La lipofuscinose neuronale infantile tardive par déficit en CLN6 est une maladie génétique autosomique récessive due a une des mutations bialléliques du gène CLN.
Fille de 6 ans, issue d’un mariage ...consanguin qui a présenté à l’âge de 4 ans des troubles de la marche, spasticité des membres et une détérioration des fonctions intellectuelles évoluant en 6 mois vers une régression psychomotrice globale. L’IRM cérébrale montre une atrophie cérébrale à prédominance postérieure. L’évolution fut marquée par une cécité avec épilepsie myoclonique contrastant avec l’installation de la même symptomatologie chez son frère âgé de 4 ans. L’EEG montre des anomalies paroxystiques faites de pointes ondes à la SLI a basses fréquences. L’examen ophtalmologique trouve une mydriase aréflexique avec abolition des RPM directs et consensuels avec au fond d’œil une grande papille pale. Une étude génétique fut demandée, qui a mis en évidence lors du séquençage à haut débit une mutation génétique au niveau de l’exon 4 du gène CLN6, ce qui a confirmé le diagnostic d’une lipofuscinose infantile tardive.
Le gène CLN6 que présente notre patiente est impliqué dans la forme infantile tardive. Le diagnostic de CLN doit être évoqué en présence de toute épilepsie myoclonique progressive. La déficience visuelle est fréquente, la photosensibilité sur l’EEG avec une SLI à basse fréquence et l’imagerie montrant une atrophie cérébrale appuient le diagnostic et l’analyse moléculaire le confirme.
Devant une épilepsie myoclonique progressive, déficience visuelle avec présence d’une photosensibilité sur l’EEG avec une SLI à basse fréquence=Pensez à une céroide lipofuscinose infantile.
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults and are grouped together by similar clinical features and the ...accumulation of autofluorescent storage material. More than a dozen genes containing over 430 mutations underlying human NCLs have been identified. These genes encode lysosomal enzymes (CLN1, CLN2, CLN10, CLN13), a soluble lysosomal protein (CLN5), a protein in the secretory pathway (CLN11), two cytoplasmic proteins that also peripherally associate with membranes (CLN4, CLN14), and many transmembrane proteins with different subcellular locations (CLN3, CLN6, CLN7, CLN8, CLN12). For most NCLs, the function of the causative gene has not been fully defined. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity, and progression, including distinct clinical phenotypes. There remain disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: “Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease).”
•Number of genes and mutations that cause NCL summarized•Correlation between genotype and phenotype discussed•Outlook on genotype and phenotype presented•Knowledge of encoded proteins summarized
Obtaining a multiresource allocation scheme for multitask influenced by uncertain factors is a critical problem in a collaborative logistics network. This paper presents an optimal allocation model ...of fuzzy resources for multistage random logistics tasks based on the six-point trapezoidal fuzzy number and the membership function. Besides, considering task demands and resource constraints, a new cost-time-quality multiobjective programming of N-N task-resource assignment is introduced, which can be divided into minimize total logistics cost and execution time, maximize total service quality. Furthermore, by setting the different simulation scenarios, the results show that if the decision maker has a higher risk preference and pursues the optimization of single or multiobjective, the higher degree membership and satisfaction function values can be obtained with a larger compensation coefficient. The allocation scheme of task-resource assignment generated by proposed model has a high global level of utilization efficiency, which can effectively utilize fuzzy resources in collaborative logistics network, and avoid resource shortage caused by the excessive occupation of local resources.
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of ...autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.
The multiport Cauer ladder network (CLN) method is an efficient and accurate model order reduction (MOR) method for multi-input/multi-output (MIMO) systems. This manuscript discusses a theoretical ...aspect of port reduction in multiport CLN to generate a further reduced system. An intuitively derived method is found to be inaccurate. A recurrence formula and its practical implementation are presented to generate an accurate reduced system, which is proven by computational examples.
The Cauer ladder network (CLN) method is a model order reduction technique for quasi-static electromagnetic field analyses. This study proposes a novel error estimation method for reduced-order ...models provided by the CLN method, using the Henrici-Pflüger truncation error bounds for continued fractions. Using the proposed method, the accuracy of truncated impedances can be evaluated without time-consuming computations. Based on the numerical results for single-port systems, the proposed method provides a good error estimation for reduced-order models.
In The Lancet Neurology, Angela Schulz and colleagues3 report long-term follow-up of the 23 children included in the previous trial.2,4 The study observation period was 240 weeks, during which all ...participants had level 1 or level 2 adverse events (pyrexia, hypersensitivity, or seizures) and fewer patients had serious level 3 or level 4 adverse events, none of which led to discontinuation of the study.3 Treated patients experienced meaningful slowing of decline on combined motor and language domains of the CLN2 Clinical Rating Scale, were less likely to experience a 2-point decline in these domains, and were less likely to die compared with untreated historical controls. Neurodegeneration and oncogenesis can be two sides of the same coin.11 Preserving language, motor function, and vision, reduction of seizure frequency, and improving quality of life are desirable outcomes for children with CLN2 disease. RB declares patents related to methods of screening for risk of proliferative disease, methods for the treatment of proliferative disease, methods of treating Batten disease, methods and compositions for treating disorders caused by deficiency in a product of the CLN gene, and functionalised pyridine carbamates with enhanced neuroprotective activity.
Abstract Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CLN2/TPP1 gene, leading to a deficiency in ...tripeptidyl peptidase 1 activity. Enzyme replacement therapy with cerliponase alfa (recombinant human TPP1 rhTPP1; Brineura®) was approved in the United States and Europe for the treatment of CLN2 disease in 2017. We retrospectively report a cohort of 19 patients with CLN2 assisted in a specialized center in Argentina, including 8 newly diagnosed cases. Speech disorders and white matter changes/ventricular system enlargement were the most frequent clinical and imaging findings at CLN2 disease onset, respectively. Patients treated with cerliponase alfa presented a stable or improved course of the disease in this Latin American real world setting, as described in clinical trials.
Ceroid lipofuscinosis neuronal (CLN) genes encode 13 proteins that localize throughout the endomembrane system to regulate a variety of cellular processes. In humans, mutations in CLN genes cause a ...devastating form of neurodegeneration called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Each CLN gene is associated with a specific subtype of the disease that differ from each other in severity and age of onset. The NCLs affect all ages and ethnicities worldwide but primarily affect children. The pathology underlying the NCLs is poorly understood, which has prevented the development of a cure or effective therapy for most subtypes of the disease. A growing body of literature supports the networking of CLN genes and proteins within cells, which aligns with the broadly similar cellular and clinical manifestations among the different subtypes of NCL. Here, all relevant literature is reviewed to provide a comprehensive overview of our current understanding of how CLN genes and proteins are networked in mammalian cells with an aim toward revealing new molecular targets for therapy development. Intriguingly, CLN gene and protein networking extends beyond the NCLs as recent work has linked several CLN genes and proteins to other forms of neurodegeneration such as Alzheimer's disease and Parkinson's disease. Thus, a deeper understanding of the pathways and cellular processes impacted by mutations in CLN genes will not only strengthen our knowledge of the pathological mechanisms underlying the NCLs but may also provide new insight into related forms of neurodegeneration.
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•Finite difference code used to assess the aquifer thermal perturbation of a GSHP.•CLN package of open source Modflow-USG adapted to simulate BHE operation in aquifer.•Validation of ...the BHE model using CLN package coupled to unstructured grid.•Possible implementation of Borefield in one numerical model by means of Modflow-USG.
Simulating heat transfer in an aquifer with one or more vertical Borehole Heat Exchangers (BHEs) of a Ground Source Heat Pump (GSHP) system by means of a finite difference code is difficult because of the square or rectangular geometry grid and computational times thus limiting the types of evaluations that can be performed. The aim of this work is to explore through MODFLOW-USG code (public domain software) a different approach towards simulating a borefield that would be more efficient computationally, in order to enable simulations of larger domains with multiple BHEs. The Connected Linear Network (CLN) package, introduced in MODFLOW-USG, generally simulates 1-D linear computational cells in a 3-D grid, such as hydraulic pipes in subsoil, but for the first time has been adapted to reproduce vertical closed loop U-pipe of a BHE. Therefore, this work evaluates the MODFLOW-USG and CLN package capability to reproduce the yearly operation of one or more BHEs in an aquifer as a simpler and faster approach compared to a very fine finite-difference discretization. Once the CLN package was adapted, a sensitivity analysis on the grid size refinement was performed. There were several findings from this work. The results of the different numerical models were in good agreement with an already validated model, in terms of exchanged energies and aquifer thermal perturbation. Same analyses were carried out for different groundwater flow velocities and it was confirmed that the exchanged energy by a BHE increases with the groundwater flow velocity in accordance with literature studies. At last, a borefield of 7 BHEs was implemented in a numerical model in a more expeditious and efficient way and without any computational effort.
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