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Hum Gene Ther 2020 Jun 24. Epub 2020 Jun 24.

Institute of Ophthalmology, Molecular Therapy, London, United Kingdom of Great Britain and Northern Ireland.

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. Read More

J Biomed Sci 2020 May 20;27(1):64. Epub 2020 May 20.

Department of Biology, Trent University, 1600 West Bank Drive, Peterborough, Ontario, K9L 0G2, Canada.

The neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, belong to a family of neurological disorders that cause blindness, seizures, loss of motor function and cognitive ability, and premature death. There are 13 different subtypes of NCL that are associated with mutations in 13 genetically distinct genes (CLN1-CLN8, CLN10-CLN14). Similar clinical and pathological profiles of the different NCL subtypes suggest that common disease mechanisms may be involved. Read More

Mol Genet Genomic Med 2020 Jul 15;8(7):e1228. Epub 2020 May 15.

Institute of Biomedical Chemistry, Moscow, Russia.

Background: Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision.

Methods: We describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). Read More

BMC Med Genet 2020 05 11;21(1):100. Epub 2020 May 11.

Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China.

Background: Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 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. Read More

Biochem Biophys Res Commun 2020 May 11;525(4):883-888. Epub 2020 Mar 11.

Department of Molecular Cell Biology and Medicine, Graduate School of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan. Electronic address:

CLN6, spanning the endoplasmic reticulum membrane, is a protein of unknown function. Mutations in the CLN6 gene are linked to an autosomal recessively inherited disorder termed CLN6 disease, classified as a form of the neuronal ceroid lipofuscinoses (NCL). The pathogenesis of CLN6 disease remains poorly understood due to a lack of information about physiological roles CLN6 plays. Read More

Nat Rev Drug Discov 2020 03;19(3):151-153

Cell Signal 2020 Jun 20;70:109572. Epub 2020 Feb 20.

Department of Biology, Trent University, Peterborough, Ontario, Canada.

The neuronal ceroid lipofuscinoses (NCLs) are a family of neurodegenerative diseases that affect people of all ages and ethnicities, yet many of the associated genes/proteins are not well characterized. Mutations in MFSD8 (major facilitator superfamily domain-containing 8) cause an infantile form of NCL referred to as CLN7 disease. In this study, we revealed the localization and binding partners of an ortholog of human MFSD8 (Mfsd8) in the social amoeba Dictyostelium discoideum. Read More

Nat Struct Mol Biol 2020 02 10;27(2):192-201. Epub 2020 Feb 10.

Appel Institute for Alzheimer's Disease Research, and Brain & Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.

Point mutations in cysteine string protein-α (CSPα) cause dominantly inherited adult-onset neuronal ceroid lipofuscinosis (ANCL), a rapidly progressing and lethal neurodegenerative disease with no treatment. ANCL mutations are proposed to trigger CSPα aggregation/oligomerization, but the mechanism of oligomer formation remains unclear. Here we use purified proteins, mouse primary neurons and patient-derived induced neurons to show that the normally palmitoylated cysteine string region of CSPα loses palmitoylation in ANCL mutants. Read More

Neurosciences (Riyadh) 2020 Jan;25(1):65-69

College of Medicine, King Faisal University, Alahsa, Kingdom of Saudi Arabia. E-mail:

Neuronal ceroid lipofuscinoses (NCLs) are the most common group of neurodegenerative diseases that presents in childhood and are characterized by seizures and progressive neurological deterioration, which results in dementia, ataxia, visual failure, and various forms of abnormal movement. The most common form of neuronal ceroid lipofuscinoses is late infantile (LI-NCL), in association with the genes CLN2, CLN5, CLN6, and CLN8. We report the cases of neuronal ceroid lipofuscinoses type 8 in 3 patients from 2 unrelated families, which was confirmed by molecular testing in 2 of them. Read More

Biochem J 2020 Feb;477(3):727-745

Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, U.S.A.

Late-infantile neuronal ceroid lipofuscinosis (LINCL) is a neurodegenerative lysosomal storage disorder caused by mutations in the gene encoding the protease tripeptidyl-peptidase 1 (TPP1). Progression of LINCL can be slowed or halted by enzyme replacement therapy, where recombinant human TPP1 is administered to patients. In this study, we utilized protein engineering techniques to increase the stability of recombinant TPP1 with the rationale that this may lengthen its lysosomal half-life, potentially increasing the potency of the therapeutic protein. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 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. Read More

Eur J Hum Genet 2020 Jun 9;28(6):783-789. Epub 2020 Jan 9.

Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Adult-onset neuronal ceroid lipofuscinoses (ANCL, Kufs disease) are rare hereditary neuropsychiatric disorders characterized by intralysosomal accumulation of ceroid in tissues. The ceroid accumulation primarily affects the brain, leading to neuronal loss and progressive neurodegeneration. Although several causative genes have been identified (DNAJC5, CLN6, CTSF, GRN, CLN1, CLN5, ATP13A2), the genetic underpinnings of ANCL in some families remain unknown. Read More

Ophthalmic Genet 2019 12 7;40(6):588-590. Epub 2020 Jan 7.

Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.

Zhejiang Da Xue Xue Bao Yi Xue Ban 2019 Jun;48(4):373-377

Key Laboratory of Reproductive Genetics, Ministry of Education, Department of Reproductive Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.

Objective: To analyze the genetic cause of a family with autosomal recessive neuronal ceroid lipofuscinoses (NCL).

Methods: The proband was screened for mutations within the coding region of the candidate genes through high-throughput targeted sequencing. Potential causative mutations were verified by PCR and Sanger sequencing in the proband and his parents. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 19;1866(9):165643. Epub 2019 Dec 19.

Centre for Rare Diseases Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark.

The neuronal ceroid lipofuscinoses (NCLs) are mostly seen as diseases affecting the central nervous system, but there is accumulating evidence that they have co-morbidities outside the brain. One of these co-morbidities is a decline in cardiac function. This is becoming increasingly recognised in teenagers and adolescents with juvenile CLN3, but it may also occur in individuals with other NCLs. Read More

Elife 2019 12 6;8. Epub 2019 Dec 6.

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States.

Experiments on flies suggest that a gain-of-function mechanism in a protein called CSPɑ contributes to the progressive brain disease CLN4. Read More

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. Read More

Ugeskr Laeger 2019 11;181(45)

This case report describes a three-year-old boy with delayed development of language, who developed erythema migrans. Soon after peroral antibiotics was initiated, he also had loss of motoric function, and he developed ataxia. Neuroborreliosis was diagnosed, and antibiotic treatment was changed to intravenous. Read More

Proc Natl Acad Sci U S A 2019 11;116(48):23866-23870

JIMD Rep 2019 Nov 3;50(1):20-30. Epub 2019 Sep 3.

Division of Clinical and Metabolic Genetics, Department of Paediatrics University of Toronto, The Hospital for Sick Children Toronto Ontario Canada.

Background: Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the genes, we reviewed Molecular Genetics Laboratory Database for molecular genetic test results of the genes from a single clinical molecular diagnostic laboratory.

Methods: We reviewed electronic patient charts. Read More

Cesk Patol 2019 ;55(3):176-181

Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders with clinical presentation predominantly in the childhood. The NCLs represent lysosomal storage disorders characterized by the accumulation of autofluorescent lipopigment storage material. The most common clinical features include development failure, psychomotor regression, seizures, and progressive loss of vision. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 31;1866(9):165570. Epub 2019 Oct 31.

Pediatric Storage Disorders Laboratory, Department of Pediatrics, Division of Genetics and Genomics, Washington University in St. Louis, School of Medicine, St Louis, MO 63110, USA.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders (LSDs), traditionally grouped together based on shared clinical symptoms. The recent emergence of new forms of NCL along with an improved understanding of endo-lysosomal system function have necessitated the reassessment of their classification and pathogenesis. Novel clinical findings, as well as observations in various animal models of NCL, have revealed significant pathological changes in regions outside the brain, as well as progression of disease along connected anatomical pathways. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 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. Read More

Dev Med Child Neurol 2020 04 1;62(4):414. Epub 2019 Nov 1.

Rare and Complex Epilepsy Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Sci Rep 2019 10 30;9(1):15592. Epub 2019 Oct 30.

Department of Developmental Neurobiology, King's College London, New Hunt's House, London, SE1 1UL, UK.

The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Read More

Elife 2019 10 30;8. Epub 2019 Oct 30.

Department of Neuroscience, University of Arizona, Tucson, United States.

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of by expressing mutant human CSPα (hCSPα) in neurons. Similar to patients, mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 23;1866(9):165559. Epub 2019 Oct 23.

Centre for Bioscience, Manchester Metropolitan University, Manchester M1 5GD, UK.

The Neuronal Ceroid Lipofuscinoses (NCL), otherwise known as Batten disease, are a group of neurodegenerative diseases caused by mutations in 13 known genes. All except one NCL is autosomal recessive in inheritance, with similar aetiology and characterised by the accumulation of autofluorescent storage material in the lysosomes of cells. Age of onset and the rate of progression vary between the NCLs. Read More

N Engl J Med 2019 10 9;381(17):1644-1652. Epub 2019 Oct 9.

From the Divisions of Genetics and Genomics (J.K., C.H., E.A.L., A.S., J.V., R.L.D., J.C., P.B.A., A.H.B., S.E.W., O.B., T.W.Y.), Newborn Medicine (P.B.A., P.E.G.), and Neuroradiology (P.E.G.), the Departments of Neurology (C.M.E.A., D.K.U., A. Poduri), Anesthesiology, Critical Care and Pain Medicine (L.C., C.B.B.), Physical and Occupational Therapy (A. Pasternak, E.R.B., K.A.P.), and Pharmacy (S.C., A. Patterson), the Institutional Centers for Clinical and Translational Research (A.K., B.B., L.W.), and the Manton Center for Orphan Disease Research (C.A.G., P.B.A., A.H.B.), Boston Children's Hospital (A.K., A.T., M.A., L.M.P., K.D., B.B., L.W., B.D.G., B.L.R., A.B.), the Department of Biomedical Informatics (J.K., P.J.P.), Harvard Medical School (J.K., C.M.E.A., E.A.L., L.C., B.D.G., B.L.R., P.B.A., A.H.B., P.E.G., D.K.U., S.E.W., P.J.P., A. Patterson, A.B., O.B., C.B.B., T.W.Y.), and the Gene Therapy Program (A.B.), Boston Children's and Dana-Farber Cancer and Blood Disorders Center (A.K., B.B., L.W.), Boston, Charles River Laboratories, Wilmington (L.E.B.), and Broad Institute of MIT and Harvard (E.A.L., O.B., T.W.Y.), Cambridge - all in Massachusetts; Charles River Laboratories, Montreal (J.D.); University of Colorado School of Medicine, Aurora (A.L.); Pendergast Consulting, Washington, DC (M.K.P.); Goldkind Consulting, Potomac, MD (S.F.G.); the Department of Neurology Feinberg School of Medicine, Northwestern University, Chicago (N.R.B., K.F., I.S., J.R.M.); the Department of Neurology, University of Rochester Medical Center, Rochester, NY (E.F.A.); Brain Hz Consulting, Del Mar, CA (C.R.); Tyndall Consulting, Wake Forest, NC (K.T.); and Brammer Bio, Alachua, FL (R.O.S.).

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. Read More

Mol Genet Genomic Med 2019 12 30;7(12):e859. Epub 2019 Sep 30.

Beyond Batten Disease Foundation, Austin, Texas.

Background: One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans.

Objectives: To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 12;1866(9):165553. Epub 2019 Sep 12.

Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy. Electronic address:

Neuronal ceroid lipofuscinoses, also collectively known as Batten disease, are a group of rare monogenic disorders caused by mutations in at least 13 different genes. They are characterized by the accumulation of lysosomal storage material and progressive neurological deterioration with dementia, epilepsy, retinopathy, motor disturbances, and early death [1]. Although the identification of disease-causing genes provides an important step for understanding the molecular mechanisms underlying neuronal ceroid lipofuscinoses, compared to other diseases, obstacles to the development of therapies for these rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Read More

Mol Genet Genomic Med 2019 11 11;7(11):e968. Epub 2019 Sep 11.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: This study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett-like phenotypes.

Methods: Targeted next-generation sequencing (NGS) was performed on 44 Chinese patients with RTT or Rett-like phenotypes, in whom genetic analysis of MECP2, CDKL5, and FOXG1 was negative.

Results: The detection rate was 31. Read More

Mol Cell Proteomics 2019 11 9;18(11):2244-2261. Epub 2019 Sep 9.

Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854

Treatments are emerging for the neuronal ceroid lipofuscinoses (NCLs), a group of similar but genetically distinct lysosomal storage diseases. Clinical ratings scales measure long-term disease progression and response to treatment but clinically useful biomarkers have yet to be identified in these diseases. We have conducted proteomic analyses of brain and cerebrospinal fluid (CSF) from mouse models of the most frequently diagnosed NCL diseases: CLN1 (infantile NCL), CLN2 (classical late infantile NCL) and CLN3 (juvenile NCL). Read More

Dev Med Child Neurol 2020 04 5;62(4):528-530. Epub 2019 Sep 5.

Robert Debré University Hospital, Paris, France.

Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low-frequency intermittent photic stimulation), visual responses, and electron microscopy. Read More

Seizure 2019 Oct 23;71:247-257. Epub 2019 Aug 23.

Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'G. Gaslini', Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.

Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. Read More

Pediatr Neurol 2019 11 17;100:12-25. Epub 2019 Jul 17.

Department of Neurology, NYU School of Medicine, New York, New York. Electronic address:

Application of molecular neuroimaging using positron emission tomographic techniques to assess pediatric neurodegenerative disorders has been limited, unlike in adults where positron emission tomography has contributed to clinical diagnosis, monitoring of neurodegenerative disease progression, and assessment of novel therapeutic approaches. Yet, there is a huge unexplored potential of molecular imaging to improve our understanding of the pathophysiology of neurodegenerative disorders in children and provide radiological biomarkers that can be applied clinically. The obstacles in performing PET scans on children include sedation, radiation exposure, and access but, as will be illustrated, these barriers can be easily overcome. Read More

Hum Gene Ther 2019 10 10;30(10):1222-1235. Epub 2019 Sep 10.

Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

In the last decade, the gene therapy (GT) field experienced a renaissance, thanks to crucial understandings and innovations in vector design, stem cell manipulation, conditioning protocols, and cell/vector delivery. These efforts were successfully coupled with unprecedented clinical results of the trials employing the newly developed technology and with the novel establishment of academic-industrial partnerships. A renewed and strengthened interest is rising in the development of gene-based approaches for inherited neurometabolic disorders with severe neurological involvement. Read More

Ann Neurol 2019 11 28;86(5):729-742. Epub 2019 Aug 28.

Neurogenetics Program, AUBMC Special Kids Clinic and Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut.

Objective: CLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatric neurodegenerative disorders. Functions of the CLN3 protein include antiapoptotic properties and facilitating anterograde transport of galactosylceramide from Golgi to lipid rafts. This study confirms the beneficial effects of long-term exogenous galactosylceramide supplementation on longevity, neurobehavioral parameters, neuronal cell counts, astrogliosis, and diminution in brain and serum ceramide levels in Cln3 knock-in mice. Read More

Mol Ther 2019 10 10;27(10):1836-1847. Epub 2019 Jul 10.

Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA; Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57069, USA. Electronic address:

CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is a rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities and early death by 12-15 years of age. We developed a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under the control of a chicken β-actin (CB) hybrid promoter. Intrathecal delivery of scAAV9. Read More

Hum Mol Genet 2019 10;28(19):3309-3322

A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

The Finnish-variant late infantile neuronal ceroid lipofuscinosis, also known as CLN5 disease, is caused by mutations in the CLN5 gene. Cln5 is strongly expressed in the developing brain and expression continues into adulthood. CLN5, a protein of unknown function, is implicated in neurodevelopment but detailed investigation is lacking. Read More

PLoS One 2019 10;14(7):e0212382. Epub 2019 Jul 10.

Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States of America.

Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL). Although the exact function of PGRN is unknown, it has been increasingly implicated in lysosomal physiology. Here we report that PGRN interacts with the lysosomal enzyme, glucocerebrosidase (GCase), and is essential for proper GCase activity. Read More

Sci Rep 2019 07 9;9(1):9891. Epub 2019 Jul 9.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK.

The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child's lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR/Cas9 gene editing technology. Read More

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. Read More

Zhonghua Er Ke Za Zhi 2019 Jun;57(6):458-464

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

To identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy (PME). In this cross-sectional study, 26 PME children (11 boys and 15 girls) sent to neurological outpatient clinics and admitted to wards of the Department of Pediatrics, Peking University First Hospital were enrolled prospectively from January 2014 to October 2018. The pathogenic gene variants of PME children and their parents were identified by Sanger sequencing, next generation sequencing panels of epilepsy or trio-based whole exome sequencing and so on. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Sep 15;1866(9):165498. Epub 2019 Jun 15.

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; NIHR Great Ormond Street Biomedical Research Centre, Great Ormond Street Hospital, UCL Great Ormond Street Institute of Child Health, UK. Electronic address:

The Neuronal Ceroid Lipofuscinoses are a group of severe and progressive neurodegenerative disorders, which generally present during childhood. With new treatments emerging on the horizon, there is a growing need to understand the specific disease mechanisms as well as identify prospective biomarkers for use to stratify patients and monitor treatment. The use of Omics technologies to NCLs has the potential to address this need. Read More

Neurology 2019 07 10;93(3):e293-e297. Epub 2019 Jun 10.

From the Departments of Metabolic Diseases (W.F.E.K., P.M.v.H.), Pediatric Gastroenterology (E.E.S.N.), and Medical Physiology, Child Development and Exercise Center (M.v.B.), Wilhelmina Children's Hospital, University Medical Center Utrecht; Bartiméus Institute for the Visually Impaired (C.v.A., L.v.E.), Zeist and Doorn; and Center for Human Movement Sciences (B.C.H.H.), University Medical Center Groningen, University of Groningen, the Netherlands.

Objective: To delineate timing of motor decline in CLN3 disease.

Methods: Motor function, assessed by the 6-Minute Walk Test (6MWT), was evaluated repeatedly in 15 patients with CLN3 disease, resulting in 65 test results and during one occasion in 2 control cohorts. One control cohort (n = 14) had isolated visual impairment; a second cohort (n = 12) exhibited visual impairment in combination with neurologic impairments. Read More

Biochim Biophys Acta Biomembr 2019 10 24;1861(10):182993. Epub 2019 May 24.

Department of Biological Sciences, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), Junín 956, 1113 Buenos Aires, Argentina; Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos (UBA), Junín 956, 1113 Buenos Aires, Argentina; Institute of Biochemistry and Biophysics, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IQUIFIB-CONICET), Junín 956, 1113 Buenos Aires, Argentina. Electronic address:

Mutations in the ATP13A2 gene (PARK9, CLN12, OMIM 610513) were initially associated with a form of Parkinson's Disease (PD) known as Kufor Rakeb Syndrome (KRS). However, the genetic spectrum of ATP13A2-associated disorders was expanded in the last years, because it has been found to underlay variants of neuronal ceroid-lipofuscinoses (NCLs) and hereditary spastic paraplegia. As ATP13A2 seems to be a key component of the endo-lysosome pathway, the fact that these pathologies are commonly characterized by endo-lysosomal dysfunction is not surprising. Read More

Brain Dev 2019 Oct 21;41(9):817-819. Epub 2019 May 21.

Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Neuronal ceroid lipofuscinoses type 2 disease (CLN2) is a very rare, autosomal recessive neurodegerative disease caused by deficient activity of the enzyme tripeptidyl peptidase 1 (TPP1). The seizures in CLN2 are polymorphic and resistant to antiepileptic drugs. In particular, myoclonus (epileptic and non-epileptic) predominant as the disease progresses. Read More

Front Genet 2019 25;10:370. Epub 2019 Apr 25.

Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.

Neuronal Ceroid Lipofuscinoses (NCLs) are progressive degenerative diseases mainly affect brain and retina. They are characterized by accumulation of autofluorescent storage material, mitochondrial ATPase subunit C, or sphingolipid activator proteins A and D in lysosomes of most cells. Heterogenous storage material in NCLs is not completely disease-specific. Read More

Mol Genet Metab 2019 05 17;127(1):107-115. Epub 2019 Apr 17.

Mason Eye Institute, University of Missouri, Columbia, MO, USA. Electronic address:

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by progressive declines in neurological functions following normal development. The NCLs are distinguished from similar disorders by the accumulation of autofluorescent lysosomal storage bodies in neurons and many other cell types, and are classified as lysosomal storage diseases. At least 13 genes contain pathogenic sequence variants that underlie different forms of NCL. Read More