Neuronal Ceroid Lipofuscinosis Type Research Articles

Physiotherapy for Children with CLN2 Disease

Abstract CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, genetic, paediatric-onset, neurodegenerative lysosomal storage disorder characterised by seizures, ataxia, rapid loss of motor function and language ability, dementia, visual loss and early death. Physiotherapy plays an important role in the management of CLN2 disease, aiming to maintain the best possible functioning and autonomy of the child, support the child’s participation in everyday life, limit secondary complications and maintain or improve quality of life. This article discusses the physiotherapeutic treatment of children diagnosed with CLN2 disease. Based on the author’s clinical experience, frequent muscular impairments associated with CLN2 disease, their impact on affected children’s sensorimotor abilities and autonomy, and physiotherapy interventions are described. Common muscular deficits included abnormal muscle tone leading to poor trunk control, difficulty standing upright, often accompanied by equinus contractures and movement disorders such as myoclonus. The use of orthotic and adaptive medical devices that support an erect posture in locomotion and positioning appear to be particularly beneficial for prolonging sensorimotor control, communication and food intake. In conclusion, early initiation of physiotherapy is recommended and should include the provision of adaptive walking, standing, sitting and positioning aids.

Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease \u2013 a new type of neuronal ceroid lipofuscinosis (CLN15)?

Homozygous mutation of TBC1 domain-containing kinase (TBCK) is the cause of a very recently defined severe childhood disorder, which is characterized by severe hypotonia, global developmental delay, intellectual disability, epilepsy, characteristic facies and premature death. The link between TBCK loss of function and symptoms in patients with TBCK deficiency disorder (TBCK-DD) remains elusive. Here we demonstrate for the first time the histopathological characteristics of TBCK deficiency consisting of 1) a widespread and massive accumulation of lipofuscin storage material in neurons of the central nervous system without notable neuronal degeneration, 2) storage deposits in few astrocytes, 3) carbohydrate-rich deposits in brain, spleen and liver and 4) vacuolated lymphocytes. Biochemical examinations ruled out more than 20 known lysosomal storage diseases. These investigations strikingly uncover TBCK-DD as a novel type of lysosomal storage disease which is characterized by different storage products rather than one specific type of accumulated material. Due to the clear predominance of intraneuronal lipofuscin storage material and the characteristic clinical presentation we propose to classify this disease as a new subtype of neuronal ceroid lipofuscinosis (CLN15). Our results and previous reports suggest an autophagosomal-lysosomal dysfunction caused by enhanced mTORC1-mediated autophagosome formation and reduced Rab-mediated autophagosome-lysosome fusion, thus disclosing potential novel targets for therapeutic approaches in TBCK-DD.

Three siblings with neuronal ceroid lipofuscinosis type 7 and 2 novel mutations in their MFSD8 gene

Objective The neuronal ceroid lipofuscinosis (CLN) are a group of severe lysosomal storage diseases.The patients present with clinically and genetically heterogeneous neurodegenerative disorders.This study aims to investigate the clinical characteristics and the gene mutations of a rare Chinese family with 3 siblings affected by CLN7. Methods The proband, a 5-year-old girl, visited us because of intermittently seizures and mental retardation for 2 years and a half in December, 2015.Clinical investigation, brain magnetic resonance imaging(MRI), biochemical and the gene analysis were performed for the etiological study. Results The proband had seizures at the age of 2 and a half years, with the progressive motor deterioration, speech disturbance, mental regression and vision loss.Her brain MRI showed diffusive cerebral atrophy.The blood aminoacids, acylcarnitine and urine organic acid profiles were normal.Lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase activities of peripheral leukocytes were normal.A compound heterozygous mutation of c. 1351-1G>A and c. 300T>G was detected on her MFSD8 gene, supporting the diagnosis of CLN7.Both of the 2 mutations were novel.Each of her parents carried one of the mutations.Two brothers of the proband had similar clinical process.Her elder brother died at the age of 7 due to severe encephalopathy of unknown etiology.The younger brother showed dyskinesia from the age of 2 years and seizures from the age of 4 years.A compound heterozygous mutation on MFSD8 gene, c.1351-1G>A and c. 300T>G, was found from the younger brother, as same as the proband. Conclusions CLN7 is a rare disorder of CLN.In this study, the diagnosis of the 3 siblings with similar clinical process were much delayed.Gene analysis was key for the diagnosis.Two novel mutations were found on MFSD8 of the family.There is still no effective treatment for neurol ceroid lipofuscinosis.The prognosis is poor.Based on the mutation diagnosis, prenatal diagnosis for the next sibling is possible to the prevention of the disease. Key words: Neuronal ceroid lipofuscinosis; Neurodegenerative disorders; Lysosomal storage diseases; MFSD8 gene

Novel in-frame deletion in MFSD8 gene revealed by trio whole exome sequencing in an Iranian affected with neuronal ceroid lipofuscinosis type 7: a case report

BackgroundThe neuronal ceroid lipofuscinoses are a group of neurodegenerative, lysosomal storage disorders. They are inherited as an autosomal recessive pattern with the exception of adult neuronal ceroid lipofuscinosis, which can be inherited in either an autosomal recessive or an autosomal dominant manner. The neuronal ceroid lipofuscinoses are characterized by accumulation of autofluorescent lipopigments in the cells and one of the most important pathological manifestations is ceroid accumulation in the lysosomes. Various types of neuronal ceroid lipofuscinoses are categorized based on the clinical manifestations and the genes involved. Accumulatively, 15 different genes have been found so far to be implicated in the pathogenesis of at least nine different types of neuronal ceroid lipofuscinoses, which result in similar pathological and clinical manifestations.Case presentationA 5-year-old Iranian boy affected by a neurodegenerative disorder with speech problems, lack of concentration, walking disability at age of 4 years leading to quadriplegia, spontaneous laughing, hidden seizure, clumsiness, psychomotor delay, and vision deterioration at age of 5 years, which could be the consequence of macular dystrophy, was referred to us for genetic testing. Trio whole exome sequencing, Sanger validation, and segregation analysis discovered a novel in-frame small deletion c.325_339del (p.Val109_Ile113del) in MFSD8 gene associated with neuronal ceroid lipofuscinosis type 7.ConclusionsThe deletion found in this patient affects the exon 5 of this gene which is the region encoding transmembrane domain. Sequencing analysis in this family has shown that the index is homozygous for 15 base pairs in-frame deletion, his uncle has normal homozygous, and his parents are heterozygous. This pattern of mutation inheritance and the signs and symptoms observed in the affected male of this family are compatible with what is described in the literature for neuronal ceroid lipofuscinosis type 7 and, therefore, suggest that the MFSD8 gene deletion found in this study is most probably the cause of disease in this family.

A novel MFSD8 mutation in a Russian patient with neuronal ceroid lipofuscinosis type 7: a case report

BackgroundNeuronal ceroid lipofuscinoses (NCLs) are the most common autosomal recessive neurodegenerative disorders in children. Clinical manifestations include progressive cognitive decline, motor impairment, ataxia, visual loss, seizures and early death. To date more than 440 NCL-causing mutations in 13 genes are known.Case presentationWe report clinical and genetic characteristics of a 5-year-old girl affected by ceroid lipofuscinosis type 7 (NCL7). She had progressive motor and mental deterioration since the age of 2,5 years. Later she developed progressive vision loss, stereotypies, action myoclonus and epilepsy. By the age of 5 years she stopped walking. Based on symptoms, diagnosis of Rett syndrome was suggested, but no abnormalities were detected in MeCP2. We identified a novel homozygous mutation in MFSD8 gene (c.525 T > A, p.Cys175Ter). To our knowledge, this is the first report of MFSD8 gene mutation in a Russian patient with variant late-infantile NCL.ConclusionsOur results enlarge mutational spectrum of ceroid lipofuscinosis type 7 and demonstrate tremendous diagnosis value of exome sequencing for pediatric NCLs. Also we confirmed that NCL should be suspected in patients with Rett-like phenotype at onset and negative MECP2 mutation.

Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study

Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients. We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death. In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years. In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies. EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathan's Battle Foundation, Cures Within Reach Foundation, Noah's Hope Foundation, Hope4Bridget Foundation.

Study of Intraventricular Cerliponase Alfa for CLN2 Disease

BackgroundRecombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children.MethodsIn a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the time until a 2-point decline in 42 historical controls. We also compared the rate of decline in the motor–language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks).ResultsTwenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor–language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor–language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement.ConclusionsIntraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device-related infections. (Funded by BioMarin Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and NCT02485899.)

Inactivation of dynamin 1 in Cln1−/− mouse brain contributes to declining synaptic pool size

Lysosomal storage disorders (LSDs) are genetic disorders caused by impaired lysosomal function, which cause accumulation of undigested substrates in the lysosome causing pathogenesis. In the majority of LSDs, neurodegeneration is a devastating manifestation. Neuronal ceroid lipofuscinoses (NCLs), are a group of the most common neurodegenerative LSDs that mostly affect children. Mutations in &gt;13 different genes (called CLNs) underlie various types of NCLs. The infantile NCL (or INCL), one of the most devastating neurodegenerative LSDs, is caused by mutations in the CLN1 gene encoding palmitoyl‐protein thioesterase‐1 (PPT1), a lysosomal depalmitoylating enzyme. Palmitoylation is the only reversible lipid modification, which regulates the function of many proteins, especially in the brain. Moreover, PPT1‐catalyzed depalmitoylation of S‐acylated proteins is essential for their degradation. Thus, PPT1‐deficiency causes lysosomal accumulation of lipid‐modified proteins (constituents of ceroid) leading to INCL. Previously, we reported that in Ppt1‐deficient Cln1−/− mice, which mimic INCL, synaptic vesicle (SV) pool‐size at the nerve terminals progressively decline with age. We found that this defect originates from impaired exocytosis and endocytosis of SV components at the presynaptic membrane impairing neurotransmission. Dynamin1 is a small neuron specific GTPase that plays critical roles in recycling and regenerating fresh SVs. Here we demonstrate that in Cln1−/− mice there is increased phosphorylation of dynamin‐1, which inactivates its GTPase activity required for regeneration of the SVs. Our results uncover an unexpected role of Ppt1 in maintaining dynamin1 activity and suggest inactivation of dynamin 1 in this mouse model of INCL contributes to impaired SV‐regeneration and progressive decline in SV‐pool size.Support or Funding InformationThis work was supported in full by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CLN2 disease (neuronal ceroid lipofuscinosis type 2): Experience in the real world with cerliponase alfa intracerebroventricular enzyme replacement therapy in a public hospital in Cordoba, Argentina

CLN2 disease (neuronal ceroid lipofuscinosis type 2): Experience in the real world with cerliponase alfa intracerebroventricular enzyme replacement therapy in a public hospital in Cordoba, Argentina

Intravitreal enzyme replacement therapy attenuates retinal disease progression in a canine model of neuronal ceroid lipofuscinosis type 2 (CLN2)

Mineralocorticoid receptor activation of the epithelial sodium channel in endothelial cells (ECs) (EnNaC) is accompanied by aldosterone induced endothelial stiffening and impaired nitric oxide (NO)-mediated arterial relaxation. Recent data support enhanced activity of the alpha subunit of EnNaC (αEnNaC) mediates this aldosterone induced endothelial stiffening and associated endothelial NO synthase (eNOS) activation. There is mounting evidence that diet induced obesity diminishes expression and activation of AMP-activated protein kinase α (AMPKα), sirtuin 1 (Sirt1), which would be expected to lead to impaired downstream eNOS activation. Thereby, we posited that enhanced EnNaC activation contributes to diet induced obesity related increases in stiffness of the endothelium and diminished NO mediated vascular relaxation by increasing oxidative stress and related inhibition of AMPKα, Sirt1, and associated eNOS inactivation.Sixteen to twenty week-old αEnNaC knockout (αEnNaC−/−) and wild type littermate (EnNaC+/+) female mice were fed a mouse chow or an obesogenic western diet (WD) containing excess fat (46%) and fructose (17.5%) for 16 weeks. Sodium currents of ECs, endothelial stiffness and NO mediated aortic relaxation were examined along with indices of aortic oxidative stress, vascular remodeling and fibrosis.Enhanced EnNaC activation-mediated WD-induced increases in sodium currents in isolated lung ECs, increased endothelial stiffness and impaired aortic endothelium-dependent relaxation to acetylcholine (10−9–10−4 mol/L). These abnormalities occurred in conjunction with WD-mediated aortic tissue oxidative stress, inflammation, and decreased activation of AMPKα, Sirt1, and downstream eNOS were substantially mitigated in αEnNaC−/− mice. Importantly, αEnNaC−/− prevented WD induced increases in endothelial stiffness and related impairment of endothelium-dependent relaxation as well as aortic fibrosis and remodeling. However, EnNaC signaling was not involved in diet-induced abnormal expression of adipokines and CYP11b2 in abdominal aortic perivascular adipose tissue.These data suggest that endothelial specific EnNaC activation mediates WD-induced endothelial stiffness, impaired eNOS activation, aortic fibrosis and remodeling through increased aortic oxidative stress and increased inflammation related to a reduction of AMPKα and Sirt 1 mediated eNOS phosphorylation/activation and NO production.

The Spectrum of Movement Disorders in Childhood-Onset Lysosomal Storage Diseases.

Movement disorders are a significant clinical problem in lysosomal storage diseases (LSD) and account for substantial morbidity. The spectrum of movement disorders in childhood-onset LSD, however, remains poorly defined. To define the spectrum of movement disorders in a well-characterized cohort of children with LSD. A retrospective chart review at a single tertiary care center (Boston Children's Hospital, Boston, MA, USA). Patients up to the age of 18 years with a clinical, genetic and/or biochemical diagnosis of an LSD and at least one predefined movement disorder (parkinsonism, dystonia, ataxia, tremor, chorea, myoclonus, ballism, restless leg syndrome) were included. 96 patients were identified and 76 patients had a sufficiently document biochemical and/or genetic diagnosis. Of these, 18 patients met inclusion criteria (mean age: 10.3±5.8 (SD) years, range: 3-18 years; 72% male). The most common LSD associated with a movement disorder was Niemann-Pick disease type C (NPC), followed by several types of neuronal ceroid lipofuscinosis (NCL) and different mucopolysaccharidoses. The most common movement disorder was ataxia followed by rest tremor, dystonia and myoclonus. The other predefined movement disorders were rare. The majority of patients presented with more than one movement disorder. The movement disorder was slowly progressive in all patients. Brain MRI changes included diffuse cerebral volume loss, white matter abnormalities with thinning of the corpus callosum, and cerebellar atrophy. Movement disorders develop in a significant number of LSD patients. Ataxia, often in patients with NPC and NCL, is the most common phenotype but significant heterogeneity exists within and between different LSD.

Prevalence of Genetic Disorders and GLUT1 Deficiency in a Ketogenic Diet Clinic.

Between July of 2012 and December of 2014, 39 patients were enrolled prospectively to investigate the prevalence of glucose transporter 1 (GLUT1) deficiency in a ketogenic diet clinic. None of them had GLUT1 deficiency. All patients seen in the same clinic within the same period were reviewed retrospectively. A total of 18 of these 85 patients had a genetic diagnosis, including GLUT1 deficiency, pathogenic copy number variants, congenital disorder of glycosylation, neuronal ceroid lipofuscinosis type II, mitochondrial disorders, tuberous sclerosis, lissencephaly, and SCN1A-, SCN8A-, and STXBP1-associated epileptic encephalopathies. The prevalence of genetic diagnoses was 21% and prevalence of GLUT1 deficiency was 2.4% in our retrospective cohort study.

Exploring Concurrent Validity of The CLN2 Clinical Rating Scale: Comparison To Pedsql Using Mixed Effects Modelling And Data From A Phase 1/2 Single-Arm Trial

Neuronal Ceroid Lipofuscinosis type 2 (CLN2) disease is a rare, autosomal recessive disorder typically manifesting in late-infantile children. The disease results in progressive language loss, movement disorders, pain, dementia, vision loss and ultimately death at 8–12 years of age. The 0–6 point Motor-Language CLN2 Clinical Rating Scale was the primary endpoint in the pivotal cerliponase alfa trial for the treatment of CLN2 disease. This analysis aimed to concurrently validate this disease-specific functional rating scale by examining its relationship to the Paediatric Quality of Life Inventory (PedsQL) tool, for which a minimal clinically important difference of 4.5 has been established.1 Data from the phase 1/2 single-arm trial of 23 CLN2 patients treated with cerliponase alfa for a minimum of 97 weeks were used in this analysis (NCT01907087). To determine the relationship between the clinician-reported CLN2 Clinical Rating Scale total score and the proxy-reported PedsQL score at both the total and domain level, simple linear regression followed by mixed effects analyses (to account for within-subject correlation) were conducted. For the simple and mixed effects analyses, there was very strong evidence of a positive correlation between the PedsQL total score and the CLN2 Clinical Rating Scale total score (p<0.001; simple regression adjusted R-squared=0.27; mixed effects CLN2 Clinical Rating Scale parameter estimate [95% confidence interval (CI)]: 5.06 [2.66, 7.44]). It appears this relationship was primarily driven by the PedsQL Physical domain (p<0.001; simple regression adjusted R-squared=0.42; mixed effects CLN2 Clinical Rating Scale parameter estimate [95% CI]: 10.41 [7.21, 13.54]). These results provide evidence of concurrent validity between the CLN2 Clinical Rating Scale and PedsQL score, in particular, with respect to physical function. This relationship suggests a 1-point change on the CLN2 Clinical Rating Scale may be meaningful to patients.

Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease.

This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes. Retrospective clinical chart review of a series of patients diagnosed with CLN2 disease from 2005 to 2015 at a single center in Italy. Clinical, MRI, and EEG findings were reviewed. A total of 14 patients were included. For the whole group, median (range) age at disease onset was 3.0 (2.0-3.8) years. Epilepsy was the most commonly reported presenting symptom (in 50% [seven of 14] of patients), occurring at the age of 3.2 (2.6-3.8) years. First seizure was myoclonic in 36% (five of 14) of patients, followed by generalized tonic-clonic in 29% (4 of 14), atonic in 22% (three of 14), and focal with motor signs in 14% (two of 14). All patients walked independently at the age of 12.0 (11.0-18.0) months, but delayed speech or regression of acquired verbal skills was present in 100% of patients at 3 years. EEGs revealed a photoparoxysmal response (PPR) on intermittent photic stimulation in 93% (13 of 14) of patients. PPR was present from the first EEG, which was performed at 3.6 (3.1-4.0) years, in 43% (six of 14) of patients; it was documented at low (1-3 Hz) stimulation frequencies in 69% (nine of 13) and took the form of a flash-per-flash response in 69% (nine of 13). First brain MRI at the age of 3.8 (3.0-5.1) years revealed cerebellar atrophy in 100% (14 of 14) of patients and alteration of the periventricular white matter signal in the posterior hemispheric region in 79% (11 of 14). Early photosensitivity (typically PPR at low stimulation frequencies of 1-3 Hz) is a hallmark of CLN2 disease. This diagnosis should be considered in a child presenting with any type of seizure, and particularly if it is accompanied by delayed speech and/or ataxia or MRI abnormalities (posterior white matter signal alteration or cerebellar atrophy).

Cerliponase Alfa: First Global Approval.

Cerliponase alfa (Brineura™) is a recombinant human tripeptidyl peptidase-1 (TPP1) being developed by BioMarin Pharmaceutical Inc. for use in patients with neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative disease caused by a deficiency in TPP1. CLN2 is characterised by progressive impairment of motor function, language deficiencies, seizures, ataxia, blindness and early death, and intracerebroventricular infusion of cerliponase alfa has been shown to reduce the progression of functional decline. This article summarizes the milestones in the development of cerliponase alfa leading to its first global approval in the USA for the treatment of motor function loss in paediatric patients ≥3years of age with CLN2, and subsequent approval in the EU for CLN2 in all ages.

Unique Characteristics of the Photoparoxysmal Response in Patients With Neuronal Ceroid Lipofuscinosis Type 2: Can EEG Be a Biomarker?

The objective was to identify unique features of the photoparoxysmal response seen in patients with neuronal ceroid lipofuscinosis type 2 as compared to patients with a photoparoxysmal response associated with other epilepsy syndromes. Electroencephalograms from patients with neuronal ceroid lipofuscinosis type 2 seen at the authors' institution in the past 10 years as well as electroencephalograms (EEGs) reported to have a photoparoxysmal response during a single year were reviewed. A photoparoxysmal response was seen in 60% of the patients with neuronal ceroid lipofuscinosis type 2. This was most commonly seen with low frequency intermittent photic stimulation (76%) which often occurred in a time-locked fashion (63%) and was seen on the patient's initial EEG (78%). A unique pattern the authors called "sentinel" discharge was identified in 30% of EEGs in patients with neuronal ceroid lipofuscinosis. Photoparoxysmal responses in patients with neuronal ceroid lipofuscinosis type 2 have features which are distinguishing from photoparoxysmal responses seen in other epilepsies.

Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis.

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders. NCLs include the rare autosomal recessive neurodegenerative disorder neuronal ceroid lipofuscinosis type 2 (CLN2) disease, caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene and the resulting TPP1 enzyme deficiency. CLN2 disease most commonly presents with seizures and/or ataxia in the late-infantile period (ages 2-4), often in combination with a history of language delay, followed by progressive childhood dementia, motor and visual deterioration, and early death. Atypical phenotypes are characterized by later onset and, in some instances, longer life expectancies. Early diagnosis is important to optimize clinical care and improve outcomes; however, currently, delays in diagnosis are common due to low disease awareness, nonspecific clinical presentation, and limited access to diagnostic testing in some regions. In May 2015, international experts met to recommend best laboratory practices for early diagnosis of CLN2 disease. When clinical signs suggest an NCL, TPP1 enzyme activity should be among the first tests performed (together with the palmitoyl-protein thioesterase enzyme activity assay to rule out CLN1 disease). However, reaching an initial suspicion of an NCL or CLN2 disease can be challenging; thus, use of an epilepsy gene panel for investigation of unexplained seizures in the late-infantile/childhood ages is encouraged. To confirm clinical suspicion of CLN2 disease, the recommended gold standard for laboratory diagnosis is demonstration of deficient TPP1 enzyme activity (in leukocytes, fibroblasts, or dried blood spots) and the identification of causative mutations in each allele of the TPP1/CLN2 gene. When it is not possible to perform both analyses, either demonstration of a) deficient TPP1 enzyme activity in leukocytes or fibroblasts, or b) detection of two pathogenic mutations in trans is diagnostic for CLN2 disease.

Secondary Cerebral Folate Deficiency Comorbidity in Neuronal Ceroid Lipofuscinosis

Secondary cerebral folate deficiency (CFD) has been described in various neurodegenerative diseases, for example, Aicardi–Goutieres syndrome, Kearns–Sayre syndrome, and other mitochondriopathies. The importance of associated CFD lies in the possibility that treatment with folinic acid may improve the outcome of these diseases, or its presence may affect the course of the disease. We describe a patient with neuronal ceroid lipofuscinosis (NCL) type 2 due to tripeptidyl-peptidase I (TPP1) deficiency with an atypical presentation of chorea and dystonia. She was subsequently found to have low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF). TPP1 level in skin fibroblast cultures was

The Neuronal Ceroid Lipofuscinoses: A Case-Based Overview

The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of inherited, progressive neurodegenerative diseases. Manifestations may begin between the neonatal period and young adulthood, depending on the various subtypes. The different phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in the remaining neurons. Neurons appear to die because of increased rates of apoptosis and altered autophagy as occurs in lysosomal storage diseases. A total of 13 neuronal ceroid lipofuscinoses (CLN) genetic forms have been identified so far (CLN type 1–14). In the present review, we propose a classification scheme of the major forms and report the case of a familial recurrence of NCL type 10, with a mutation in the CLN10 gene coding for the cathepsin D protein.

Expert recommendations for the laboratory diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Diagnostic algorithm and best practice guidelines for a timely diagnosis

Expert recommendations for the laboratory diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Diagnostic algorithm and best practice guidelines for a timely diagnosis