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1.
Am J Med Genet A ; 182(6): 1491-1495, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32216080

RESUMEN

Mucopolysaccharidosis Type IVA (MPS IVA), also known as Morquio A syndrome, is an autosomal recessive lysosomal storage disorder that results from variants in the GALNS gene that encodes the enzyme galactosamine-6-sulfate sulfatase. This syndrome has systemic manifestations including, but not limited to, musculoskeletal, respiratory, cardiovascular, rheumatologic, neurologic, dental, ophthalmologic, and otologic. This condition is usually detected within the first few years of life with an average life expectancy of 25.3 ± 17.43 years. We report the natural history of two of the oldest known females with MPS IVA, who were each clinically diagnosed at 4 years of age and who are now 74 and 70 years of age, respectively. They are both affected by pathogenic variants c.319G>A (p.Ala107Thr) and c.824 T>C (p.Leu275Pro) in the GALNS gene.


Asunto(s)
Condroitinsulfatasas/genética , Mucopolisacaridosis IV/genética , Anciano , Femenino , Humanos , Mucopolisacaridosis IV/epidemiología , Mucopolisacaridosis IV/patología , Mutación/genética
2.
Sci Adv ; 5(9): eaax2166, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31579823

RESUMEN

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.


Asunto(s)
Trastorno Autístico/diagnóstico , Trastorno Autístico/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Variación Genética , Neurogénesis/genética , Proteínas de Unión al ARN/genética , Transmisión Sináptica/genética , Adolescente , Animales , Trastorno Autístico/psicología , Niño , Preescolar , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Estudios de Asociación Genética , Sitios Genéticos , Humanos , Masculino , Ratones , Neuronas/metabolismo , Linaje , Fenotipo , Proteínas de Unión al ARN/metabolismo , Sinapsis/genética , Sinapsis/metabolismo , Adulto Joven
3.
Am J Med Genet A ; 179(10): 2075-2082, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31361404

RESUMEN

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.


Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Facies , Femenino , Humanos , Lactante , Masculino , Fenotipo , Síndrome
4.
Mol Genet Metab ; 127(1): 1-11, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31103398

RESUMEN

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 µmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 µmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.


Asunto(s)
Biopterinas/análogos & derivados , Dieta , Fenilcetonurias/dietoterapia , Fenilcetonurias/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Biopterinas/uso terapéutico , Consenso , Femenino , Humanos , Internacionalidad , Fenilcetonurias/diagnóstico , Médicos , Embarazo
5.
Am J Hum Genet ; 104(6): 1073-1087, 2019 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-31079899

RESUMEN

Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290∗) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.


Asunto(s)
Anomalías Craneofaciales/etiología , Dineínas/genética , Discapacidad Intelectual/etiología , Malformaciones Arteriovenosas Intracraneales/etiología , Microcefalia/etiología , Mutación , Pez Cebra/crecimiento & desarrollo , Adulto , Alelos , Secuencia de Aminoácidos , Animales , Preescolar , Anomalías Craneofaciales/patología , Dineínas/química , Dineínas/metabolismo , Exoma , Femenino , Homocigoto , Humanos , Lactante , Discapacidad Intelectual/patología , Malformaciones Arteriovenosas Intracraneales/patología , Masculino , Microcefalia/patología , Linaje , Fenotipo , Conformación Proteica , Homología de Secuencia , Secuenciación del Exoma , Adulto Joven , Pez Cebra/genética , Pez Cebra/metabolismo
6.
J Med Genet ; 54(7): 460-470, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28377535

RESUMEN

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.


Asunto(s)
Encefalopatías/genética , Mutación/genética , Receptores de N-Metil-D-Aspartato/genética , Encefalopatías/tratamiento farmacológico , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Memantina/uso terapéutico , Terapia Molecular Dirigida , Neuroimagen , Fenotipo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo
7.
Genet Med ; 18(3): 239-48, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26795590

RESUMEN

PURPOSE: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006. METHODS: Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination. RESULTS: Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease. CONCLUSIONS: The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.


Asunto(s)
Galactosilceramidasa/genética , Galactosilceramidasa/metabolismo , Leucodistrofia de Células Globoides/diagnóstico , Tamizaje Neonatal/métodos , Polimorfismo de Nucleótido Simple , Algoritmos , Pruebas con Sangre Seca , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recién Nacido , Leucodistrofia de Células Globoides/enzimología , Leucodistrofia de Células Globoides/terapia , Espectrometría de Masas , New York , Valor Predictivo de las Pruebas , Resultado del Tratamiento
8.
Pediatr Clin North Am ; 62(2): 411-26, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25836705

RESUMEN

Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes.


Asunto(s)
Trastornos de los Cromosomas/diagnóstico , Epigénesis Genética , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 18 , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/diagnóstico , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Metilación de ADN , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de Down/diagnóstico , Asesoramiento Genético , Humanos , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/genética , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Trisomía/diagnóstico , Síndrome de la Trisomía 13 , Síndrome de la Trisomía 18 , Síndrome de Turner/diagnóstico , Síndrome de Turner/genética , Síndrome WAGR/diagnóstico , Síndrome WAGR/genética , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética
9.
J Pediatr ; 158(3): 410-5, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20884009

RESUMEN

OBJECTIVE: To describe patient selection, treatment administration, response evaluation, and side effect management associated with sapropterin therapy in infants and children aged <4 years. STUDY DESIGN: Six case reports are presented from 4 US metabolic clinics treating phenylketonuria with sapropterin in patients aged 7 months to 4 years. Outcomes included blood phenylalanine (Phe) levels before and during treatment. For 3 of 6 cases, diet records were used to monitor changes in dietary Phe. RESULTS: Severity of phenylketonuria ranged from mild to severe (classic). Treatment with sapropterin was safe and generally well tolerated. Blood Phe levels were reduced, or maximum dietary Phe tolerance was increased in patients with blood Phe that was well controlled by diet. CONCLUSIONS: Given the increasing evidence that maintaining blood Phe levels below 360 µmol/L is important for the normal development of neurocognitive and behavioral function, sapropterin can be combined with a Phe-restricted diet to control blood Phe levels in young patients responsive to sapropterin therapy.


Asunto(s)
Biopterinas/análogos & derivados , Fenilcetonurias/tratamiento farmacológico , Biopterinas/administración & dosificación , Biopterinas/efectos adversos , Biopterinas/uso terapéutico , Preescolar , Femenino , Humanos , Lactante , Masculino , Selección de Paciente , Fenilalanina/sangre , Resultado del Tratamiento
10.
Mol Genet Metab ; 99(3): 263-8, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20036593

RESUMEN

INTRODUCTION: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. METHOD: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. RESULTS: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. DISCUSSION: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.


Asunto(s)
Acil-CoA Deshidrogenasas/deficiencia , Acil-CoA Deshidrogenasas/genética , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/fisiopatología , Tamizaje Neonatal/métodos , Carnitina/análogos & derivados , Carnitina/sangre , Ácidos Grasos/metabolismo , Femenino , Genotipo , Humanos , Recién Nacido , Masculino , Errores Innatos del Metabolismo/genética , Mutación , New York , Fenotipo , Pronóstico
11.
Genet Med ; 12(1): 19-24, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20027113

RESUMEN

BACKGROUND: Systemic primary carnitine deficiency is an autosomal recessive disorder of the carnitine cycle caused by mutations in the SLC22A5 gene that encodes the carnitine transporter, organic cation transporter. Systemic primary carnitine deficiency typically presents in childhood with either metabolic decompensation or cardiomyopathy. We report five families in which low free carnitine levels in the infants' newborn screening have led to the diagnosis of maternal systemic primary carnitine deficiency. METHODS: Blood samples from the infants and /or their family members were used to extract the DNA. The entire coding regions of the SLC22A5 gene were sequenced. The clinical data were obtained from the referring metabolic specialists. RESULT: Sequencing the SLC22A5 gene allowed molecular confirmation with identification of three novel mutations: c.1195C>T (p.R399W), c.1324_1325GC>AT (p.A442I), and c.43G>T (p.G15W). All infants were asymptomatic at the time of diagnosis, and one was found to have systemic primary carnitine deficiency. Three mothers are asymptomatic, one had decreased stamina during pregnancy, and one has mild fatigability and developed preeclampsia. DISCUSSION: These findings provide further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from a metabolic decompensation in infancy to an asymptomatic adult. The maternal systemic primary carnitine deficiency was uncovered by the newborn screening results supporting the previous notion that newborn screening can identify some of the maternal inborn errors of metabolism. It also emphasizes the importance of maternal evaluation after identification of a low free carnitine level in the newborn screening.


Asunto(s)
Carnitina/deficiencia , Enfermedades del Recién Nacido/diagnóstico , Tamizaje Neonatal/métodos , Adulto , Carnitina/sangre , Preescolar , Familia , Femenino , Humanos , Lactante , Recién Nacido , Enfermedades del Recién Nacido/sangre , Tamizaje Masivo , Intercambio Materno-Fetal , Mutación , Proteínas de Transporte de Catión Orgánico/genética , Embarazo , Miembro 5 de la Familia 22 de Transportadores de Solutos
12.
Pediatr Neurol ; 40(4): 245-52; discussion 253-5, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19302934

RESUMEN

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.


Asunto(s)
Leucodistrofia de Células Globoides/diagnóstico , Tamizaje Neonatal/organización & administración , Tamizaje Neonatal/normas , Análisis Mutacional de ADN , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Potenciales Evocados Visuales/fisiología , Estudios de Seguimiento , Galactosilceramidasa/análisis , Galactosilceramidasa/metabolismo , Trasplante de Células Madre Hematopoyéticas , Humanos , Recién Nacido , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Imagen por Resonancia Magnética , Modelos Organizacionales , Conducción Nerviosa/fisiología , Examen Neurológico , New York , Derivación y Consulta , Medición de Riesgo , Resultado del Tratamiento
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