[Neuronal ceroid lipofuscinosis. Type 6 late infantile variant in two compound heterozygous siblings with novel mutations]. / Lipofuscinosis ceroidea neuronal. Variante infantil tardía de tipo 6 en dos hermanos heterocigotos compuestos con mutaciones nuevas.

INTRODUCTION: There are 14 forms of lipofuscinosis, among them type 6 in its late childhood form is found, it starts between three and eight years with epilepsy, motor disorders, myoclonus, dysarthria, ataxia and neurological regression associated with vision loss and motor skills, and early death. It occurs from mutations in the CLN6 gene, most patients have homozygote variants associated with consanguinity, and rarely, with compound heterozygote variants. CASE REPORT: Siblings, started at 4 and 5 years each, with unstable gear, frequent falls and difficult running. Subsequently, loss of gait, myoclonus, dysphagia, and hallucinations. On physical examination, present optic nerve atrophy, Babinski and trunk ataxia. Electroencephalogram with widespread slow wave bursts during non-REM sleep, non photoparoxystic response, MRI with periventricular white substance hyperintensity, cerebellar atrophy and cortical. Panel of lipofuscinosis report two mutations, c.552del and c.244G>C, not described previously, in both patients. The mother was the carrier of the 552 deletion and the father and paternal grandmother of the G>C substitution (Gly82Arg). CONCLUSIONS: Differential diagnosis in neuroregression disorders is difficult because clinical signs are nonspecific, like many other neurodegenerative disorders with progressive myoclonic epilepsy. We report the clinical findings in two Mexican siblings with the late childhood variant of CLN6 with two new heterozygote mutations that contribute to the knowledge of mutations in the Mexican population and point out the relevance of performing next-generation genetic sequencing studies which will allow a better genetic counseling practice.

TITLE: Lipofuscinosis ceroidea neuronal. Variante infantil tardía de tipo 6 en dos hermanos heterocigotos compuestos con mutaciones nuevas.Introducción. Existen 14 formas de lipofuscinosis. La de tipo 6, en su forma infantil tardía, comienza entre los 3 y 8 años con alteraciones motoras, mioclonos, disartria, ataxia, pérdida de la visión y las habilidades motoras, y muerte temprana. Ocurre por mutaciones en el gen CLN6. La mayoría de los pacientes presenta variantes en estado homocigoto, asociadas a consanguinidad o endogamia, y son poco frecuentes las variantes en estado heterocigoto compuesto. Casos clínicos. Hermanos con síntomas desde los 4 y 5 años, con marcha inestable, caídas frecuentes, posteriormente pérdida de la marcha, mioclonías, disfagia y alucinaciones visuales. En el examen físico presentaban atrofia del nervio óptico, Babinski y ataxia del tronco. El electroencefalograma mostraba brotes de ondas lentas generalizadas, sin respuesta fotoparoxística, y la resonancia magnética de cráneo, hiperintensidad de la sustancia blanca periventricular, y atrofia cerebelosa y cortical. El panel de lipofuscinosis reveló dos mutaciones nuevas en el gen CLN6, c.552del y c.244G>C (p.Gly82Arg), no descritas previamente. La madre resultó portadora de la deleción 552, y el padre y la abuela paterna, de la sustitución G>C (Gly82Arg). Conclusiones. El diagnóstico diferencial en los trastornos con neurorregresión se dificulta debido a que los signos clínicos son inespecíficos, similares a otras epilepsias mioclónicas progresivas. Presentamos los hallazgos clínicos en dos hermanos mexicanos con la variante infantil tardía de CLN6 por dos mutaciones heterocigotas nuevas que contribuyen al conocimiento de las mutaciones en la población mexicana y señalan la relevancia de realizar estudios genéticos aplicando la secuenciación de nueva generación para permitir un adecuado asesoramiento genético.

Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses.

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1-CLN8, CLN10-CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

Late-onset childhood neuronal ceroid lipofuscinosis: Early clinical and electroencephalographic markers.

PURPOSE: The objective of the study was to describe the initial clinical and electroencephalographic findings in children with late-infantile neuronal ceroid lipofuscinosis (LINCL). METHOD: The clinical charts of 35 patients seen between 1990 and 2016 were reviewed. The patients were divided into two groups: Group 1 (G1) consisting of 12 patients with NCL type 2 (CLN2) disease confirmed by enzymatic activity in dried blood spots on filter paper and/or genetic studies, and Group 2 (G2) consisting of 23 patients with a diagnosis of LINCL based on pathology studies by muscle biopsy. RESULTS: Mean age at symptom onset was 3 years in G1 and 3.4 years in G2. Symptoms at onset were epilepsy in 58%, language delay in 34%, and gait disturbances in 8% of patients in G1 and epilepsy in 52.1%, language delay in 26%, gait disturbances in 17.4%, and loss of visual acuity in 4.5% in G2. The most common seizure types in G1 patients were myoclonic in 3/7, generalized tonic-clonic in 2/7, focal motor in 1/7, and febrile seizures in 1/7; in G2 patients they were myoclonic in 5/12, generalized tonic-clonic in 3/12, myoclonic-atonic in 2/12, and febrile seizures in 2/12. A photoparoxysmal response to intermittent photic stimulation (IPS) was found in the initial EEG in 9/12 patients in G1 (mean age 3.8 years) and in 10/13 patients in G2 (mean age 3.9 years). CONCLUSIONS: There were no significant differences between both groups. Seizures, especially myoclonic, are the most common symptom at onset followed by language delay and gait disturbances. Low-frequency IPS is a useful study that may help facilitate the diagnosis of the disease.

Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease).

OBJECTIVE: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. METHODS: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. RESULTS: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. CONCLUSIONS: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.

Classification and natural history of the neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses represent a group of disorders characterized by neurodegeneration and intracellular accumulation of an auto-fluorescent lipopigment (ceroid lipofuscin). Together, they represent the most prevalent class of childhood neurodegenerative disease. The neuronal ceroid lipofuscinoses encompass several distinct biological entities that vary in age of onset, specific neurologic phenotype, and rate of progression. In this review, we describe 9 major forms and present a classification scheme. Understanding the age of onset, clinical features, and natural history can inform rational diagnostics. Better knowledge of the natural histories of these disorders is necessary to shed light on the underlying pathobiology and to develop new therapeutics.

NCL diseases - clinical perspectives.

The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage disorders and together are the most common degenerative brain diseases in childhood. They are a group of disorders linked by the characteristic accumulation of abnormal storage material in neurons and other cell types, and a degenerative disease course. All NCLs are characterized by a combination of dementia, epilepsy, and motor decline. For most childhood NCLs, a progressive visual failure is also a core feature. The characteristics of these symptoms can vary and the age at disease onset ranges from birth to young adulthood. Genetic heterogeneity, with fourteen identified NCL genes and wide phenotypic variability render diagnosis difficult. A new NCL classification system based on the affected gene and the age at disease onset allows a precise and practical delineation of an individual patient's NCL type. A diagnostic algorithm to identify each NCL form is presented here. Precise NCL diagnosis is essential not only for genetic counseling, but also for the optimal delivery of care and information sharing with the family and other caregivers. These aspects are challenging because there are also potential long term complications which are specific to NCL type. Therefore care supported by a specifically experienced team of clinicians is recommended. As the underlying pathophysiological mechanism is still unclear for all NCL forms, the development of curative therapies remains difficult. This article is part of a Special Issue entitled: The neuronal ceroid lipofuscinoses or Batten Disease.

Human pathology in NCL.

In childhood the neuronal ceroid lipofuscinoses (NCL) are the most frequent lysosomal diseases and the most frequent neurodegenerative diseases but, in adulthood, they represent a small fraction among the neurodegenerative diseases. Their morphology is marked by: (i) loss of neurons, foremost in the cerebral and cerebellar cortices resulting in cerebral and cerebellar atrophy; (ii) an almost ubiquitous accumulation of lipopigments in nerve cells, but also in extracerebral tissues. Loss of cortical neurons is selective, indiscriminate depletion in early childhood forms occurring only at an advanced stage, whereas loss of neurons in subcortical grey-matter regions has not been quantitatively documented. Among the fourteen different forms of NCL described to date, CLN1 and CLN10 are marked by granular lipopigments, CLN2 by curvilinear profiles (CVPs), CLN3 by fingerprint profiles (FPPs), and other forms by a combination of these features. Among extracerebral tissues, lymphocytes, skin, rectum, skeletal muscle and, occasionally, conjunctiva are possible guiding targets for diagnostic identification, the precise type of NCL then requiring molecular analysis within the clinical and morphological context. Autosomal-recessive adult NCL has been linked molecularly to different childhood forms, i.e. CLN1, CLN5, and CLN6, whilst autosomal-dominant adult NCL, now designated as CLN4, is caused by a newly identified separate gene, DNAJC5. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses.

We provide a new classification for the neuronal ceroid lipofuscinoses (NCLs) that takes into account recent genetic and biochemical advances. This was originally developed by an international group with clinical, molecular genetic, biological, and morphologic interests, further revised by a panel of world experts in the NCLs, and is now updated in light of recent research findings. The aim is to provide young people, carers, and professionals with a diagnostic label that is informative, leads to effective clinical management of symptoms and in the future perhaps a cure, as well as aiding basic scientific and clinical research. We suggest that clinicians should aim to provide every child and family with detailed diagnostic information at clinical, biochemical, and genetic levels where possible, which the new classification allows in a gene-led hierarchical manner. The robustness and applicability of this updated new classification have been independently audited in the clinical setting using a series of patients previously diagnosed with NCL according to standard ultrastructural, biochemical, or genetic criteria.

[Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the Finnish (CLN5) and Turkish (CLN7) variants late infantile]. / Lipofuscinosis neuronal ceroidea: algoritmo diagnóstico y descripción clínica de las variantes infantil tardía finlandesa (CLN5) y turca (CLN7).

INTRODUCTION: The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in child-hood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). CASE REPORTS: We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started with behaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia, loss of walking ability within 2-3 years and vegetative state at 11 years of age. CONCLUSIONS: The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies.

The neuronal ceroid lipofuscinoses: the same, but different?

The NCLs (neuronal ceroid lipofuscinoses) (also known as Batten disease) are a group of at least ten fatal inherited storage disorders. Despite the identification of many of the disease-causing genes, very little is known about the underlying disease mechanisms. However, now that we have mouse or large-animal models for most forms of NCL, we can investigate pathogenesis and compare what happens in the brain in different types of the disease. Broadly similar neuropathological themes have emerged, including the highly selective nature of neuron loss, early effects upon the presynaptic compartment, together with an early and localized glial activation. These events are especially pronounced within the thalamocortical system, but it is clear that where and when they occur varies markedly between different forms of NCL. It is now becoming apparent that, despite having pathological endpoints that resemble one another, these are reached by a sequence of events that is specific to each subtype of NCL.

Current therapies for the soluble lysosomal forms of neuronal ceroid lipofuscinosis.

The NCLs (neuronal ceroid lipofuscinoses) are the most common inherited paediatric neurodegenerative disorder. Although genetically distinct, NCLs can be broadly divided into two categories: one in which the mutation results in a defect in a transmembrane protein, and the other where the defect lies in a soluble lysosomal enzyme. A number of therapeutic approaches are applicable to the soluble lysosomal forms of NCL based on the phenomenon of cross-correction, whereby the ubiquitously expressed mannose 6-phosphate/IGF (insulin-like growth factor) II receptor provides an avenue for endocytosis, trafficking and lysosomal processing of extracellularly delivered enzyme. The present review discusses therapeutic utilization of cross-correction by enzyme-replacement therapy, gene therapy and stem cell therapy for the NCLs, along with an overview of the recent progress in translating these treatments into the clinic.

Neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCL) are severe neurodegenerative lysosomal storage disorders of childhood, characterized by accumulation of autofluorescent ceroid lipopigments in most cells. NCLs are caused by mutations in at least ten recessively inherited human genes, eight of which have been characterized. The NCL genes encode soluble and transmembrane proteins, localized to the endoplasmic reticulum (ER) or the endosomal/lysosomal organelles. The precise function of most of the NCL proteins has remained elusive, although they are anticipated to carry pivotal roles in the central nervous system. Common clinical features in NCL, including retinopathy, motor abnormalities, epilepsia and dementia, also suggest that the proteins may be functionally linked. All subtypes of NCLs present with selective neurodegeneration in the cerebral and cerebellar cortices. Animal models have provided valuable data about the pathological characteristics of NCL and revealed that early glial activation precedes neuron loss in the thalamocortical system. The mouse models have also been efficiently utilized for the evaluation of therapeutic strategies. The tools generated by the accomplishments in genomics have further substantiated global analyses and these have initially provided new insights into the NCL field. This review summarizes the current knowledge of the NCL proteins, basic characteristics of each disease and studies of pathogenetic mechanisms in animal models of these diseases.

Assessing disease severity in late infantile neuronal ceroid lipofuscinosis using quantitative MR diffusion-weighted imaging.

BACKGROUND AND PURPOSE: Late infantile neuronal ceroid lipofuscinosis (LINCL), a form of Batten disease, is a fatal neurodegenerative genetic disorder, diagnosed via DNA testing, that affects approximately 200 children in the United States at any one time. This study was conducted to evaluate whether quantitative data derived by diffusion-weighted MR imaging (DWI) techniques can supplement clinical disability scale information to provide a quantitative estimate of neurodegeneration, as well as disease progression and severity. MATERIALS AND METHODS: This study prospectively analyzed 32 DWI examinations from 18 patients having confirmed LINCL at various stages of disease. A whole-brain apparent diffusion coefficient (ADC) histogram was fitted with a dual Gaussian function combined with a function designed to model voxels containing a partial volume fraction of brain parenchyma versus CSF. Previously published whole-brain ADC values of age-matched control subjects were compared with those of the LINCL patients. Correlations were tested between the peak ADC of the fitted histogram and patient age, disease severity, and a CNS disability scale adapted for LINCL. RESULTS: ADC values assigned to brain parenchyma were higher than published ADC values for age-matched control subjects. ADC values between patients and control subjects began to differ at 5 years of age based on 95% confidence intervals. ADC values had a nearly equal correlation with patient age (R2=0.71) and disease duration (R2=0.68), whereas the correlation with the central nervous system disability scale (R2=0.27) was much weaker. CONCLUSION: This study indicates that brain ADC values acquired using DWI may be used as an independent measure of disease severity and duration in LINCL.

[Adult-onset neuronal ceroid lipofuscinosis]. / Neuronale Zeroidlipofuszinosen des Erwachsenenalters.

Neuronal ceroid lipofuscinoses are a heterogenous group of genetic progressive neurodegenerative disorders. Curative therapeutic strategies are not known. These are largely diseases of childhood; adult-onset forms are rare and poorly characterized. The classical adult variant is CLN4 (Kufs' disease), in which autosomal-recessive and autosomal dominant forms are known. Furthermore the "classic infantile" CLN1, caused by a deficiency of the enzyme palmitoylprotein-thioesterase, may be of adult onset Neuronal ceroid lipofuscinoses in adulthood are multifaceted diseases. Their clinical picture is mainly characterized by progressive dementia, seizures, and extrapyramidal motor symptoms. In contrast to the infantile forms, visual loss is an uncommon feature that appears only in adult CLN1 but not CLN4, which may be helpful in clinical differential diagnosis.

Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis.

Model systems provide an invaluable tool for investigating the molecular mechanisms underlying the NCLs, devastating neurodegenerative disorders that affect the relatively inaccessible tissues of the central nervous system. These models have enabled the assessment of behavioural, pathological, cellular, and molecular abnormalities, and also allow for development and evaluation of novel therapies. This review highlights the relative advantages of the two available small vertebrate species, the mouse and zebrafish, in modelling NCL disease, summarising how these have been useful in NCL research and their potential for the development and testing of prospective disease treatments. A panel of mouse mutants is available representing all the cloned NCL gene disorders (Cathepsin D, CLN1, CLN2, CLN3, CLN5, CLN6, CLN8). These NCL mice all have progressive neurodegenerative phenotypes that closely resemble the pathology of human NCL. The analysis of these models has highlighted several novel aspects underlying NCL pathogenesis including the selective nature of neurodegeneration, evidence for glial responses that precede neuronal loss and identification of the thalamus as an important pathological target early in disease progression. Studies in mice have also highlighted an unexpected heterogeneity underlying NCL phenotypes, and novel potential NCL-like mouse models have been described including mice with mutations in cathepsins, CLC chloride channels, and other lysosome-related genes. These new models are likely to provide significant new information on the spectrum of NCL disease. Information on NCL mice is available in the NCL Mouse Model Database (). There are homologs of most of the NCL genes in zebrafish, and NCL zebrafish models are currently in development. This model system provides additional advantages to those provided by NCL mouse models including high-throughput mutational, pharmacogenetic and therapeutic technique analyses. Mouse and zebrafish models are an important shared resource for NCL research, offering a unique possibility to dissect disease mechanisms and to develop therapeutic approaches.

The neuronal ceroid-lipofuscinoses: from past to present.

The neuronal ceroid-lipofuscinoses (NCLs) are inherited lysosomal storage diseases and constitute the most common group of children's progressive encephalopathies. Most childhood forms of NCL are clinically characterized by progressive loss of vision as well as mental and motor deterioration, epileptic seizures, and premature death, while the rare adult forms are dominated by dementia. All forms of NCL share common pathomorphological features. Autofluorescent, periodic acid-Schiff- and Sudan black B-positive granules, resistant to lipid solvents, accumulate in the cytoplasm of most nerve cells, and there is progressive and remarkably selective neuronal degeneration and loss. For a long time, the NCLs were grouped under the heading of the "amaurotic family idiocies" and conceived as lipidoses. However, in the late 1980s and 1990s the NCL storage cytosomes were shown to consist largely of two hydrophobic proteins: either subunit c of mitochondrial ATP synthase or sphingolipid activator proteins A and D. Since 1995 numerous mutations in at least seven different genes have been shown to underlie the multiple human and animal forms of NCL. This review discusses the historical evolution of the NCL concept and the impact of the recent biochemical and molecular genetic findings on our views on the classification and pathogenesis of these devastating brain disorders.

Diagnosis of the neuronal ceroid lipofuscinoses: an update.

For the majority of families affected by one of the neuronal ceroid lipofuscinoses (NCLs), a biochemical and/or genetic diagnosis can be achieved. In an individual case this information not only increases understanding of the condition but also may influence treatment choices and options. The presenting clinical features prompt initial investigation and also guide clinical care. The clinical labels "infantile NCL", "late infantile NCL" and "juvenile NCL", therefore remain useful in practice. In unusual or atypical cases ultra-structural analysis of white blood cells or other tissue samples enables planning and prioritisation of biochemical and genetic tests. This review describes current methods available to achieve clinical, pathological, biochemical and genetic diagnosis in children presenting with symptoms suggestive of one of the NCLs.

Molecular genetics of the NCLs -- status and perspectives.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent storage material in many cell types, including neurons. Most NCL subtypes are inherited in an autosomal recessive manner and characterized clinically by epileptic seizures, progressive psychomotor decline, visual failure, variable age of onset, and premature death. To date, seven genes underlying human NCLs have been identified. Most of the mutations in these genes are associated with specific disease subtypes, while some result in variable disease onset, severity and progression. In addition to these, there are still disease subgroups with unknown molecular genetic backgrounds. Although apparent clinical homogeneity exists within some of these subgroups, actual genetic heterogeneity may complicate gene identification. Additional clues to the identification of these unknown genes may come from animal models of NCL and from functional studies of already known genes which may suggest further candidates.

[Pitfalls in the clinical and electroencephalographic diagnosis of ceroid lipofuscinosis]. / Dificuldades no diagnóstico clínico e eletrencefalográfico de lipofuscinose ceróide neuronal.

Neuronal ceroid lipofuscinosis (NCL) were traditionally classified according to age of onset and clinical features in four main groups. Recently, a combination of clinical, ultra structural and genetics data led to the recognition of eight forms of NCL, providing a more precise framework to classify atypical cases. By the other hand, it was shown that mutations in the same gene could be responsible for a large variety of clinical phenotypes. The objective of this study is to describe two brothers with clinical and electroencephalographic abnormalities characteristic of juvenile NCL, but with ultra structural abnormalities suggestive of late infantile NCL. Electroencephalogram is useful for clinical diagnosis of NCL but it is not helpful in its classification.