Haploidentical haematopoietic stem cell transplantation combined with post-transplant cyclophosphamide in neuronal ceroid lipofuscinosis: Experience in eight patients

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(B) T2-FLAIR shows bilateral periventricular hyper-intensity (red arrows). (C) T2WI shows a mild low signal of bilateral thalami (red arrows). (D) Brain atrophy progression. T1WI from baseline MRI shows cerebral atrophy (a1 and a2)." ] ] ] "textoCompleto" => "BackgroundNeuronal ceroid lipofuscinoses (NCLs) were classified by onset ages of patients as: (1) infantile NCL (INCL); (2) late INCL; (3) juvenile NCL; and (4) adult NCL.<a class="elsevierStyleCrossRefs" href="#bib0050">1,2</a> Hematopoietic stem cell transplantation (HSCT) has been recommended to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes.<a class="elsevierStyleCrossRef" href="#bib0060">3</a> A series of studies have shown the successful use of haploidentical donors in the treatment of hematologic malignancies and severe aplastic anemia. Failure of allo-HSCT limits its application in treatment of benign diseases, especially inherited metabolic disorders, the transplantation failure rate of which is higher than 20%.<a class="elsevierStyleCrossRef" href="#bib0065">4</a>In this study, allo-HSCT followed by the modified PT/Cy regimen on eight NCL pediatric patients was performed. All patients are still alive at present and develop no severe transplantation-related complications. Progression of symptoms caused by disease began to slow down after 12 months of transplantation. Observations reported in this study suggest potential to treat NCLs with haplo-HSCT and PT/Cy. At strong request of parents and approved by ethics committee of the research center, this study conducted hematopoietic stem cell transplantation in NCL children. Initial observation was effective subsequently a series of treatments were carried out for children.Material and methodsPatientsNCL pediatric patients who underwent allo-HSCT at Affiliated Children's Hospital of Capital Institute of Pediatrics from January 2018 to May 2019 were involved. A combination of medical histories, clinical features, and genetic analyses was used for the diagnosis of all patients. The written consent form for allo-HSCT was obtained from patient's guardian, which was then reviewed and approved by ethics committee before the procedure.Haploidentical HSCTBefore haploidentical HSCT, a combination of rabbit anti-human thymocyte immunoglobulin, cyclophosphamide, fludarabine, and busulfan (ATG+CTX+Flu+Bu) was given to the eight patients, with specific details as: 2.5mg/kg/d ATG from 9 to 7 days before transplantation (total dose: 7.5mg/kg); 14.5mg/kg/d CTX from 6 to 5 days before transplantation (total duration: 2 days, total dose: 29mg/kg); 35mg/m2/d Flu from 6 to 2 days before transplantation (total duration: 5 days, total dose: 165mg/m2); and 4mg/kg/d Bu was administered intravenously from 5 to 2 days before transplantation (total duration: 4 days, total dose: 12mg/kg). Medicine order is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Definitions of related diagnoses(1) Granulocyte reconstitution: absolute peripheral blood granulocyte count ≥0.5×109/L for 3 continuous days. Platelet reconstitution: platelet count ≥20×109/L for 7 continuous days.<a class="elsevierStyleCrossRef" href="#bib0070">5</a> (2) Acute GvHD and chronic GvHD: diagnosis and grading were referenced from existing studies.<a class="elsevierStyleCrossRef" href="#bib0075">6</a> Grading was based on the skin (rash area), gastrointestinal tract (number of daily diarrhea episodes), and liver (total bilirubin level) findings. Then, an overall grade was obtained based on degree of injury to each organ from Grade I to IV. Grade III–IV acute GvHD was defined as severe GvHD. Chronic GvHD was graded according to the US National Institutes of Health.<a class="elsevierStyleCrossRef" href="#bib0080">7</a>ResultsClinical presentationsEight pediatric patients who had NCLs and underwent allo-HSCT were joined as two males and six females (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). All patients except patient 2 had mental and motor disorders. They presented with myoclonic seizures and/or vision loss and received 1–4 oral anticonvulsants. Patient 2 only presented with dysarthria and had the youngest age when diagnosed (2.6 years old, median age at diagnosis of 4.5 years). Patients 2 and 3 were full sisters. Patient 3 was diagnosed with CLN6, and patient 2 was suspected to have the same disease. Cranial magnetic resonance imaging (MRI) and genetic analysis were achieved, and a definitive diagnosis of CLN6 was confirmed. All pediatric patients showed abnormal cranial MRI results (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Haploidentical HSCTNo identically matched donor was found in any of eight patients. They finally received allo-HSCT from haploidentical HLA-matched parent donors (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). All donors were healthy. Median age of the donors was 34 (31–48 years). Donors of six-pediatric patients were fathers and donors of two pediatric patients were mothers. Three donors were haploidentical and HLA-matched at 6/12 sites, two donors were matched at 10/12 sites, one donor was matched at 7/12 sites, and two donors were matched at 6/12 sites. G-CSF-mobilized bone marrow and peripheral blood were used as sources of stem cells for the patients. Median nucleated cell count used for infusion was 25.37 (10–34.41)×108/kg and median CD34+ count was 13.7 (8.95–22)×106/kg (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Median neutrophil reconstitution time was 12 days (11–14 days), and median platelet reconstitution time was 12 days (9–14 days) after transplantation. Full donor chimerism (>99%) was achieved in T, B, and NK cells one month after transplantation in all patients. No acute or chronic GvHD appeared. All pediatric patients revealed agile eye expression, increased speech and limb movements, and significantly improved myoclonus, which was maintained for 2–4 weeks after granulocyte reconstitution. Five of these eight-pediatric patients developed CMV viremia 2–4 weeks after transplantation, which improved after reducing dose of immunosuppressive agents and adding ganciclovir or foscarnet sodium to therapy. Viremia persisted for two weeks. One patient developed EBV viremia 27 days after transplantation and tested negative after one week of dose reduction of immunosuppressant's. None of eight-pediatric patients developed an oral infection, intestinal infection, lung infection, hemorrhagic cystitis, or other complications (<a class="elsevierStyleCrossRef" href="#sec0075">Table S1</a>).Post-transplantation follow-upUntil September 30th, 2020, all patients (100%) had nonevent survival, with a median follow-up duration of 2.2 years (1.5–2.6 years). All patients succeeded in a full donor chimerism one month after transplantation and DNA fingerprints of seven pediatric patients who survived more than one year showed complete donor chimerism during follow-up. Youngest patient (2.6-years old) had dysarthria before transplantation, while symptoms did not progress after transplantation. As patient was prone to thrombosis, femoral vein thrombosis occurred after insertion of a central venous catheter in left femoral vein. Femoral vein thrombosis still persists, causing unstable gait with no other symptoms noted. Mental and motor deficits in other pediatric patients began to slow down at 9–12 months after transplantation. However, regression persisted. Myoclonic seizures and vision loss gradually improved after transplantation and dose of anticonvulsant medications was gradually reduced (<a class="elsevierStyleCrossRef" href="#sec0075">Table S1</a>).DiscussionTreatment of pediatric patients suffering from lysosomal disorders with neurological symptoms is facing major challenges.<a class="elsevierStyleCrossRef" href="#bib0085">8</a> Many treatments have been tried in China. Most treatments are still under experimental work and show limited efficiency. An ERT regimen used in treating NCL2 has been established. Efficacy has not been proven and the drugs used in treatment are not available in China. There are no effective approaches to control or improve the condition of pediatric NCL patients. Only supportive treatments could have been given to the patients. HSCT has been recommended as treatment of lysosomal disorders with brain damage caused by a soluble lysosomal enzyme deficiency, but no related reports are available in China. Allo-HSCT using cells from matched sibling donors is primary treatment of benign diseases in children. It is difficult to get suitable donors. GvHD remains a major obstacle to the success of HSCT. Compared with conventional T cell depletion methods, PT/Cy regimen used in recent years is more cost-effective and has fewer complications. It allows pediatric patients to rapidly undergo immune reconstitution, expanding the pool of HSCT donors.<a class="elsevierStyleCrossRef" href="#bib0090">9</a>Prevalence of haplo-HSCT is increasing year by year in China. There are no reports on treating NCLs with HSCT in China. Cases of using PT/Cy regimen to treat benign diseases in Chinese pediatric patients are rare. HSCT treatment combined with PT/Cy is still in the clinical trial phase abroad. We are the first to perform this treatment in NCL patients. HSC transplantation with reconstituted granulocytes and platelets in eight patients was successful. Complete chimerism was achieved. No acute/chronic GvHD occurred. Hematopoietic and immune reconstitution was ultimately attained. Results indicated a satisfactory transplantation result. Genetic and cranial imaging abnormalities were observed in patient 2, who presented no disease-related symptoms. Delay of disease progression observed in patient 2 suggested that early transplantation may be beneficial in these patients. Some patients developed infections during the period of virus activation and granulocytopenia. Donor selection and physical examination must be performed before transplantation to prevent latent infections when using this regimen in future. Post-transplantation monitoring of CMV activity in recipients and prompt administration of ganciclovir antiviral treatment to protect the heart, liver, and spleen. Empiric broad-spectrum antibiotics must be given to pediatric patients with a persistent fever over 38.5°C and adjusted after pathology results are obtained to control the infection as soon as possible to ensure a better transplantation outcome and patient survival.No symptoms occurred except for the youngest patient (2.6-years old) who had dysarthria before transplantation and dysarthria symptoms did not progress after transplantation. At the time of follow-up, the patient was 3-years and 8-months old. Compared with her full elder sister (patient 3), this patient had convulsions and experienced falls when standing up, so anticonvulsant therapy was gradually increased. Mental and motor disorders continued to develop in other pediatric patients. Progression slowed down at 9–12 months after transplantation. Myoclonic seizures and vision loss gradually improved after transplantation and dose of anticonvulsants was gradually reduced. All eight-pediatric patients have achieved rapid complete donor chimerism. Seven patients maintained full donor chimerism at follow-up after more than 1 year. Overall survival rate is encouraging. Haploidentical HSCT is safe and feasible to treat NCLs. Further follow-up observations are still needed to assess the long-term efficacy of this method.Haploidentical HSCT results show significantly low toxicity and high implantation rates. Preliminary follow-up data suggest that donor chimerism was stable and persistent. Further long-term follow-up and extensive neurocognitive studies are still necessary to determine the effects and efficiency of transplantation on NCLs natural progression. Consideration of how to rapidly reconstitute microglial cells derived from donor in the central nervous system is also required to achieve disease stabilization within a short period after HSCT.In summary, high-dose PT/Cy can be used after haplo-HSCT to successfully treat NCLs in children and prevent GvHD. Early transplantation shows a better result with control of acute/chronic GvHD and major transplantation-related events. Immunosuppressant is gradually discontinued, and immune reconstitution occurs rapidly. This method further expands the allo-HSCT donor pool, making it a viable option for patients without suitable donors. However, efficacy of HSCT for NCLs remains low. More clinical trials are still required to investigate the safety of NCL treatment.Ethical approvalThis study was approved by the research ethics committee of the Children's Hospital of Capital Institute of Pediatrics (Identifier: SHERLLM2020015). The guardians of the pediatric patients also signed written informed consent forms for the investigation and publication of articles.Authors’ contributionsAs the principal investigator, Rong Liu had full access to all data in this study and is responsible for the integrity and authenticity of the data. The study concept and design were made by Zeliang Song, Rong Liu, Xiaodai Cui and Xiaodong Shi. Data were collected and analyzed by Juanjuan Li, Shunqiao Feng, Zhaoxia Zhang. Zeliang Song drafted the manuscript. Di Cui critically revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. All processes were completed under the supervision of Rong Liu.FundingThis research received no external funding.Conflicts of interestThe authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres2098877" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1788390" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2098878" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1788389" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Haploidentical HSCT" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Definitions of related diagnoses" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Clinical presentations" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Haploidentical HSCT" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Post-transplantation follow-up" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Ethical approval" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Authors’ contributions" ] 10 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 12 => array:2 [ "identificador" => "xack731166" "titulo" => "Acknowledgments" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-02-10" "fechaAceptado" => "2023-07-27" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1788390" "palabras" => array:4 [ 0 => "Neuronal ceroid lipofuscinosis" 1 => "Haploidentical stem cell transplantation" 2 => "Post-transplant cyclophosphamide" 3 => "Haplo-HSCT" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1788389" "palabras" => array:4 [ 0 => "Lipofuscinosis neuronal ceroidea" 1 => "Trasplante de células madre haploidénticas" 2 => "Ciclofosfamida postrasplante" 3 => "Haplo-HSCT" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundNeuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. There are no previous reports on treating NCLs with HSCT in China. Material and methodNCL pediatric patients who underwent allo-HSCT at Affiliated Children's Hospital of Capital Institute of Pediatrics were involved. A combination of medical histories, clinical features, and genetic analyses was used for the diagnosis of all patients. The written consent form for allo-HSCT was attained from the patient's guardian, which was then reviewed and approved by the ethics committee before the procedure. ResultsFrom January 2018 to May 2019, the haplo-HSCT followed by PT/Cy on eight NCL pediatric patients was performed. The median age was 4.5 years (ranging from 2.8 to 7 years). The donors were their haploidentical HLA-matched parents, as no identically matched donors were found. The median nucleated cell count was 25.37 (10–34.41)×108/kg, and the median CD34+ count was 13.7 (8.95–22)×106/kg. Neutrophil reconstitution occurred 12 days (11–14 days) after transplantation, and the median platelet reconstitution time was 12 days (9–14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II–IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5–2.6) years. All patients are still alive at present and develop no severe transplantation-related complications. The mental motor disorders, myoclonic seizures, and vision loss of all patients continued to progress. However, the progression slowed at 12 months after transplantation. ConclusionThis study demonstrated that it is safe and efficacious to treat NCLs with haplo-HSCT. Transplantation should be performed at an early stage for the survival quality of pediatric patients." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesLas lipofuscinosis neuronales ceroides (NCL) son trastornos raros del almacenamiento lisosomal caracterizados por retraso mental progresivo y regresión del desarrollo motor y convulsiones mioclónicas. Se ha sugerido que el trasplante de células madre hematopoyéticas (HSCT) se utilice en el tratamiento de trastornos lisosomales y daño cerebral causado por una deficiencia de enzimas lisosomales solubles. No hay informes previos sobre el tratamiento de NCL con HSCT en China. Material y métodoPacientes pediátricos de NCL que se sometieron a alo-TCMH en el Hospital de Niños Afiliado del Instituto Capital de Pediatría involucrados. Se utilizó una combinación de historias clínicas, características clínicas y análisis genéticos para el diagnóstico de todos los pacientes. El formulario de consentimiento por escrito para el allo-TCMH se obtuvo del tutor del paciente, que luego fue revisado y aprobado por el comité de ética antes del procedimiento. ResultadosDe enero de 2018 a mayo de 2019, se realizó el haplo-HSCT seguido de TP/Cy en 8 pacientes pediátricos con NCL. La mediana de edad fue de 4,5 años (variando de 2,8 a 7 años). Los donantes eran sus padres haploidénticos compatibles con HLA, ya que no se encontraron donantes idénticos. La mediana del recuento de células nucleadas fue de 25,37 (10–34,41)×108/kg, y la mediana del recuento de CD34+ fue de 13,7 (8,95-22)×106/kg. La reconstitución de neutrófilos ocurrió 12 días (11-14 días) después del trasplante, y el tiempo medio de reconstitución plaquetaria fue de 12 días (9-14 días) después del trasplante. Todos los pacientes alcanzaron quimerismo total del donante y no desarrollaron EICH aguda de grado II-IV o EICH crónica después del trasplante. La mediana del período de seguimiento fue de 2,2 (1,5–2,6) años. Todos los pacientes siguen vivos en la actualidad y no desarrollan complicaciones graves relacionadas con el trasplante. Los trastornos mentales motores, las convulsiones mioclónicas y la pérdida de visión de todos los pacientes continuaron progresando. Sin embargo, la progresión se ralentizó a los 12 meses después del trasplante. ConclusiónEste estudio demostró que es seguro y eficaz tratar las NCL con haplo-TCMH. El trasplante debe realizarse en una etapa temprana para la calidad de supervivencia de los pacientes pediátricos." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:2 [ 0 => array:4 [ "apendice" => "Juanjuan Li, Jing Cao, Shunqiao Feng Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing 100020, China" "etiqueta" => "Appendix A" "titulo" => "Working group" "identificador" => "sec0075" ] 1 => array:4 [ "apendice" => "The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix B" "titulo" => "Supplementary data" "identificador" => "sec0085" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1346 "Ancho" => 2508 "Tamanyo" => 207079 ] ] "descripcion" => array:1 [ "en" => "Conditioning regimens for patients with NCL: the ATG indicates antithymoglobulin; BM, bone marrow; Bu, busulfan; Cy/CTX, cyclophosphamide; Flu, fludarabine; MMF, mycophenolate mofetil; PB, peripheral blood stem cell; FK506, tacrolimus; IVIG, human immunoglobulin for intravenous injection; and G-CSF, granulocyte colony stimulating factor." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 897 "Ancho" => 1819 "Tamanyo" => 232929 ] ] "descripcion" => array:1 [ "en" => "Representative images of abnormal brain MRI in patients: (A) T1WI shows diffuse atrophy of the cerebrum and cerebellum, a thinned cortex, prominent sulci, and enlarged ventricles. (B) T2-FLAIR shows bilateral periventricular hyper-intensity (red arrows). (C) T2WI shows a mild low signal of bilateral thalami (red arrows). (D) Brain atrophy progression. T1WI from baseline MRI shows cerebral atrophy (a1 and a2)." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "TTP1, tripeptidyl peptidase 1; MFSD, major facilitator superfamily domain containing 8; CLN, ceroid-lipofuscinosis neuronal." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patient \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sex \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Height (cm)/weight (kg) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age at diagnosis/transplantation (years) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical presentation \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Imaging presentation \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Enzymology of TTP1 (nmol/g/min) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Genetic analysis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HLA relationship \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">128/16.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.1/7.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Convulsions, dysarthria, blurred vision \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral atrophy, pronounced at bilateral cerebellum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MFSD8 (c.553G>A, p.V185I; c.1391C>T, p. A464V) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/12 (Father) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">95/13.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.6/2.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysarthria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possible demyelination lesions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CLN6 (c.184C>T, p.R62C; c.158T>C, p.L53P) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10/12 (Father) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">105/17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9/4.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Convulsions, dysarthria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CLN6 (c.184C>T, p.R62C; c.158T>C, p.L53P) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10/12 (Father) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">114/14.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/5.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Convulsions, dysarthria, unstable gait \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TPP1 (c.1361C>A, p.A454E; c.1222_1224del, p.S408del) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/12 (Father) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">105/15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.1/4.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blurred vision, unstable gait \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral atrophy, pronounced at bilateral cerebellum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MFSD8 (c.1102G>C, p.D368H; c.103C>T, p.R35X) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/12 (Father) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">98/14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.5/5.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysarthria, unstable gait, limb tremors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral atrophy, pronounced at bilateral cerebellum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MFSD8 (c.416G>A, p.R139H; c.114delG, p.E381Kfs*33) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8/12 (Mother) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">120/17.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.8/5.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysarthria, unstable gait, limb tremors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CLN6 (c.794_c.796delCCT, p.S265_F266delinsF; c.826T>G, p.W276G) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/12 (Mother) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">110/18.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4/5.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Convulsions, limb tremors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral atrophy, pronounced at bilateral cerebellum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TPP1 (c.1417G>A, p.G473R; c.1613C>A, p.S538Y) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8/12 (Father) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3473082.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical data of pediatric patients who underwent transplantation." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Patient \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grafted cell count</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">NeutrophilReconstitution duration (d) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">PlateletReconstitution duration (d) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">30D post-transplantationChimerism (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Acute/chronic GvHD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">CMV/EBV activationTime (d) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Follow-up period (months) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Monocyte count(×108/kg) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD34+ count(×106/kg) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+15/− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+19/− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+21/− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000016200000005/v1_202403010948/S2387020624000482/v1_202403010948/en/main.assets" "Apartado" => array:4 [ "identificador" => "43315" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Clinical report" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000016200000005/v1_202403010948/S2387020624000482/v1_202403010948/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020624000482?idApp=UINPBA00004N"]

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Clinical report

Haploidentical haematopoietic stem cell transplantation combined with post-transplant cyclophosphamide in neuronal ceroid lipofuscinosis: Experience in eight patients

Trasplante de progenitores hematopoyéticos haploidénticos con ciclofosfamida postrasplante en lipofuscinosis neuronal ceroidea: experiencia en 8 pacientes

Zeliang Songa, Xiaodai Cuib, Zhaoxia Zhanga, Rong Liua,

Corresponding author

liu_rong_doctor@163.com

Corresponding authors.

, Xiaodong Shia,

Corresponding author

xsusan28@sina.com

Corresponding authors.

a Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing 100020, China

b Department of Key Laboratory, Capital Institute of Pediatrics, Beijing 100020, China

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Failure of allo-HSCT limits its application in treatment of benign diseases&#44; especially inherited metabolic disorders&#44; the transplantation failure rate of which is higher than 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In this study&#44; allo-HSCT followed by the modified PT&#47;Cy regimen on eight NCL pediatric patients was performed&#46; All patients are still alive at present and develop no severe transplantation-related complications&#46; Progression of symptoms caused by disease began to slow down after 12 months of transplantation&#46; Observations reported in this study suggest potential to treat NCLs with haplo-HSCT and PT&#47;Cy&#46; At strong request of parents and approved by ethics committee of the research center&#44; this study conducted hematopoietic stem cell transplantation in NCL children&#46; Initial observation was effective subsequently a series of treatments were carried out for children&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0015" class="elsevierStylePara elsevierViewall">NCL pediatric patients who underwent allo-HSCT at Affiliated Children&#39;s Hospital of Capital Institute of Pediatrics from January 2018 to May 2019 were involved&#46; A combination of medical histories&#44; clinical features&#44; and genetic analyses was used for the diagnosis of all patients&#46; The written consent form for allo-HSCT was obtained from patient&#39;s guardian&#44; which was then reviewed and approved by ethics committee before the procedure&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Haploidentical HSCT</span><p id="par0020" class="elsevierStylePara elsevierViewall">Before haploidentical HSCT&#44; a combination of rabbit anti-human thymocyte immunoglobulin&#44; cyclophosphamide&#44; fludarabine&#44; and busulfan &#40;ATG<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Flu<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Bu&#41; was given to the eight patients&#44; with specific details as&#58; 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d ATG from 9 to 7 days before transplantation &#40;total dose&#58; 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#59; 14&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d CTX from 6 to 5 days before transplantation &#40;total duration&#58; 2 days&#44; total dose&#58; 29<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#59; 35<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;d Flu from 6 to 2 days before transplantation &#40;total duration&#58; 5 days&#44; total dose&#58; 165<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#59; and 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d Bu was administered intravenously from 5 to 2 days before transplantation &#40;total duration&#58; 4 days&#44; total dose&#58; 12<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#46; Medicine order is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Definitions of related diagnoses</span><p id="par0025" class="elsevierStylePara elsevierViewall">&#40;1&#41; Granulocyte reconstitution&#58; absolute peripheral blood granulocyte count &#8805;0&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L for 3 continuous days&#46; Platelet reconstitution&#58; platelet count &#8805;20<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L for 7 continuous days&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> &#40;2&#41; Acute GvHD and chronic GvHD&#58; diagnosis and grading were referenced from existing studies&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> Grading was based on the skin &#40;rash area&#41;&#44; gastrointestinal tract &#40;number of daily diarrhea episodes&#41;&#44; and liver &#40;total bilirubin level&#41; findings&#46; Then&#44; an overall grade was obtained based on degree of injury to each organ from Grade I to IV&#46; Grade III&#8211;IV acute GvHD was defined as severe GvHD&#46; Chronic GvHD was graded according to the US National Institutes of Health&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Clinical presentations</span><p id="par0030" class="elsevierStylePara elsevierViewall">Eight pediatric patients who had NCLs and underwent allo-HSCT were joined as two males and six females &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; All patients except patient 2 had mental and motor disorders&#46; They presented with myoclonic seizures and&#47;or vision loss and received 1&#8211;4 oral anticonvulsants&#46; Patient 2 only presented with dysarthria and had the youngest age when diagnosed &#40;2&#46;6 years old&#44; median age at diagnosis of 4&#46;5 years&#41;&#46; Patients 2 and 3 were full sisters&#46; Patient 3 was diagnosed with CLN6&#44; and patient 2 was suspected to have the same disease&#46; Cranial magnetic resonance imaging &#40;MRI&#41; and genetic analysis were achieved&#44; and a definitive diagnosis of CLN6 was confirmed&#46; All pediatric patients showed abnormal cranial MRI results &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Haploidentical HSCT</span><p id="par0035" class="elsevierStylePara elsevierViewall">No identically matched donor was found in any of eight patients&#46; They finally received allo-HSCT from haploidentical HLA-matched parent donors &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; All donors were healthy&#46; Median age of the donors was 34 &#40;31&#8211;48 years&#41;&#46; Donors of six-pediatric patients were fathers and donors of two pediatric patients were mothers&#46; Three donors were haploidentical and HLA-matched at 6&#47;12 sites&#44; two donors were matched at 10&#47;12 sites&#44; one donor was matched at 7&#47;12 sites&#44; and two donors were matched at 6&#47;12 sites&#46; G-CSF-mobilized bone marrow and peripheral blood were used as sources of stem cells for the patients&#46; Median nucleated cell count used for infusion was 25&#46;37 &#40;10&#8211;34&#46;41&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">8</span>&#47;kg and median CD34<span class="elsevierStyleSup">&#43;</span> count was 13&#46;7 &#40;8&#46;95&#8211;22&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;kg &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Median neutrophil reconstitution time was 12 days &#40;11&#8211;14 days&#41;&#44; and median platelet reconstitution time was 12 days &#40;9&#8211;14 days&#41; after transplantation&#46; Full donor chimerism &#40;&#62;99&#37;&#41; was achieved in T&#44; B&#44; and NK cells one month after transplantation in all patients&#46; No acute or chronic GvHD appeared&#46; All pediatric patients revealed agile eye expression&#44; increased speech and limb movements&#44; and significantly improved myoclonus&#44; which was maintained for 2&#8211;4 weeks after granulocyte reconstitution&#46; Five of these eight-pediatric patients developed CMV viremia 2&#8211;4 weeks after transplantation&#44; which improved after reducing dose of immunosuppressive agents and adding ganciclovir or foscarnet sodium to therapy&#46; Viremia persisted for two weeks&#46; One patient developed EBV viremia 27 days after transplantation and tested negative after one week of dose reduction of immunosuppressant&#39;s&#46; None of eight-pediatric patients developed an oral infection&#44; intestinal infection&#44; lung infection&#44; hemorrhagic cystitis&#44; or other complications &#40;<a class="elsevierStyleCrossRef" href="#sec0075">Table S1</a>&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Post-transplantation follow-up</span><p id="par0045" class="elsevierStylePara elsevierViewall">Until September 30th&#44; 2020&#44; all patients &#40;100&#37;&#41; had nonevent survival&#44; with a median follow-up duration of 2&#46;2 years &#40;1&#46;5&#8211;2&#46;6 years&#41;&#46; All patients succeeded in a full donor chimerism one month after transplantation and DNA fingerprints of seven pediatric patients who survived more than one year showed complete donor chimerism during follow-up&#46; Youngest patient &#40;2&#46;6-years old&#41; had dysarthria before transplantation&#44; while symptoms did not progress after transplantation&#46; As patient was prone to thrombosis&#44; femoral vein thrombosis occurred after insertion of a central venous catheter in left femoral vein&#46; Femoral vein thrombosis still persists&#44; causing unstable gait with no other symptoms noted&#46; Mental and motor deficits in other pediatric patients began to slow down at 9&#8211;12 months after transplantation&#46; However&#44; regression persisted&#46; Myoclonic seizures and vision loss gradually improved after transplantation and dose of anticonvulsant medications was gradually reduced &#40;<a class="elsevierStyleCrossRef" href="#sec0075">Table S1</a>&#41;&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0050" class="elsevierStylePara elsevierViewall">Treatment of pediatric patients suffering from lysosomal disorders with neurological symptoms is facing major challenges&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> Many treatments have been tried in China&#46; Most treatments are still under experimental work and show limited efficiency&#46; An ERT regimen used in treating NCL2 has been established&#46; Efficacy has not been proven and the drugs used in treatment are not available in China&#46; There are no effective approaches to control or improve the condition of pediatric NCL patients&#46; Only supportive treatments could have been given to the patients&#46; HSCT has been recommended as treatment of lysosomal disorders with brain damage caused by a soluble lysosomal enzyme deficiency&#44; but no related reports are available in China&#46; Allo-HSCT using cells from matched sibling donors is primary treatment of benign diseases in children&#46; It is difficult to get suitable donors&#46; GvHD remains a major obstacle to the success of HSCT&#46; Compared with conventional T cell depletion methods&#44; PT&#47;Cy regimen used in recent years is more cost-effective and has fewer complications&#46; It allows pediatric patients to rapidly undergo immune reconstitution&#44; expanding the pool of HSCT donors&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Prevalence of haplo-HSCT is increasing year by year in China&#46; There are no reports on treating NCLs with HSCT in China&#46; Cases of using PT&#47;Cy regimen to treat benign diseases in Chinese pediatric patients are rare&#46; HSCT treatment combined with PT&#47;Cy is still in the clinical trial phase abroad&#46; We are the first to perform this treatment in NCL patients&#46; HSC transplantation with reconstituted granulocytes and platelets in eight patients was successful&#46; Complete chimerism was achieved&#46; No acute&#47;chronic GvHD occurred&#46; Hematopoietic and immune reconstitution was ultimately attained&#46; Results indicated a satisfactory transplantation result&#46; Genetic and cranial imaging abnormalities were observed in patient 2&#44; who presented no disease-related symptoms&#46; Delay of disease progression observed in patient 2 suggested that early transplantation may be beneficial in these patients&#46; Some patients developed infections during the period of virus activation and granulocytopenia&#46; Donor selection and physical examination must be performed before transplantation to prevent latent infections when using this regimen in future&#46; Post-transplantation monitoring of CMV activity in recipients and prompt administration of ganciclovir antiviral treatment to protect the heart&#44; liver&#44; and spleen&#46; Empiric broad-spectrum antibiotics must be given to pediatric patients with a persistent fever over 38&#46;5<span class="elsevierStyleHsp" style=""></span>&#176;C and adjusted after pathology results are obtained to control the infection as soon as possible to ensure a better transplantation outcome and patient survival&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">No symptoms occurred except for the youngest patient &#40;2&#46;6-years old&#41; who had dysarthria before transplantation and dysarthria symptoms did not progress after transplantation&#46; At the time of follow-up&#44; the patient was 3-years and 8-months old&#46; Compared with her full elder sister &#40;patient 3&#41;&#44; this patient had convulsions and experienced falls when standing up&#44; so anticonvulsant therapy was gradually increased&#46; Mental and motor disorders continued to develop in other pediatric patients&#46; Progression slowed down at 9&#8211;12 months after transplantation&#46; Myoclonic seizures and vision loss gradually improved after transplantation and dose of anticonvulsants was gradually reduced&#46; All eight-pediatric patients have achieved rapid complete donor chimerism&#46; Seven patients maintained full donor chimerism at follow-up after more than 1 year&#46; Overall survival rate is encouraging&#46; Haploidentical HSCT is safe and feasible to treat NCLs&#46; Further follow-up observations are still needed to assess the long-term efficacy of this method&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Haploidentical HSCT results show significantly low toxicity and high implantation rates&#46; Preliminary follow-up data suggest that donor chimerism was stable and persistent&#46; Further long-term follow-up and extensive neurocognitive studies are still necessary to determine the effects and efficiency of transplantation on NCLs natural progression&#46; Consideration of how to rapidly reconstitute microglial cells derived from donor in the central nervous system is also required to achieve disease stabilization within a short period after HSCT&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In summary&#44; high-dose PT&#47;Cy can be used after haplo-HSCT to successfully treat NCLs in children and prevent GvHD&#46; Early transplantation shows a better result with control of acute&#47;chronic GvHD and major transplantation-related events&#46; Immunosuppressant is gradually discontinued&#44; and immune reconstitution occurs rapidly&#46; This method further expands the allo-HSCT donor pool&#44; making it a viable option for patients without suitable donors&#46; However&#44; efficacy of HSCT for NCLs remains low&#46; More clinical trials are still required to investigate the safety of NCL treatment&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Ethical approval</span><p id="par0075" class="elsevierStylePara elsevierViewall">This study was approved by the research ethics committee of the Children&#39;s Hospital of Capital Institute of Pediatrics &#40;Identifier&#58; SHERLLM2020015&#41;&#46; The guardians of the pediatric patients also signed written informed consent forms for the investigation and publication of articles&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Authors&#8217; contributions</span><p id="par0080" class="elsevierStylePara elsevierViewall">As the principal investigator&#44; Rong Liu had full access to all data in this study and is responsible for the integrity and authenticity of the data&#46; The study concept and design were made by Zeliang Song&#44; Rong Liu&#44; Xiaodai Cui and Xiaodong Shi&#46; Data were collected and analyzed by Juanjuan Li&#44; Shunqiao Feng&#44; Zhaoxia Zhang&#46; Zeliang Song drafted the manuscript&#46; Di Cui critically revised the manuscript&#46; All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work&#46; All processes were completed under the supervision of Rong Liu&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0085" class="elsevierStylePara elsevierViewall">This research received no external funding&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest&#46;</p></span></span>"
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            0 => "Neuronal ceroid lipofuscinosis"
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            0 => "Lipofuscinosis neuronal ceroidea"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Neuronal ceroid lipofuscinoses &#40;NCLs&#41; are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures&#46; Hematopoietic stem cell transplantation &#40;HSCT&#41; has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes&#46; There are no previous reports on treating NCLs with HSCT in China&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">NCL pediatric patients who underwent allo-HSCT at Affiliated Children&#39;s Hospital of Capital Institute of Pediatrics were involved&#46; A combination of medical histories&#44; clinical features&#44; and genetic analyses was used for the diagnosis of all patients&#46; The written consent form for allo-HSCT was attained from the patient&#39;s guardian&#44; which was then reviewed and approved by the ethics committee before the procedure&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">From January 2018 to May 2019&#44; the haplo-HSCT followed by PT&#47;Cy on eight NCL pediatric patients was performed&#46; The median age was 4&#46;5 years &#40;ranging from 2&#46;8 to 7 years&#41;&#46; The donors were their haploidentical HLA-matched parents&#44; as no identically matched donors were found&#46; The median nucleated cell count was 25&#46;37 &#40;10&#8211;34&#46;41&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">8</span>&#47;kg&#44; and the median CD34<span class="elsevierStyleSup">&#43;</span> count was 13&#46;7 &#40;8&#46;95&#8211;22&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;kg&#46; Neutrophil reconstitution occurred 12 days &#40;11&#8211;14 days&#41; after transplantation&#44; and the median platelet reconstitution time was 12 days &#40;9&#8211;14 days&#41; after transplantation&#46; All patients achieved full donor chimerism and did not develop Grade II&#8211;IV acute GvHD or chronic GvHD after transplantation&#46; The median follow-up period was 2&#46;2 &#40;1&#46;5&#8211;2&#46;6&#41; years&#46; All patients are still alive at present and develop no severe transplantation-related complications&#46; The mental motor disorders&#44; myoclonic seizures&#44; and vision loss of all patients continued to progress&#46; However&#44; the progression slowed at 12 months after transplantation&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study demonstrated that it is safe and efficacious to treat NCLs with haplo-HSCT&#46; Transplantation should be performed at an early stage for the survival quality of pediatric patients&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las lipofuscinosis neuronales ceroides &#40;NCL&#41; son trastornos raros del almacenamiento lisosomal caracterizados por retraso mental progresivo y regresi&#243;n del desarrollo motor y convulsiones miocl&#243;nicas&#46; Se ha sugerido que el trasplante de c&#233;lulas madre hematopoy&#233;ticas &#40;HSCT&#41; se utilice en el tratamiento de trastornos lisosomales y da&#241;o cerebral causado por una deficiencia de enzimas lisosomales solubles&#46; No hay informes previos sobre el tratamiento de NCL con HSCT en China&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Pacientes pedi&#225;tricos de NCL que se sometieron a alo-TCMH en el Hospital de Ni&#241;os Afiliado del Instituto Capital de Pediatr&#237;a involucrados&#46; Se utiliz&#243; una combinaci&#243;n de historias cl&#237;nicas&#44; caracter&#237;sticas cl&#237;nicas y an&#225;lisis gen&#233;ticos para el diagn&#243;stico de todos los pacientes&#46; El formulario de consentimiento por escrito para el allo-TCMH se obtuvo del tutor del paciente&#44; que luego fue revisado y aprobado por el comit&#233; de &#233;tica antes del procedimiento&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">De enero de 2018 a mayo de 2019&#44; se realiz&#243; el haplo-HSCT seguido de TP&#47;Cy en 8 pacientes pedi&#225;tricos con NCL&#46; La mediana de edad fue de 4&#44;5 a&#241;os &#40;variando de 2&#44;8 a 7 a&#241;os&#41;&#46; Los donantes eran sus padres haploid&#233;nticos compatibles con HLA&#44; ya que no se encontraron donantes id&#233;nticos&#46; La mediana del recuento de c&#233;lulas nucleadas fue de 25&#44;37 &#40;10&#8211;34&#44;41&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">8</span>&#47;kg&#44; y la mediana del recuento de CD34<span class="elsevierStyleSup">&#43;</span> fue de 13&#44;7 &#40;8&#44;95-22&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;kg&#46; La reconstituci&#243;n de neutr&#243;filos ocurri&#243; 12 d&#237;as &#40;11-14 d&#237;as&#41; despu&#233;s del trasplante&#44; y el tiempo medio de reconstituci&#243;n plaquetaria fue de 12 d&#237;as &#40;9-14 d&#237;as&#41; despu&#233;s del trasplante&#46; Todos los pacientes alcanzaron quimerismo total del donante y no desarrollaron EICH aguda de grado II-IV o EICH cr&#243;nica despu&#233;s del trasplante&#46; La mediana del per&#237;odo de seguimiento fue de 2&#44;2 &#40;1&#44;5&#8211;2&#44;6&#41; a&#241;os&#46; Todos los pacientes siguen vivos en la actualidad y no desarrollan complicaciones graves relacionadas con el trasplante&#46; Los trastornos mentales motores&#44; las convulsiones miocl&#243;nicas y la p&#233;rdida de visi&#243;n de todos los pacientes continuaron progresando&#46; Sin embargo&#44; la progresi&#243;n se ralentiz&#243; a los 12 meses despu&#233;s del trasplante&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este estudio demostr&#243; que es seguro y eficaz tratar las NCL con haplo-TCMH&#46; El trasplante debe realizarse en una etapa temprana para la calidad de supervivencia de los pacientes pedi&#225;tricos&#46;</p></span>"
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            "apendice" => "<p id="par0100" class="elsevierStylePara elsevierViewall">Juanjuan Li&#44; Jing Cao&#44; Shunqiao Feng</p> <p id="par0105" class="elsevierStylePara elsevierViewall">Department of Hematology&#44; Children&#39;s Hospital of Capital Institute of Pediatrics&#44; Beijing 100020&#44; China</p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Working group"
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            "apendice" => "<p id="par0115" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix B"
            "titulo" => "Supplementary data"
            "identificador" => "sec0085"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Conditioning regimens for patients with NCL&#58; the ATG indicates antithymoglobulin&#59; BM&#44; bone marrow&#59; Bu&#44; busulfan&#59; Cy&#47;CTX&#44; cyclophosphamide&#59; Flu&#44; fludarabine&#59; MMF&#44; mycophenolate mofetil&#59; PB&#44; peripheral blood stem cell&#59; FK506&#44; tacrolimus&#59; IVIG&#44; human immunoglobulin for intravenous injection&#59; and G-CSF&#44; granulocyte colony stimulating factor&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Representative images of abnormal brain MRI in patients&#58; &#40;A&#41; T1WI shows diffuse atrophy of the cerebrum and cerebellum&#44; a thinned cortex&#44; prominent sulci&#44; and enlarged ventricles&#46; &#40;B&#41; T2-FLAIR shows bilateral periventricular hyper-intensity &#40;red arrows&#41;&#46; &#40;C&#41; T2WI shows a mild low signal of bilateral thalami &#40;red arrows&#41;&#46; &#40;D&#41; Brain atrophy progression&#46; T1WI from baseline MRI shows cerebral atrophy &#40;a1 and a2&#41;&#46;</p>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Imaging presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Enzymology of TTP1 &#40;nmol&#47;g&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Genetic analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HLA relationship&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">128&#47;16&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;1&#47;7&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Convulsions&#44; dysarthria&#44; blurred vision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral atrophy&#44; pronounced at bilateral cerebellum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MFSD8</span> &#40;c&#46;553G&#62;A&#44; p&#46;V185I&#59; c&#46;1391C&#62;T&#44; p&#46; A464V&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;12 &#40;Father&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">95&#47;13&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;6&#47;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysarthria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Possible demyelination lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CLN6</span> &#40;c&#46;184C&#62;T&#44; p&#46;R62C&#59; c&#46;158T&#62;C&#44; p&#46;L53P&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#47;12 &#40;Father&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">105&#47;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;9&#47;4&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Convulsions&#44; dysarthria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral atrophy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CLN6</span> &#40;c&#46;184C&#62;T&#44; p&#46;R62C&#59; c&#46;158T&#62;C&#44; p&#46;L53P&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#47;12 &#40;Father&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">114&#47;14&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;5&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Convulsions&#44; dysarthria&#44; unstable gait&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral atrophy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TPP1</span> &#40;c&#46;1361C&#62;A&#44; p&#46;A454E&#59; c&#46;1222&#95;1224del&#44; p&#46;S408del&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#47;12 &#40;Father&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">105&#47;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;1&#47;4&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blurred vision&#44; unstable gait&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral atrophy&#44; pronounced at bilateral cerebellum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MFSD8</span> &#40;c&#46;1102G&#62;C&#44; p&#46;D368H&#59; c&#46;103C&#62;T&#44; p&#46;R35X&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;12 &#40;Father&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&#47;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;5&#47;5&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysarthria&#44; unstable gait&#44; limb tremors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral atrophy&#44; pronounced at bilateral cerebellum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MFSD8</span> &#40;c&#46;416G&#62;A&#44; p&#46;R139H&#59; c&#46;114delG&#44; p&#46;E381Kfs&#42;33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#47;12 &#40;Mother&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">120&#47;17&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;8&#47;5&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysarthria&#44; unstable gait&#44; limb tremors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral atrophy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CLN6</span> &#40;c&#46;794&#95;c&#46;796delCCT&#44; p&#46;S265&#95;F266delinsF&#59; c&#46;826T&#62;G&#44; p&#46;W276G&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;12 &#40;Mother&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Convulsions&#44; limb tremors&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">TPP1</span> &#40;c&#46;1417G&#62;A&#44; p&#46;G473R&#59; c&#46;1613C&#62;A&#44; p&#46;S538Y&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8&#47;12 &#40;Father&#41;&nbsp;\t\t\t\t\t\t\n
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                  """
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                  \t\t\t\t" scope="col">Patient&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grafted cell count</th><th class="td" title="\n
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                  \t\t\t\t" scope="col">NeutrophilReconstitution duration &#40;d&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">30D post-transplantationChimerism &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Follow-up period &#40;months&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Monocyte count&#40;&#215;10<span class="elsevierStyleSup">8</span>&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD34<span class="elsevierStyleSup">&#43;</span> count&#40;&#215;10<span class="elsevierStyleSup">6</span>&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2023.07.029

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