Publications by authors named "Sara E Mole"

75 Publications

Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients.

Orphanet J Rare Dis 2021 Apr 21;16(1):185. Epub 2021 Apr 21.

Evelina, London Children's Hospital, London, UK.

Background: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition.

Methods: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria.

Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality).

Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available.
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http://dx.doi.org/10.1186/s13023-021-01813-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059011PMC
April 2021

Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease.

Sci Rep 2021 Mar 18;11(1):6332. Epub 2021 Mar 18.

MRC Laboratory for Molecular Cell Biology and Great Ormond Street, Institute of Child Health, University College London, London, WC1E 6BT, UK.

Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype-phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events.
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http://dx.doi.org/10.1038/s41598-021-85471-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973434PMC
March 2021

Urine proteomics analysis of patients with neuronal ceroid lipofuscinoses.

iScience 2021 Feb 31;24(2):102020. Epub 2020 Dec 31.

Inborn Errors of Metabolism Section, Genetics & Genomic Medicine Unit, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.

The neuronal ceroid lipofuscinoses (NCL) are a group of 13 rare neurodegenerative disorders characterized by accumulation of cellular storage bodies. There are few therapeutic options, and existing tests do not monitor disease progression and treatment response. However, urine biomarkers could address this need. Proteomic analysis of CLN2 patient urine revealed activation of immune response pathways and pathways associated with the unfolded protein response. Analysis of CLN5 and CLN6 sheep model urine showed subtle changes. To confirm and investigate the relevance of candidate biomarkers a targeted LC-MS/MS proteomic assay was created. We applied this assay to additional CLN2 samples as well as other patients with NCL (CLN1, CLN3, CLN5, CLN6, and CLN7) and demonstrated that hexosaminidase-A, aspartate aminotransferase-1, and LAMP1 are increased in NCL samples and betaine-homocysteine S-methyltransferase-1 was specifically increased in patients with CLN2. These proteins could be used to monitor the effectiveness of future therapies aimed at treating systemic NCL disease.
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http://dx.doi.org/10.1016/j.isci.2020.102020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822952PMC
February 2021

Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world.

J Paediatr Child Health 2021 04 30;57(4):519-525. Epub 2020 Dec 30.

UCL MRC Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Aim: Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, leading to progressive deterioration of neurological functions commonly occurring in children aged 2-4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes.

Methods: Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in São Paulo, Brazil, in October 2018.

Results: Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified.

Conclusion: Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy.
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http://dx.doi.org/10.1111/jpc.15250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049023PMC
April 2021

Gene Therapy Targeting the Inner Retina Rescues the Retinal Phenotype in a Mouse Model of CLN3 Batten Disease.

Hum Gene Ther 2020 07;31(13-14):709-718

Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.

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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http://dx.doi.org/10.1089/hum.2020.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404834PMC
July 2020

Special edition: The NCLs/Batten disease.

Biochim Biophys Acta Mol Basis Dis 2020 09 5;1866(9):165824. Epub 2020 May 5.

UCL MRC Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, United Kingdom.

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http://dx.doi.org/10.1016/j.bbadis.2020.165824DOI Listing
September 2020

Experimental gene therapies for the NCLs.

Biochim Biophys Acta Mol Basis Dis 2020 09 24;1866(9):165772. Epub 2020 Mar 24.

UCL School of Pharmacy, University College London, UK. Electronic address:

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of rare monogenic neurodegenerative diseases predominantly affecting children. All NCLs are lethal and incurable and only one has an approved treatment available. To date, 13 NCL subtypes (CLN1-8, CLN10-14) have been identified, based on the particular disease-causing defective gene. The exact functions of NCL proteins and the pathological mechanisms underlying the diseases are still unclear. However, gene therapy has emerged as an attractive therapeutic strategy for this group of conditions. Here we provide a short review discussing updates on the current gene therapy studies for the NCLs.
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http://dx.doi.org/10.1016/j.bbadis.2020.165772DOI Listing
September 2020

Future perspectives: What lies ahead for Neuronal Ceroid Lipofuscinosis research?

Biochim Biophys Acta Mol Basis Dis 2020 09 8;1866(9):165681. Epub 2020 Jan 8.

UCL MRC Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.bbadis.2020.165681DOI Listing
September 2020

Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease.

Hum Mol Genet 2019 12;28(23):3867-3879

Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.
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http://dx.doi.org/10.1093/hmg/ddz210DOI Listing
December 2019

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses.

Biochim Biophys Acta Mol Basis Dis 2020 09 31;1866(9):165571. Epub 2019 Oct 31.

Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute, 185 Cambridge St, Boston, MA 02114, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbadis.2019.165571DOI Listing
September 2020

Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease.

Hum Mutat 2019 11 26;40(11):1924-1938. Epub 2019 Jul 26.

UCL MRC Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1 G>C and c.622 C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease-associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late-infantile CLN2, represents 13% of individuals recorded with associated phenotype. NCBI ClinVar currently holds records for 37% of variants collected here. Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before a diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first-line diagnostic test for pediatric-onset neurological disease.
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http://dx.doi.org/10.1002/humu.23860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851559PMC
November 2019

Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features.

Brain 2019 01;142(1):59-69

Department of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.
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http://dx.doi.org/10.1093/brain/awy297DOI Listing
January 2019

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis.

Lancet Neurol 2019 01 21;18(1):107-116. Epub 2018 Nov 21.

UCL Institute of Ophthalmology, University College London, London, UK.

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.
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http://dx.doi.org/10.1016/S1474-4422(18)30368-5DOI Listing
January 2019

Gene Therapy Approaches to Treat the Neurodegeneration and Visual Failure in Neuronal Ceroid Lipofuscinoses.

Adv Exp Med Biol 2018 ;1074:91-99

UCL Institute of Ophthalmology, Department of Genetics & NIHR BRC at Moorfields Eye Hospital, London, UK.

Neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, inherited lysosomal storage disorders mostly affecting the central nervous system of children. Symptoms include vision loss, seizures, motor deterioration and cognitive decline ultimately resulting in premature death. Studies in animal models showed that the diseases are amenable to gene supplementation therapies, and over the last decade, major advances have been made in the (pre)clinical development of these therapies. This mini-review summarises and discusses current gene therapy approaches for NCL targeting the brain and the eye.
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http://dx.doi.org/10.1007/978-3-319-75402-4_12DOI Listing
May 2019

Prevention of Photoreceptor Cell Loss in a Cln6 Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells.

Mol Ther 2018 05 2;26(5):1343-1353. Epub 2018 Mar 2.

Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, City Road, London EC1V 2PD, UK. Electronic address:

The neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage disorders characterized by general neurodegeneration and premature death. Sight loss is also a major symptom in NCLs, severely affecting the quality of life of patients, but it is not targeted effectively by brain-directed therapies. Here we set out to explore the therapeutic potential of an ocular gene therapy to treat sight loss in NCL due to a deficiency in the transmembrane protein CLN6. We found that, although Cln6 mice presented mainly with photoreceptor degeneration, supplementation of CLN6 in photoreceptors was not beneficial. Because the level of CLN6 is low in photoreceptors but high in bipolar cells (retinal interneurons that are only lost in Cln6-deficient mice at late disease stages), we explored the therapeutic effects of delivering CLN6 to bipolar cells using adeno-associated virus (AAV) serotype 7m8. Bipolar cell-specific expression of CLN6 slowed significantly the loss of photoreceptor function and photoreceptor cells. This study shows that the deficiency of a gene normally expressed in bipolar cells can cause the loss of photoreceptors and that this can be prevented by bipolar cell-directed treatment.
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http://dx.doi.org/10.1016/j.ymthe.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993939PMC
May 2018

Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation.

Hum Mol Genet 2018 05;27(10):1711-1722

Section Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Defects in the MFSD8 gene encoding the lysosomal membrane protein CLN7 lead to CLN7 disease, a neurodegenerative lysosomal storage disorder belonging to the group of neuronal ceroid lipofuscinoses. Here, we have performed a SILAC-based quantitative analysis of the lysosomal proteome using Cln7-deficient mouse embryonic fibroblasts (MEFs) from a Cln7 knockout (ko) mouse model. From 3335 different proteins identified, we detected 56 soluble lysosomal proteins and 29 highly abundant lysosomal membrane proteins. Quantification revealed that the amounts of 12 different soluble lysosomal proteins were significantly reduced in Cln7 ko MEFs compared with wild-type controls. One of the most significantly depleted lysosomal proteins was Cln5 protein that underlies another distinct neuronal ceroid lipofuscinosis disorder. Expression analyses showed that the mRNA expression, biosynthesis, intracellular sorting and proteolytic processing of Cln5 were not affected, whereas the depletion of mature Cln5 protein was due to increased proteolytic degradation by cysteine proteases in Cln7 ko lysosomes. Considering the similar phenotypes of CLN5 and CLN7 patients, our data suggest that depletion of CLN5 may play an important part in the pathogenesis of CLN7 disease. In addition, we found a defect in the ability of Cln7 ko MEFs to adapt to starvation conditions as shown by impaired mammalian target of rapamycin complex 1 reactivation, reduced autolysosome tubulation and increased perinuclear accumulation of autolysosomes compared with controls. In summary, depletion of multiple soluble lysosomal proteins suggest a critical role of CLN7 for lysosomal function, which may contribute to the pathogenesis and progression of CLN7 disease.
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http://dx.doi.org/10.1093/hmg/ddy076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932567PMC
May 2018

The value of a comprehensive natural history in late infantile CLN5 disease.

Authors:
Sara E Mole

Dev Med Child Neurol 2017 08 29;59(8):777-778. Epub 2017 May 29.

MRC Laboratory for Molecular Cell Biology, Department of Genetics, Evolution and Environment & UCL GOSH Institute of Child Health, University College London, London, UK.

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http://dx.doi.org/10.1111/dmcn.13472DOI Listing
August 2017

NCLs and ER: A stressful relationship.

Biochim Biophys Acta Mol Basis Dis 2017 06 6;1863(6):1273-1281. Epub 2017 Apr 6.

MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom; Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT; UCL GOS Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom.

The Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are a group of inherited neurodegenerative disorders with variable age of onset, characterized by the lysosomal accumulation of autofluorescent ceroid lipopigments. The endoplasmic reticulum (ER) is a critical organelle for normal cell function. Alteration of ER homeostasis leads to accumulation of misfolded protein in the ER and to activation of the unfolded protein response. ER stress and the UPR have recently been linked to the NCLs. In this review, we will discuss the evidence for UPR activation in the NCLs, and address its connection to disease pathogenesis. Further understanding of ER-stress response involvement in the NCLs may encourage development of novel therapeutical agents targeting these pathogenic pathways.
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http://dx.doi.org/10.1016/j.bbadis.2017.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479446PMC
June 2017

CLN8 disease caused by large genomic deletions.

Mol Genet Genomic Med 2017 Jan 23;5(1):85-91. Epub 2016 Nov 23.

MRC Laboratory for Molecular Cell Biology Genetics and Genomics Medicine Unit Department of Genetics, Evolution and Environment Institute of Child Health University College London Gower Street London WC1E 6BT UK.

Background: The presence of deletions can complicate genetic diagnosis of autosomal recessive disease.

Method: The DNA of patients was analyzed in a diagnostic setting.

Results: We present three unrelated patients each carrying deletions that encompass the 37 kb gene and discuss their phenotype. Two of the cases were hemizygous for a mutant allele - their deletions unmasked a mutation in on the other chromosome.

Conclusion: Microarray analysis is recommended in any patient suspected of NCL who is apparently homozygous for a mutation that is not present in one of the parents or when the family has no known consanguinity.
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http://dx.doi.org/10.1002/mgg3.263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241206PMC
January 2017

Neuronal ceroid lipofuscinoses.

Epileptic Disord 2016 Sep;18(S2):73-88

Division of Neurology, The Hospital for Sick Children, University of Toronto, and Center for Brain and Mental Health, Sick Kids Research Institute, Canada.

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.
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http://dx.doi.org/10.1684/epd.2016.0844DOI Listing
September 2016

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

Mol Genet Metab 2016 09 25;119(1-2):160-7. Epub 2016 Jul 25.

BioMarin Pharmaceutical Inc., Novato, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ymgme.2016.07.011DOI Listing
September 2016

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

Neurology 2016 Aug 13;87(6):579-84. Epub 2016 Jul 13.

From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK.

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.
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http://dx.doi.org/10.1212/WNL.0000000000002943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977374PMC
August 2016

Mutation of TBCK causes a rare recessive developmental disorder.

Neurol Genet 2016 Jun 24;2(3):e76. Epub 2016 May 24.

Department of Molecular Neuroscience (R.J.G., J.B.), Institute of Neurology; MRC Laboratory for Molecular Cell Biology (R.B., S.E.M.), University College London; Manchester Centre for Genomic Medicine (D.D.), University of Manchester and Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust; Royal Preston Hospital (C.d.G.), Genetics and Genomics Medicine Programme (S.E.M.), UCL Institute of Child Health and Department of Genetics, Evolution and Environment, University College London, UK.

Objective: To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.

Methods: Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. Inspection of genetic variability within this region led to the identification of a novel mutation. Sanger sequencing confirmed segregation of the mutation with disease.

Results: All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del).

Conclusions: This finding provides the genetic cause of a severe inherited disease in a family and extends the number of mutations and phenotypes associated with this recently identified disease gene.
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http://dx.doi.org/10.1212/NXG.0000000000000076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881620PMC
June 2016

The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

J Neurosci Res 2016 Apr 13;94(4):339-47. Epub 2016 Jan 13.

Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.

Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease.
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http://dx.doi.org/10.1002/jnr.23710DOI Listing
April 2016

A central role for TOR signalling in a yeast model for juvenile CLN3 disease.

Microb Cell 2015 Nov 11;2(12):466-480. Epub 2015 Nov 11.

MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK. ; UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. ; Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.

Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of , the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeast . A global screen for genetic interactions with highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases.
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http://dx.doi.org/10.15698/mic2015.12.241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354605PMC
November 2015

Special issue: Molecular basis of NCL.

Biochim Biophys Acta 2015 Oct 27;1852(10 Pt B):2235-6. Epub 2015 Jun 27.

Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bbadis.2015.06.023DOI Listing
October 2015

Guidelines for incorporating scientific knowledge and practice on rare diseases into higher education: neuronal ceroid lipofuscinoses as a model disorder.

Biochim Biophys Acta 2015 Oct 24;1852(10 Pt B):2316-23. Epub 2015 Jun 24.

Centro de Estudio de las Metabolopatías Congénitas (CEMECO), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Ferroviarios 1250, 5014 Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Rivadavia 1917, C1033AAJ CABA, Argentina. Electronic address:

This article addresses the educational issues associated with rare diseases (RD) and in particular the Neuronal Ceroid Lipofuscinoses (NCLs, or CLN diseases) in the curricula of Health Sciences and Professional's Training Programs. Our aim is to develop guidelines for improving scientific knowledge and practice in higher education and continuous learning programs. Rare diseases (RD) are collectively common in the general population with 1 in 17 people affected by a RD in their lifetime. Inherited defects in genes involved in metabolism are the commonest group of RD with over 8000 known inborn errors of metabolism. The majority of these diseases are neurodegenerative including the NCLs. Any professional training program on NCL must take into account the medical, social and economic burdens related to RDs. To address these challenges and find solutions to them it is necessary that individuals in the government and administrative authorities, academia, teaching hospitals and medical schools, the pharmaceutical industry, investment community and patient advocacy groups all work together to achieve these goals. The logistical issues of including RD lectures in university curricula and in continuing medical education should reflect its complex nature. To evaluate the state of education in the RD field, a summary should be periodically up dated in order to assess the progress achieved in each country that signed up to the international conventions addressing RD issues in society. It is anticipated that auditing current practice will lead to higher standards and provide a framework for those educators involved in establishing RD teaching programs world-wide.
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http://dx.doi.org/10.1016/j.bbadis.2015.06.018DOI Listing
October 2015

Genetics of the neuronal ceroid lipofuscinoses (Batten disease).

Biochim Biophys Acta 2015 Oct 27;1852(10 Pt B):2237-41. Epub 2015 May 27.

Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.

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)."
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http://dx.doi.org/10.1016/j.bbadis.2015.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567481PMC
October 2015

Future perspectives: Moving towards NCL treatments.

Biochim Biophys Acta 2015 Oct 7;1852(10 Pt B):2336-8. Epub 2015 Apr 7.

Centro de Estudio de las Metabolopatías Congénitas (CEMECO), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba. Ferroviarios 1250, (5014) Córdoba, Argentina.

Clinicians, basic researchers, representatives from pharma and families from around the world met in Cordoba, Argentina in October, 2014 to discuss recent research progress at the 14th International Congress on Neuronal Ceroid Lipofuscinoses (NCLs; Batten disease), a group of clinically overlapping fatal, inherited lysosomal disorders with primarily neurodegenerative symptoms. This brief review article will provide perspectives on the anticipated future directions of NCL basic and clinical research as we move towards improved diagnosis, care and treatment of NCL patients. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease).
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http://dx.doi.org/10.1016/j.bbadis.2015.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567439PMC
October 2015

Cathepsin D deficiency causes juvenile-onset ataxia and distinctive muscle pathology.

Neurology 2014 Nov 8;83(20):1873-5. Epub 2014 Oct 8.

From UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery (J.H., N.W.W., H.H.); Great Ormond Street Hospital for Children NHS Foundation Trust (D.B., G.A., T.S.J.); UCL Institute of Child Health (R.C., T.S.J., P.M., P.G.); Barts NHS Trust (J.F.), Royal London Hospital; and UCL (P.G., S.E.M.), London, UK.

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http://dx.doi.org/10.1212/WNL.0000000000000981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240432PMC
November 2014