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Neuronal ceroid lipofuscinosis type 2: an Australian case series.

ABSTRACT: AIM:Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare neurodegenerative disorder presenting in children aged 2-4?years with seizures and loss of motor and language skills, followed by blindness and death in late childhood. Initial presenting features are similar to a range of common epilepsies. We aim to highlight typical clinical and radiological features that may prompt diagnosis of CLN2 disease in early disease stages. METHODS:We present a series of 13 Australian patients with CLN2 disease, describing clinical features, disease evolution, neuroimaging, electroencephalogram, biochemical and genetic results. Expert neuroradiological magnetic resonance imaging (MRI) analysis was retrospectively performed on 10 cases. RESULTS:Twelve patients presented with seizures, with initial seizures being focal (n = 4), generalised tonic-clonic (n = 3), absence (n = 3) and febrile (n = 2). Eleven patients (85%) had a language delay before the onset of seizures. Cerebellar or cerebral atrophy was noted in all patients on centralised MRI review, with abnormalities of the brain-stem, ventricles, corpus callosum and hippocampi. CONCLUSIONS:Early language delay with the onset of seizures at 2-4?years of age is the hallmark of CLN2 disease. MRI findings of early subtle atrophy in the cerebellum or posterior cortical regions should hasten testing for CLN2 disease to enable early initiation of enzyme replacement therapy.

SUBMITTER: Johnson AM

PROVIDER: S-EPMC7497200 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Neuronal ceroid lipofuscinosis type 2: an Australian case series.

Johnson Alexandra M AM Mandelstam Simone S Andrews Ian I Boysen Katja K Yaplito-Lee Joy J Fietz Michael M Nagarajan Lakshmi L Rodriguez-Casero Victoria V Ryan Monique M MM Smith Nicholas N Scheffer Ingrid E IE Ellaway Carolyn C

Journal of paediatrics and child health 20200424 8

<h4>Aim</h4>Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare neurodegenerative disorder presenting in children aged 2-4 years with seizures and loss of motor and language skills, followed by blindness and death in late childhood. Initial presenting features are similar to a range of common epilepsies. We aim to highlight typical clinical and radiological features that may prompt diagnosis of CLN2 disease in early disease stages.<h4>Methods</h4>We present a series of ...[more]

PMID: 32329550

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Project description:BackgroundCeroid lipofuscinosis type 8 belongs to a heterogenous group of vision and life-threatening neurodegenerative diseases, neuronal ceroid lipofuscinosis (NCL). Effective therapy is limited to a single drug for treatment of ceroid lipofuscinosis type 2, necessitating animal disease models to facilitate further therapeutic development. Murine models are advantageous for therapeutic development due to easy genetic manipulation and rapid breeding, however appropriate genetic models need to be identified and characterized before being used for therapy testing. To date, murine models of ocular disease associated with ceroid lipofuscinosis type 8 have only been characterized in motor neuron degeneration mice.MethodsCln8-/- mice were produced by CRISPR/Cas9 genome editing through the International Mouse Phenotyping Consortium. Ophthalmic examination, optical coherence tomography, electroretinography, and ocular histology was performed on Cln8-/- mice and controls at 16 weeks of age. Quantification of all retinal layers, retinal pigmented epithelium, and the choriocapillaris was performed using images acquired with ocular coherence tomography and planimetry of histologic sections. Necropsy was performed to investigate concurrent systemic abnormalities. Clinical correlation with human patients with CLN8-associated retinopathy is provided.ResultsRetinal degeneration characterized by retinal pigment epithelium mottling, scattered drusen, and retinal vascular attenuation was noted in all Cln8-/- mice. Loss of inner and outer photoreceptor segment demarcation was noted on optical coherence tomography, with significant thinning of the whole retina (P=1e-9), outer nuclear layer (P=1e-9), and combined photoreceptor segments (P=1e-9). A global reduction in scotopic and photopic electroretinographic waveforms was noted in all Cln8-/- mice. Slight thickening of the inner plexiform layer (P=0.02) and inner nuclear layer (P=0.004), with significant thinning of the whole retina (P=0.03), outer nuclear layer (P=0.01), and outer photoreceptor segments (P=0.001) was appreciated on histologic sections. Scattered lipid vacuoles were noted in splenic red pulp of all Cln8-/- mice, though no gross systemic abnormalities were detected on necropsy. Retinal findings are consistent with those seen in patients with ceroid lipofuscinosis type 8.ConclusionsThis study provides detailed clinical characterization of retinopathy in adult Cln8-/- mice. Findings suggest that Cln8-/- mice may provide a useful murine model for development of novel therapeutics needed for treating ocular disease in patients with ceroid lipofuscinosis type 8.

Project description:The present review is focused on juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) due to a mutation in CLN3. Functional vision impairment occurring around 5-6 years of age is the first symptom in more than 80% of patients. Approximately 2 years later (though sometimes simultaneously), obvious signs of cognitive impairment appear. Behavior problems can occur in advance, especially in boys. These include anxious and depressed mood, aggressive behavior, and hallucinations, and even psychotic symptoms. Following the teens, severe dementia is present, including loss of memory, attention, and general reasoning abilities, as well as loss of independent adaptive skills such as mobility, feeding, and communicating. Sleep abnormalities, such as settling problems, nocturnal awakenings, and nightmares, are reported in more than half of patients. The vast majority, if not all, patients develop seizures, starting at approximately 10 years of age. Generalized tonic-clonic seizure occurs as the only type of seizure in approximately half of patients, and in combination with partial seizures in a third of patients. There seems to be no difference in seizure severity according to sex or genotype, and there is great variation in seizure activity among patients. Soon after diagnosis, patients begin to have slight ataxic symptoms, and at adolescence extrapyramidal symptoms (rigidity, bradykinesia, slow steps with flexion in hips and knees) occur with increasing frequency. Chewing and swallowing difficulties emerge as well, and food intake is hampered in the late teens. Disabling periodically involuntary movements may occur as well. A progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus-node dysfunction, ultimately leading to severe bradycardia and/or other conduction abnormalities, starts in the mid-teens. Patients are usually bedridden at 20 years of age, and death usually occurs in the third decade of life.

Project description:Neuronal ceroid lipofuscinoses (NCL) represent a class of neurodegenerative disorders involving defective lysosomal processing enzymes or receptors, leading to lysosomal storage disorders, typically characterized by observation of cognitive and visual impairments, epileptic seizures, ataxia, and deterioration of motor skills. Recent success of a biologic (Brineura®) for the treatment of neurologic manifestations of the central nervous system (CNS) has led to renewed interest in therapeutics for NCL, with the goal of ablating or reversing the impact of these devastating disorders. Despite complex challenges associated with CNS therapy, many treatment modalities have been evaluated, including enzyme replacement therapy, gene therapy, stem cell therapy, and small molecule pharmacotherapy. Because the clinical endpoints for the evaluation of candidate therapies are complex and often reliant on subjective clinical scales, the development of quantitative biomarkers for NCLs has become an apparent necessity for the validation of potential treatments. We will discuss the latest findings in the search for relevant biomarkers for assessing disease progression. For this review, we will focus primarily on recent pre-clinical and clinical developments for treatments to halt or cure these NCL diseases. Continued development of current therapies and discovery of newer modalities will be essential for successful therapeutics for NCL.Areas coveredThe reader will be introduced to the NCL subtypes, natural histories, experimental animal models, and biomarkers for NCL progression; challenges and different therapeutic approaches, and the latest pre-clinical and clinical research for therapeutic development for the various NCLs. This review corresponds to the literatures covering the years from 1968 to mid-2019, but primarily addresses pre-clinical and clinical developments for the treatment of NCL disease in the last decade and as a follow-up to our 2013 review of the same topic in this journal.Expert opinionMuch progress has been made in the treatment of neurologic diseases, such as the NCLs, including better animal models and improved therapeutics with better survival outcomes. Encouraging results are being reported at symposiums and in the literature, with multiple therapeutics reaching the clinical trial stage for the NCLs. The potential for a cure could be at hand after many years of trial and error in the preclinical studies. The clinical development of enzyme replacement therapy (Brineura® for CLN2), immunosuppression (CellCept® for CLN3), and gene therapy vectors (for CLN1, CLN2, CLN3, and CLN6) are providing encouragement to families that have a child afflicted with NCL. We believe that successful therapies in the future may involve the combination of two or more therapeutic modalities to provide therapeutic benefit especially as the patients grow older.

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Neuronal ceroid lipofuscinosis type 2: an Australian case series.

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Neuronal ceroid lipofuscinosis type 2: an Australian case series.

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