwise bothered by discomfort and as in PSH following TBI, the attacks are difficult to prevent and/or treat.Aim and methodsBased on present knowledge of triggering factors, the neural anxiety/fear circuit, its afferent and efferent pathways and documented CLN3 disease-impact on these tracks, the current study discusses a rational approach how to prevent and/or treat the attacks.ResultsPatients with JNCL have a disturbed somatosensory modulation leading to a reduced threshold of pain; a degeneration within the neural anxiety/fear circuit leading to an imbalance of central network inhibition and excitation pathways; and finally, an, with advancing age, increasing autonomic imbalance leading to a significant dominance of the sympathetic neural system.DiscussionTheoretically, there are three points of attack how to prevent or treat the episodes: (1) increase in threshold of discomfort impact; (2) modulation of imbalance of central network inhibition and excitation, and (3) restoring the balance between the sympathetic and parasympathetic neural systems prompted by a parasympathetic withdrawal. As to (1) and (2), prevention should have the greatest priority. As regards (3), research of transcutaneous vagal stimulation treatment in JNCL is warranted.

Background: The Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology as the common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation. Methods: We have tested this hypothesis by comparing known differences in symptomatology and pathology of the CLN1 phenotype caused by complete loss of PPT1 function (i.e., the classical infantile form) and of the classical juvenile CLN3 phenotype. These two forms of NCL represent early onset and rapidly progressing vs. late onset and slowly progressing disease modalities respectively. Results: Despite displaying similar pathological endpoints, the clinical phenotypes and the evidence of imaging and postmortem studies reveal strikingly different time courses and distributions of disease propagation. Data from CLN1 disease are indicative of disease propagation from the body, with early effects within the spinal cord and subsequently within the brainstem, the cerebral hemispheres, cerebellum and retina. In contrast, the retina appears to be the most vulnerable organ in CLN3, and the site where pathology is first present. Pathology subsequently is present in the occipital connectome of the CLN3 brain, followed by a top-down propagation in which cerebral and cerebellar atrophy in early adolescence is followed by involvement of the peripheral nerves in later adolescence/early twenties, with the extrapyramidal system also affected during this time course. Discussion: The propagation of disease in these two NCLs therefore hasmuch in common with the "Brain-first" vs. "Body-first" models of alpha-synuclein propagation in Parkinson's disease. CLN1 disease represents a "Body-first" or bottom-up disease propagation and CLN3 disease having a "Brain-first" and top-down propagation. It is noteworthy that the varied phenotypes of CLN1 disease, whether it starts in infancy (infantile form) or later in childhood(juvenile form), still fit with our proposed hypothesis of a bottom-up disease propagation in CLN1. Likewise, in protracted CLN3 disease, where both cognitive and motor declines are delayed, the initial manifestations of disease are also seen in thethe outer retinal layers, i.e., identical to classical Juvenile NCL disease. [ABSTRACT FROM AUTHOR]

BackgroundThe Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology as the common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation.MethodsWe have tested this hypothesis by comparing known differences in symptomatology and pathology of the CLN1 phenotype caused by complete loss of PPT1 function (i.e., the classical infantile form) and of the classical juvenile CLN3 phenotype. These two forms of NCL represent early onset and rapidly progressing vs. late onset and slowly progressing disease modalities respectively.ResultsDespite displaying similar pathological endpoints, the clinical phenotypes and the evidence of imaging and postmortem studies reveal strikingly different time courses and distributions of disease propagation. Data from CLN1 disease are indicative of disease propagation from the body, with early effects within the spinal cord and subsequently within the brainstem, the cerebral hemispheres, cerebellum and retina. In contrast, the retina appears to be the most vulnerable organ in CLN3, and the site where pathology is first present. Pathology subsequently is present in the occipital connectome of the CLN3 brain, followed by a top-down propagation in which cerebral and cerebellar atrophy in early adolescence is followed by involvement of the peripheral nerves in later adolescence/early twenties, with the extrapyramidal system also affected during this time course.DiscussionThe propagation of disease in these two NCLs therefore has much in common with the “Brain-first” vs. “Body-first” models of alpha-synuclein propagation in Parkinson's disease. CLN1 disease represents a “Body-first” or bottom-up disease propagation and CLN3 disease having a “Brain-first” and top-down propagation. It is noteworthy that the varied phenotypes of CLN1 disease, whether it starts in infancy (infantile form) or later in childhood (juvenile form), still fit with our proposed hypothesis of a bottom-up disease propagation in CLN1. Likewise, in protracted CLN3 disease, where both cognitive and motor declines are delayed, the initial manifestations of disease are also seen in the outer retinal layers, i.e., identical to classical Juvenile NCL disease.

The neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative lysosomal storage disorders mainly affecting the brain and the retina. In the NCLs, disease-causing mutations in 13 different ceroid lipofuscinoses genes (CLN) have been identified. The clinical symptoms include seizures, progressive neurological decline, deterioration of motor and language skills, and dementia resulting in premature death. In addition, the deterioration and loss of vision caused by progressive retinal degeneration is another major hallmark of NCLs. To date, there is no curative therapy for the treatment of retinal degeneration and vision loss in patients with NCL. In this review, the key findings of different experimental approaches in NCL animal models aimed at attenuating progressive retinal degeneration and the decline in retinal function are discussed. Different approaches, including experimental enzyme replacement therapy, gene therapy, cell-based therapy, and immunomodulation therapy were evaluated and showed encouraging therapeutic benefits. Recent experimental ocular gene therapies in NCL animal models with soluble lysosomal enzyme deficiencies and transmembrane protein deficiencies have shown the strong potential of gene-based approaches to treat retinal dystrophies in NCLs. In CLN3 and CLN6 mouse models, an adeno-associated virus (AAV) vector-mediated delivery of CLN3 and CLN6 to bipolar cells has been shown to attenuate the retinal dysfunction. Therapeutic benefits of ocular enzyme replacement therapies were evaluated in CLN2 and CLN10 animal models. Since brain-targeted gene or enzyme replacement therapies will most likely not attenuate retinal neurodegeneration, there is an unmet need for treatment options additionally targeting the retina in patients with NCL. The long-term benefits of these therapeutic interventions aimed at attenuating retinal degeneration and vision loss in patients with NCL remain to be investigated in future clinical studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative lysosomal storage disorders mainly affecting the brain and the retina. In the NCLs, disease-causing mutations in 13 different ceroid lipofuscinoses genes (CLN) have been identified. The clinical symptoms include seizures, progressive neurological decline, deterioration of motor and language skills, and dementia resulting in premature death. In addition, the deterioration and loss of vision caused by progressive retinal degeneration is another major hallmark of NCLs. To date, there is no curative therapy for the treatment of retinal degeneration and vision loss in patients with NCL. In this review, the key findings of different experimental approaches in NCL animal models aimed at attenuating progressive retinal degeneration and the decline in retinal function are discussed. Different approaches, including experimental enzyme replacement therapy, gene therapy, cell-based therapy, and immunomodulation therapy were evaluated and showed encouraging therapeutic benefits. Recent experimental ocular gene therapies in NCL animal models with soluble lysosomal enzyme deficiencies and transmembrane protein deficiencies have shown the strong potential of gene-based approaches to treat retinal dystrophies in NCLs. In CLN3 and CLN6 mouse models, an adeno-associated virus (AAV) vector-mediated delivery of CLN3 and CLN6 to bipolar cells has been shown to attenuate the retinal dysfunction. Therapeutic benefits of ocular enzyme replacement therapies were evaluated in CLN2 and CLN10 animal models. Since brain-targeted gene or enzyme replacement therapies will most likely not attenuate retinal neurodegeneration, there is an unmet need for treatment options additionally targeting the retina in patients with NCL. The long-term benefits of these therapeutic interventions aimed at attenuating retinal degeneration and vision loss in patients with NCL remain to be investigated in future clinical studies.

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.