- Loss of Cln5 leads to altered Gad1 expression and deficits in interneuron development in mice. [Journal Article]
- HMHum Mol Genet 2019 Jul 11
- The Finnish variant Late Infantile Neuronal Ceroid Lipofuscinosis (vLINCLFin), also known as CLN5 disease, is caused by mutations in the CLN5 gene. Cln5 is strongly expressed in the developing brain …
The Finnish variant Late Infantile Neuronal Ceroid Lipofuscinosis (vLINCLFin), 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. Using Cln5-/- embryos of various ages and cells harvested from Cln5-/- brains we investigated the hitherto unknown role of Cln5 in the developing brain. Loss of Cln5 results in neuronal differentiation deficits and delays in interneuron development during in utero period. Spesifically, the radial thickness of dorsal telencephalon was significantly decreased in Cln5-/- mouse embryos at embryonic day 14.5 (E14.5), and expression of Tuj1, an important neuronal marker during development, was down-regulated. An interneuron marker calbindin and a mitosis marker p-H3 showed down-regulation in ganglionic eminences. Neurite outgrowth was compromised in primary cortical neuronal cultures derived from E16 Cln5-/- embryos compared to WT embryos. We show that the developmental deficits of interneurons may be linked to increased levels of the Repressor Element 1-Silencing Transcription factor (REST), which we report to bind to Gad1, which encodes glutamate decarboxylase (GAD) 67, a rate-limiting enzyme in the production of GABA. Indeed, adult Cln5-/- mice presented deficits in hippocampal parvalbumin-positive interneurons. Furthermore, adult Cln5-/- mice showed age-independent cortical hyper excitability as measured by electroencephalogram and auditory-evoked potentials. This study highlights the importance of Cln5 in neurodevelopment and suggests that in contrast to earlier reports, CLN5 disease is likely to develop during embryonic stages.
- Progranulin deficiency leads to reduced glucocerebrosidase activity. [Journal Article]
- PlosPLoS One 2019; 14(7):e0212382
- 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 compl…
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. GCase activity is significantly reduced in tissue lysates from PGRN-deficient mice. This is further evidence that reduced lysosomal hydrolase activity may be a pathological mechanism in cases of GRN-related FTLD and NCL.
- CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease). [Journal Article]
- SRSci Rep 2019 Jul 09; 9(1):9891
- 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…
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. Three PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17 ± 1 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.
- CADTH Canadian Drug Expert Committee Recommendation: Cerliponase Alfa (Brineura — Biomarin Pharmaceutical [Canada] Inc.): Indication: For the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency [BOOK]
- BOOKCanadian Agency for Drugs and Technologies in Health: Ottawa (ON)
- Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease. [Journal Article]
- HMHum Mutat 2019 Jul 08
- 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 peptida…
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 literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1G>C and c.622C>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 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. This article is protected by copyright. All rights reserved.
- Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis. [Journal Article]
- AAutophagy 2019 Jul 16; :1-15
- CTSD (cathepsin D) is one of the major lysosomal proteases indispensable for the maintenance of cellular proteostasis by turning over substrates of endocytosis, phagocytosis and autophagy. Consequent…
CTSD (cathepsin D) is one of the major lysosomal proteases indispensable for the maintenance of cellular proteostasis by turning over substrates of endocytosis, phagocytosis and autophagy. Consequently, CTSD deficiency leads to a strong impairment of the lysosomal-autophagy machinery. In mice and humans CTSD dysfunction underlies the congenital variant (CLN10) of neuronal ceroid lipofuscinosis (NCL). NCLs are distinct lysosomal storage disorders (LSDs) sharing various hallmarks, namely accumulation of protein aggregates and ceroid lipofuscin leading to neurodegeneration and blindness. The most established and clinically approved approach to treat LSDs is enzyme replacement therapy (ERT) aiming to replace the defective hydrolase with an exogenously applied recombinant protein. Here we reveal that recombinant human pro-CTSD produced in a mammalian expression system can be efficiently taken up by a variety of cell models, is correctly targeted to lysosomes and processed to the active mature form of the protease. In proof-of-principle experiments we provide evidence that recombinant human CTSD (rhCTSD) can improve the biochemical phenotype of CTSD-deficient hippocampal slice cultures in vitro and retinal cells in vivo. Furthermore, we demonstrate that dosing of rhCTSD in the murine CLN10 model leads to a correction of lysosomal hypertrophy, storage accumulation and impaired autophagic flux in the viscera and central nervous system (CNS). We establish that direct delivery of the recombinant protease to the CNS is required for improvement of neuropathology and lifespan extension. Together these data support the continuation of the pre-clinical studies for the application of rhCTSD in the treatment of NCL. Abbreviations: AIF1/IBA1: allograft inflammatory factor 1; BBB: blood brain barrier; CNS: central nervous system; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; ERT: enzyme replacement therapy; GFAP: glial fibrillary acidic protein; INL: inner nuclear layer; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LDL: low-density lipoprotein; LRP1: low density lipoprotein receptor-related protein 1; LSD: lysosomal storage disorder; MEFs: mouse embryonic fibroblasts; M6P: mannose 6-phosphate; mCTSD: mature CTSD; NCL: neuronal ceroid lipofuscinosis; ONL: outer nuclear layer; PB: phosphate buffer; proCTSD: pro-cathepsin D; LRPAP1: low density lipoprotein receptor-related protein associated protein 1; rhCTSD: human recombinant CTSD; SAPC: saposin C; SAPD: saposin D; ATP5G1: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit C1 (subunit 9); SQSTM1/p62: sequestosome 1; TPP1: tripeptidyl peptidase I.
- Successful treatment of psychosis in a patient with Kufor-Rakeb syndrome with low dose aripiprazole: a case report. [Journal Article]
- NNeurocase 2019 Jun - Aug; 25(3-4):133-137
- We present a case of a 32-year-old male with Kufor-Rakeb syndrome (KRS), a form of juvenile parkinsonism due to mutations of the ATP13A2 gene at PARK9 locus. The patient was seen for daily behavioral…
We present a case of a 32-year-old male with Kufor-Rakeb syndrome (KRS), a form of juvenile parkinsonism due to mutations of the ATP13A2 gene at PARK9 locus. The patient was seen for daily behavioral outbursts and psychotic symptoms. At first assessment, CGI scale was estimated at 5; "Markedly ill". Aripiprazole was started at 2 mg and then increased to 3 mg. Two years later, psychotic symptoms were judged to be "much improved" (CGI-C = 2). This significant improvement without drug-induced motor side effects suggests that aripiprazole at low doses (2-5 mg) is effective and tolerated in patients with KRS.
- A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder. [Journal Article]
- CTClin Trials 2019 Jun 11; :1740774519855715
- CONCLUSIONS: This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.
- Clinical approach to neurodegenerative disorders in childhood: an updated overview. [Review]
- ANActa Neurol Belg 2019 Jun 03
- Neurodegenerative disorders include a group of severe diseases that share a core including a gradual loss of previously acquired motor, sensory and cognitive functions. In pediatric age, the main dia…
Neurodegenerative disorders include a group of severe diseases that share a core including a gradual loss of previously acquired motor, sensory and cognitive functions. In pediatric age, the main diagnostic issues are the discrimination between the loss of previously acquired competencies and the lack of achievement of specific developmental milestones. An ideal classification of these disorders could be based on the combination of genetic, clinical and neuroimaging features. Diagnostic workup should be organized with a special attention to the few diseases with an available and effective therapeutic treatment. The present paper reports a proposal of classification that is based on the prominently involved structure and summarizes the hallmarks for clinical approach and therapeutic management.
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- 16- Overview of advances in educational and social supports for young persons with NCL disorders. [Review]
- BBBiochim Biophys Acta Mol Basis Dis 2019 May 30
- Vision loss, dementia, and motor and speech declines all impact the educational experience of individuals with Batten disease and can adversely impact effective learning. There are as yet limited dat…
Vision loss, dementia, and motor and speech declines all impact the educational experience of individuals with Batten disease and can adversely impact effective learning. There are as yet limited data to support evidence-based approaches to meeting the educational needs of affected individuals. This paper provides an overview of recent work to evaluate and address educational issues with a life-long perspective relevant to individuals with juvenile-onset neuronal ceroid lipofuscinosis (JNCL) and the professionals that provide them with educational support. In particular, several main activities of the recently completed 'JNCL and Education' project are summarised, including a survey of parents, educational professionals and social/health workers, development of a formative assessment tool to identify and respond to an individual student's strengths and needs in the learning environment, and proposed strategies for prolonging literacy and language skills. A key concept that should be emphasised in the educational plan for students with JNCL is that of 'proactive' and 'hastened' learning, that is, providing an early emphasis on adaptive skills that will be required in the later stages of disease progression when new learning will be more difficult to achieve. An additional key concept is participation in real-life activities to maintain skills and quality of life, particularly in the later stages of disease progression.