The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults and are grouped together by similar clinical features and the ...accumulation of autofluorescent storage material. More than a dozen genes containing over 430 mutations underlying human NCLs have been identified. These genes encode lysosomal enzymes (CLN1, CLN2, CLN10, CLN13), a soluble lysosomal protein (CLN5), a protein in the secretory pathway (CLN11), two cytoplasmic proteins that also peripherally associate with membranes (CLN4, CLN14), and many transmembrane proteins with different subcellular locations (CLN3, CLN6, CLN7, CLN8, CLN12). For most NCLs, the function of the causative gene has not been fully defined. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity, and progression, including distinct clinical phenotypes. There remain disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: “Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease).”
•Number of genes and mutations that cause NCL summarized•Correlation between genotype and phenotype discussed•Outlook on genotype and phenotype presented•Knowledge of encoded proteins summarized
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of ...autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.
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.
•Number of genes and mutations that cause NCL summarized•Correlation between genotype and phenotype discussed•Outlook on genotype and phenotype presented
We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and ...2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.
Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature ...death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease.
Neuronal ceroid lipofuscinoses Nita, Dragos A.; Mole, Sara E.; Minassian, Berge A.
Epileptic disorders,
September 2016, Letnik:
18, Številka:
s2
Journal Article
Recenzirano
The neuronal ceroid lipofuscinoses (NCL) are neurodegenerative conditions that associate cognitive decline, progressive cerebellar atrophy, retinopathy, and myoclonic epilepsy. NCL result from the ...excessive accumulation of neuronal and extraneuronal lipopigments, despite having diverse underlying biochemical aetiologies. Here we review the clinical presentation, pathophysiology and genetics of these conditions as well as the approach to diagnosis and management.
The neuronal ceroid lipofuscinoses (NCL) are a group of disorders defined by shared clinical and pathological features, including seizures and progressive decline in vision, neurocognition, and motor ...functioning, as well as accumulation of autofluorescent lysosomal storage material, or ‘ceroid lipofuscin’. Research has revealed thirteen distinct genetic subtypes. Precisely how the gene mutations lead to the clinical phenotype is still incompletely understood, but recent research progress is starting to shed light on disease mechanisms, in both gene-specific and shared pathways. As the application of new sequencing technologies to genetic disease diagnosis has grown, so too has the spectrum of clinical phenotypes caused by mutations in the NCL genes. Most genes causing NCL have probably been identified, underscoring the need for a shift towards applying genomics approaches to achieve a deeper understanding of the molecular basis of the NCLs and related disorders. Here, we summarize the current understanding of the thirteen identified NCL genes and the proteins they encode, touching upon the spectrum of clinical manifestations linked to each of the genes, and we highlight recent progress leading to a broader understanding of key pathways involved in NCL disease pathogenesis and commonalities with other neurodegenerative diseases.
•The neuronal ceroid lipofuscinoses are a group of inherited neurodegenerative disorders with lysosomal pathology.•There are thirteen distinct genetic subtypes of neuronal ceroid lipofuscinosis, CLN1-14.•With new sequencing technologies, the spectrum of phenotypes associated with NCL gene mutations has widened.•We summarize knowledge on NCL genes and proteins, highlighting areas of intersection among NCLs and related disorders.•Shifting towards genomics approaches will establish a more in-depth understanding of the NCLs and related disorders.
Treatment of the neuronal ceroid lipofuscinoses, also known as Batten disease, is at the start of a new era because of diagnostic and therapeutic advances relevant to this group of inherited ...neurodegenerative and life-limiting disorders that affect children. Diagnosis has improved with the use of comprehensive DNA-based tests that simultaneously screen for many genes. The identification of disease-causing mutations in 13 genes provides a basis for understanding the molecular mechanisms underlying neuronal ceroid lipofuscinoses, and for the development of targeted therapies. These targeted therapies include enzyme replacement therapies, gene therapies targeting the brain and the eye, cell therapies, and pharmacological drugs that could modulate defective molecular pathways. Such therapeutic developments have the potential to enable earlier diagnosis and better targeted therapeutic management. The first approved treatment is an intracerebroventricularly administered enzyme for neuronal ceroid lipofuscinosis type 2 disease that delays symptom progression. Efforts are underway to make similar progress for other forms of the disorder.
Progress is being made in all aspects of Neuronal Ceroid Lipofuscinosis (NCL) research, resulting in many recent advances. These advances encompass several areas that were previously thought ...intractable, ranging from basic science, through to a better understanding of the clinical presentation of different forms of NCL, therapeutic development, and new clinical trials that are underway. Increasing numbers of original NCL research papers continue to be published, and this new sense of momentum is greatly encouraging for the field. Here, we make some predictions as to what we can anticipate in the next few years.
•Progress is being made in all aspects of Neuronal Ceroid Lipofuscinosis research.•Advances range from better understanding of basic science to clinical presentation.•Advances are also being made in therapeutic development, including new clinical trials.•This article makes some predictions about prospects for the next few years.
The neuronal ceroid lipofuscinoses (NCLs), often referred to as Batten disease, are inherited lysosomal storage disorders that represent the most common neurodegeneration during childhood. Symptoms ...include seizures, vision loss, motor and cognitive decline, and premature death. The development of brain-directed treatments for NCLs has made noteworthy progress in recent years. Clinical trials are currently ongoing or planned for different forms of the disease. Despite these promising advances, it is unlikely that therapeutic interventions targeting the brain will prevent loss of vision in patients as retinal cells remain untreated and will continue to degenerate. Here, we demonstrate that
mice, a mouse model of CLN3 Batten disease with juvenile onset, suffer from a decline in inner retinal function resulting from the death of rod bipolar cells, interneurons vital for signal transmission from photoreceptors to ganglion cells in the retina. We also show that this ocular phenotype can be treated by adeno-associated virus (AAV)-mediated expression of
in cells of the inner retina, leading to significant survival of bipolar cells and preserved retinal function. In contrast, the treatment of photoreceptors, which are lost in patients at late disease stages, was not therapeutic in
mice, underlining the notion that CLN3 disease is primarily a disease of the inner retina with secondary changes in the outer retina. These data indicate that bipolar cells play a central role in this disease and identify this cell type as an important target for ocular AAV-based gene therapies for CLN3 disease.
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