BBA - Molecular Basis of Disease (v.1832, #11)

Special issue: Molecular basis of the NCLs by Sara E. Mole; Ruth E. Williams; Jonathan D. Cooper (1793-1794).

The neuronal ceroid-lipofuscinoses: A historical introduction by Matti Haltia; Hans H. Goebel (1795-1800).
The neuronal ceroid-lipofuscinoses (Batten disease) collectively constitute one of the most common groups of inherited childhood onset neurodegenerative disorders, and have also been identified in many domestic and laboratory animals. The group of human neuronal ceroid-lipofuscinoses currently comprises 14 genetically distinct disorders, mostly characterised by progressive mental, motor and visual deterioration with onset in childhood or adolescence. Abnormal autofluorescent, electron-dense granules accumulate in the cytoplasm of nerve cells, and this storage process is associated with selective destruction and loss of neurons in the brain and retina. The present paper outlines nearly 200 years of clinical, neuropathological, biochemical and molecular genetic research, gradually leading, since 1995, to the identification of 13 different genes and over 360 mutations that underlie these devastating brain disorders and form the basis of a new classification system. These genes are evidently of vital importance for the normal development and maintenance of cerebral neurons. Elucidation of their functions and interactions in health and disease is a prerequisite for the identification of possible therapeutic targets, but may also further our understanding of the basic mechanisms of neurodegeneration and ageing. An account is also given of the development of international cooperation and free access electronic resources facilitating NCL research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.► The neuronal ceroid-lipofuscinoses (NCLs, Batten disease): 200 years of research ► Evolution of the concept of neuronal ceroid-lipofuscinosis ► Molecular genetic classification based on 14 genes, over 360 mutations ► Ideas on pathogenesis of the NCLs, neurodegeneration and ageing ► International collaboration and electronic resources in NCL research
Keywords: Neuronal ceroid-lipofuscinosis; Batten disease; History; Neurodegeneration; Ageing; Molecular genetic classification;

NCL diseases — clinical perspectives by Angela Schulz; Alfried Kohlschütter; Jonathan Mink; Alessandro Simonati; Ruth Williams (1801-1806).
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.
Keywords: Batten; Ceroid; NCLs; Disease classification; Diagnostic algorithm;

Human pathology in NCL by Glenn W. Anderson; Hans H. Goebel; Alessandro Simonati (1807-1826).
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.► NCL pathology is marked by neuronal loss and lipopigment accretion. ► In NCL, lipopigments accrue in extracerebral tissues. ► Characteristic ultrastructure of lipopigments defines clinical and molecular forms. ► Biopsy is best performed on blood lymphocytes, skin, and rectum.
Keywords: Electron microscopy; Brain; Extracerebral tissues; Granular osmiophilic deposits; Curvilinear; Fingerprint;

Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses by Varun Warrier; Mariana Vieira; Sara E. Mole (1827-1830).
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that mainly affect children and are grouped together by similar clinical features and the accumulation of autofluorescent storage material. More than a dozen genes containing nearly 400 mutations underlying human NCLs have been identified. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity and progression. There are still disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
Keywords: Batten; CLN; Neuronal ceroid lipofuscinosis; NCL;

Bioinformatic perspectives in the neuronal ceroid lipofuscinoses by Stanislav Kmoch; Viktor Stránecký; Richard D. Emes; Hannah M. Mitchison (1831-1841).
The neuronal ceroid lipofuscinoses (NCLs) are a group of rare genetic diseases characterised clinically by the progressive deterioration of mental, motor and visual functions and histopathologically by the intracellular accumulation of autofluorescent lipopigment – ceroid – in affected tissues. The NCLs are clinically and genetically heterogeneous and more than 14 genetically distinct NCL subtypes have been described to date (CLN1CLN14) (Haltia and Goebel, 2012 [1]). In this review we will chronologically summarise work which has led over the years to identification of NCL genes, and outline the potential of novel genomic techniques and related bioinformatic approaches for further genetic dissection and diagnosis of NCLs. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.► Computational work has aided NCL genetics, protein topology and mutation prediction. ► Past genetic linkage and modern genomics defines 14 NCL genes subtypes and new disease links. ► Allied genomic-bioinformatic studies have re-shaped the phenotypic complexity of NCLs. ► Defining the full NCL genomic/proteomic landscape will assist targeted therapies.
Keywords: Neuronal ceroid lipofuscinosis; Bioinformatics; Linkage analysis; Next generation sequencing; Topology;

Use of model organisms for the study of neuronal ceroid lipofuscinosis by Michael Bond; Sophia-Martha kleine Holthaus; Imke Tammen; Guy Tear; Claire Russell (1842-1865).
Neuronal ceroid lipofuscinoses are a group of fatal progressive neurodegenerative diseases predominantly affecting children. Identification of mutations that cause neuronal ceroid lipofuscinosis, and subsequent functional and pathological studies of the affected genes, underpins efforts to investigate disease mechanisms and identify and test potential therapeutic strategies. These functional studies and pre-clinical trials necessitate the use of model organisms in addition to cell and tissue culture models as they enable the study of protein function within a complex organ such as the brain and the testing of therapies on a whole organism. To this end, a large number of disease models and genetic tools have been identified or created in a variety of model organisms. In this review, we will discuss the ethical issues associated with experiments using model organisms, the factors underlying the choice of model organism, the disease models and genetic tools available, and the contributions of those disease models and tools to neuronal ceroid lipofuscinosis research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.► Summary of historically and currently available animal models for NCL ► Summary of currently available transgenic animal tools for NCL research ► Update on protein functions, disease mechanisms and experimental therapies for NCL ► Highlighting the major contributions of models organisms to the study of NCL
Keywords: Batten disease; Lysosomal storage disorder; Animal model; Disease mechanism; Pathology; Experimental therapy;

Cell biology and function of neuronal ceroid lipofuscinosis-related proteins by Katrin Kollmann; Kristiina Uusi-Rauva; Enzo Scifo; Jaana Tyynelä; Anu Jalanko; Thomas Braulke (1866-1881).
Neuronal ceroid lipofuscinoses (NCL) comprise a group of inherited lysosomal disorders with variable age of onset, characterized by lysosomal accumulation of autofluorescent ceroid lipopigments, neuroinflammation, photoreceptor- and neurodegeneration. Most of the NCL-related genes encode soluble and transmembrane proteins which localize to the endoplasmic reticulum or to the endosomal/lysosomal compartment and directly or indirectly regulate lysosomal function. Recently, exome sequencing led to the identification of four novel gene defects in NCL patients and a new NCL nomenclature currently comprising CLN1 through CLN14. Although the precise function of most of the NCL proteins remains elusive, comprehensive analyses of model organisms, particularly mouse models, provided new insight into pathogenic mechanisms of NCL diseases and roles of mutant NCL proteins in cellular/subcellular protein and lipid homeostasis, as well as their adaptive/compensatorial regulation at the transcriptional level. This review summarizes the current knowledge on the expression, function and regulation of NCL proteins and their impact on lysosomal integrity. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.► The roles of 14 NCL proteins in cellular homeostasis and metabolism are proposed. ► NCL protein–protein interactions will provide new insight into pathomechanisms. ► Impaired trafficking of NCL proteins causes lysosomal dysfunction.
Keywords: Lysosome; Neurodegeneration; Lysosomal storage disorder; Mannose 6-phosphate; CSPα; Progranulin;

NCL disease mechanisms by David N. Palmer; Lucy A. Barry; Jaana Tyynelä; Jonathan D. Cooper (1882-1893).
Despite the identification of a large number of disease-causing genes in recent years, it is still unclear what disease mechanisms operate in the neuronal ceroid lipofuscinoses (NCLs, Batten disease). As a group they are defined by the specific accumulation of protein, either subunit c of mitochondrial ATP synthase or SAPs A and D in lysosome-derived organelles, and regionally specific neurodegeneration. Evidence from biochemical and cell biology studies indicates related lesions in intracellular vesicle trafficking and lysosomal function. There is also extensive immunohistological evidence of a causative role of disease associated neuroinflammation. However the nature of these lesions is not clear nor is it clear why they lead to the defining pathology. Several different theories have proposed a range of potential mechanisms, but it remains to be determined which are central to pathogenesis, and whether there is a mechanism consistent across the group, or if it differs between disease forms. This review summarises the evidence that is currently available and the progress that has been made in understanding these profoundly disabling disorders. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
Keywords: Pathogenesis; Selective neuron loss; Glial activation; Synaptic pathology; Storage material accumulation; Biochemical abnormalities;

Juvenile neuronal ceroid lipofuscinosis and education by Stephen von Tetzchner; Per Fosse; Bengt Elmerskog (1894-1905).
Juvenile neuronal ceroid lipofuscinosis (JNCL) is characterized by severe visual impairment with onset around age 4–8 years, and a developmental course that includes blindness, epilepsy, speech problems, dementia, motor coordination problems, and emotional reactions. There is presently no cure and the disease leads to premature death. There have been few studies of non-medical intervention for individuals with JNCL, probably because of the negative prognosis. The present chapter discusses the education of children and adolescents with JNCL on the basis of current knowledge about the variation in perceptual, cognitive and language abilities through the course of the disease, and the possibilities that exist for supporting coping and learning within and outside the classroom. Adapted and special needs education may contribute significantly to improved learning conditions, better maintenance of skills and less frustration for individuals with JNCL. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
Keywords: Batten disease; Juvenile neuronal ceroid lipofuscinoses; Education; School; Development;

Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease) by Jacqueline A. Hawkins-Salsbury; Jonathan D. Cooper; Mark S. Sands (1906-1909).
The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases. Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the lifespan of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as juvenile neuronal ceroid lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
Keywords: Neuronal ceroid lipofuscinosis; Batten disease; Neurodegeneration; Neuroinflammation; Lysosomal storage disease; Gene therapy;

Funding resources for rare disease research by F. Stehr; M. Forkel (1910-1912).
Research is an expensive venture requiring multiple sources of funding for small projects that test new theories, large projects to make major advancements, training the next generation of researchers and facilitating meetings to share findings and support collaboration. For rare conditions, such as Batten disease, research funds can be difficult to find.To see how investigators supported their work in the past, we did a key word search of the Acknowledgement Section of peer-reviewed literature published in Batten disease in the last 6.5 years. Interestingly, we discovered 193 separate funding sources. The authors hope that, by showing where funds are available, we will enable Batten disease researchers to continue their pursuits and expand their studies; moving key findings from discovery to application phases. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
Keywords: Funding; Rare disease; Neuronal Ceroid Lipofuscinosis; Batten disease; Lysosomal storage disease; Orphan disease;