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1.
J Huntingtons Dis ; 12(4): 377-380, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38073394

RESUMEN

The term "senile chorea" was previously used to describe cases of insidious onset chorea in elderly patients who lacked family history of chorea. However, many of these patients have an identifiable etiology for their chorea. In this article, we discuss a case of generalized, insidious onset chorea in an 89-year-old man and apply a systematic diagnostic approach to chorea in the elderly to arrive at a diagnosis of late-onset Huntington's disease. He is to our knowledge the second oldest case of late-onset Huntington's disease reported in the literature and his case lends support to the expanding phenotype of Huntington's disease.


Asunto(s)
Corea , Enfermedad de Huntington , Masculino , Anciano de 80 o más Años , Humanos , Anciano , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Corea/diagnóstico , Corea/etiología , Octogenarios , Diagnóstico Diferencial
2.
Artículo en Inglés | MEDLINE | ID: mdl-37637852

RESUMEN

Background: Epsilon-sarcoglycan (SGCE) myoclonus-dystonia is autosomal dominant (AD) with reduced penetrance due to maternal imprinting 95% of the time. Patients may lack family history delaying diagnosis and treatment. Additionally, counseling patients on their risk of passing on the variant differs for females versus males. Case Report: A woman in her thirties with typical phenotype of myoclonus-dystonia but lacking an AD pedigree was found to have a pathogenic variant in the SGCE gene. She was counseled that her daughters each have a 2.5% chance of expressing the phenotype. Discussion: Understanding the genetics of SGCE-myoclonus-dystonia enables effective genetic counseling and arrival at a timely diagnosis and treatment. Summary: In an era of advancing genetic analysis and precision medicine-based treatments, neurologists will be faced with increasing responsibility to properly counsel patients on the results of genetic testing. This case highlights a genetics pearl for counseling patients with epsilon-sarcoglycan myoclonus-dystonia, an autosomal dominant condition with penetrance differing by sex.


Asunto(s)
Trastornos Distónicos , Femenino , Humanos , Masculino , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/tratamiento farmacológico , Trastornos Distónicos/genética , Sarcoglicanos/genética
4.
JIMD Rep ; 48(1): 26-35, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31392110

RESUMEN

Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched-chain 2-ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched-chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary-specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1. SYNOPSIS: Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis.

5.
Pediatr Clin North Am ; 65(2): 209-230, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29502910

RESUMEN

When a child presents with high-anion gap metabolic acidosis, the pediatrician can proceed with confidence by recalling some basic principles. Defects of organic acid, pyruvate, and ketone body metabolism that present with acute acidosis are reviewed. Flowcharts for identifying the underlying cause and initiating life-saving therapy are provided. By evaluating electrolytes, blood sugar, lactate, ammonia, and urine ketones, the provider can determine the likelihood of an inborn error of metabolism. Freezing serum, plasma, and urine samples during the acute presentation for definitive diagnostic testing at the provider's convenience aids in the differential diagnosis.


Asunto(s)
Acidosis/diagnóstico , Errores Innatos del Metabolismo/diagnóstico , Acidosis/etiología , Acidosis/terapia , Diagnóstico Diferencial , Humanos , Recién Nacido , Cetonas/sangre , Errores Innatos del Metabolismo/terapia , Tamizaje Neonatal/métodos
6.
Ann Neurol ; 83(4): 703-717, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29466837

RESUMEN

OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit ß1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala). METHODS: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria. RESULTS: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels. INTERPRETATION: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703-717.


Asunto(s)
Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.3/genética , Canales de Sodio/genética , Espasmos Infantiles/genética , Adolescente , Adulto , Análisis de Varianza , Línea Celular Transformada , Preescolar , Estudios de Cohortes , Estimulación Eléctrica , Femenino , Humanos , Lacosamida/farmacología , Imagen por Resonancia Magnética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Modelos Moleculares , Técnicas de Placa-Clamp , Fenitoína/farmacología , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/fisiopatología , Transfección , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología
7.
Ann Neurol ; 82(3): 466-478, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28856709

RESUMEN

OBJECTIVE: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions. METHODS: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole-exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models. RESULTS: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. INTERPRETATION: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.


Asunto(s)
Mutación , Receptores de GABA-B/genética , Síndrome de Rett/genética , Espasmos Infantiles/genética , Exoma , Genotipo , Células HEK293 , Humanos , Proteína 2 de Unión a Metil-CpG/genética , Fenotipo , Transducción de Señal/genética
8.
Pediatr Neurol ; 73: 101-105, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28647130

RESUMEN

BACKGROUND: We identified a group of patients with ATP1A3 mutations at residue 756 who display a new phenotype, distinct from alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndromes. METHODS: Four patients with c.2267G>A (R756H) mutations from two families and two patients with c.2267G>T (R756L) mutations from one family are described and compared with the previously reported patients with mutations resulting in R756H and R756C protein variants. RESULTS: Patients with ATP1A3 R756H have onset in childhood of infrequent, fever-triggered paroxysms of encephalopathy and weakness with slowly improving but persistent deficits. Motor findings of weakness are mostly generalized, and patients may also have bulbar or oculomotor problems. Longer-term outcomes range from mild motor apraxia with near-normal function to persistent dysphagia, dysarthria, cognitive deficit, motor apraxia, and inability to walk because of ataxia. Patients with ATP1A3 R756L have a similar phenotype that includes paroxysmal, stepwise progression of ataxia associated with infections. CONCLUSIONS: ATP1A3 mutations affecting residue 756 result in a clinical syndrome, separate from those associated with previously described ATP1A3 mutations, which consists chiefly of fever-induced paroxysmal weakness and encephalopathy (FIPWE). Patients with R756L and R756C protein variants display more prominent ataxia, overlapping with the relapsing encephalopathy with cerebellar ataxia syndrome previously described in a patient with the c.2266C>T (R756C) mutation. All patients reported with mutations at residue 756 to date have had a similar episodic course and clinical features. Patients with mutations of ATP1A3 residue 756 appear to have a distinct clinical phenotype compared with patients with other ATP1A3 mutations, with fever-induced encephalopathy as key differentiating feature.


Asunto(s)
Encefalopatías/etiología , Fiebre/complicaciones , Fiebre/genética , Debilidad Muscular/complicaciones , Mutación/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Niño , Salud de la Familia , Femenino , Humanos , Masculino , Fenotipo
9.
Mol Genet Metab ; 120(4): 342-349, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28202214

RESUMEN

Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and cerebrospinal fluid lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain α-ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts were normal. Oxidative phosphorylation analysis on intact digitonin-permeabilized fibroblasts was suggestive of slightly reduced PDC activity relative to control range in mitochondria. We reviewed 16 other cases with mutations in ECHS1 where PDC activity was also assayed in order to determine how common and generalized secondary PDC deficiency is associated with primary SCEH deficiency. For reasons that remain unexplained, we find that about half of cases with primary SCEH deficiency also exhibit secondary PDC deficiency. The patient died on day-of-life 39, prior to establishing his diagnosis, highlighting the importance of early and rapid neonatal diagnosis because of possible adverse effects of certain therapeutic interventions, such as administration of ketogenic diet, in this disorder. There is a need for better understanding of the pathogenic mechanisms and phenotypic variability in this relatively recently discovered disorder.


Asunto(s)
Enoil-CoA Hidratasa/deficiencia , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/mortalidad , Análisis de Secuencia de ADN/métodos , Enoil-CoA Hidratasa/genética , Exoma , Humanos , Recién Nacido , Masculino , Polimorfismo de Nucleótido Simple , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética
10.
Mol Genet Metab ; 120(3): 213-222, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27913098

RESUMEN

Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 developed Leigh syndrome, severe GI dysmotility, intermittent anemia, hypogammaglobulinemia and eventually succumbed to his disorder. The mitochondrial DNA contents in skeletal muscle (SM) were normal in both siblings. Pyruvate dehydrogenase complex, ketoglutarate dehydrogenase complex, and several mitochondrial electron transport chain (ETC) activities were low or at the low end of the reference range in frozen SM from S1 and/or S2. In contrast, activities of PDC, other mitochondrial enzymes of pyruvate metabolism, ETC and, integrated oxidative phosphorylation, in skin fibroblasts were not significantly impaired. Although we show that propionyl-CoA inhibits PDC, it does not appear to account for decreased PDC activity in SM. A better understanding of the mechanisms of phenotypic variability and the etiology for tissue-specific secondary deficiencies of mitochondrial enzymes of oxidative metabolism, and independently mitochondrial DNA depletion (common in other cases of A-SCS deficiency), is needed given the implications for control of lactic acidosis and possible clinical management.


Asunto(s)
Enfermedades Mitocondriales/genética , Músculo Esquelético/enzimología , Polimorfismo de Nucleótido Simple , Succinato-CoA Ligasas/deficiencia , Adolescente , Niño , ADN Mitocondrial/genética , Resultado Fatal , Humanos , Masculino , Enfermedades Mitocondriales/enzimología , Músculo Esquelético/metabolismo , Eliminación de Secuencia , Hermanos , Succinato-CoA Ligasas/genética
11.
Neurocase ; 22(5): 476-483, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27801611

RESUMEN

Young onset dementias present significant diagnostic challenges. We present the case of a 35-year-old Kuwaiti man with social withdrawal, drowsiness, irritability, anxiety, aphasia, memory loss, hypereflexia, and Parkinsonism. Brain MRI showed bilateral symmetric gradient echo hypointensities in the globi pallidi and substantiae nigrae. Left cortical hypometabolism was seen on brain fluorodeoxyglucose positron emission tomography. A cortical brain biopsy revealed a high Lewy body burden. Genetic testing revealed a homozygous p.T11M mutation in the C19orf12 gene consistent with mitochondrial membrane protein-associated neurodegeneration. This is the oldest onset age of MPAN reported.


Asunto(s)
Proteínas Mitocondriales/genética , Mutación/genética , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/genética , Adulto , Salud de la Familia , Pruebas Genéticas , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones
13.
PLoS One ; 10(5): e0127045, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25996915

RESUMEN

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.


Asunto(s)
Hemiplejía/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Hemiplejía/fisiopatología , Humanos , Lactante , Masculino , Sistema de Registros
14.
Mitochondrion ; 14(1): 26-33, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23891656

RESUMEN

Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.


Asunto(s)
Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/terapia , Médicos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Humanos , Enfermedades Mitocondriales/prevención & control , América del Norte
15.
Mol Genet Metab ; 107(3): 394-402, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23021068

RESUMEN

Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DLAT, n = 2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained. 39% of these subjects (23/59) have died. Of these, 91% (21/23) died before age 4 years, 61% (14/23) before 1 year, and 43% (10/23) before 3 months. 56% of males died compared with 25% of females. Causes of death included severe lactic acidosis, respiratory failure, and infection. In subjects surviving past 6 months, a broad range of intellectual outcomes was observed. Of 42 subjects whose intellectual abilities were professionally evaluated, 19% had normal or borderline intellectual ability (CQ/IQ ≥ 70), 10% had mild intellectual disability (ID) (CQ/IQ 55-69), 17% had moderate ID (CQ/IQ 40-54), 24% had severe ID (CQ/IQ 25-39) and 33% had profound ID (CQ/IQ<25). Assessment by parents was comparable. Of 10 subjects who reached age 12 years, 9 had had professional IQ assessments, and only 4 had IQs ≥ 70 (only 2 of these 4 had assessments after age 12 years). The average outcome for females was severe-to-profound ID, whereas that of males was mild-to-moderate ID. Of subjects for whom specific neurological data were available, the majority had hypotonia (89%), and hypertonia or mixed hyper-/hypotonia (49%) were common. Seizures (57%), microcephaly (49%), and structural brain abnormalities including ventriculomegaly (67%) and agenesis, dysgenesis, or hypoplasia of the corpus callosum (55%) were common. Leigh syndrome was found in only 35%. Structural brain abnormalities were more common in females, and Leigh syndrome was more common in males. In a subgroup of 16 ambulatory subjects >3.5 years in whom balance was evaluated, ataxia was found in 13. Peripheral neuropathy was documented in 2 cases but not objectively evaluated in most subjects. Outcomes of this population with genetically confirmed PDC deficiency are heterogeneous and not distinctive. Correlations between specific genotypes and outcomes were not established. Although more females survive, related to the prevalence of X-linked PDHA1 mutations, symptomatic surviving females are generally more severely impaired cognitively and have a different pattern of neurological impairment compared to males. Neonatal or infant onset of symptoms was associated with poor outcomes. Males with PDHA1 mutations and low fibroblast PDC activity were less likely to survive beyond infancy. Recurrence rate in siblings of subjects with PDHA1 mutation was less than 5%. Paradoxically, in this retrospective review, potential factors considered possibly relevant to development, such as in vitro PDC activity, specific mutations, use of ketogenic diets, supplements, or medications, were generally not confirmed to be significantly correlated with objective outcomes of survival or neuro-cognitive function. Therefore, the basis of variability of these outcomes remains largely undetermined.


Asunto(s)
Autoantígenos/genética , Acetiltransferasa de Residuos Dihidrolipoil-Lisina/genética , Enfermedad de Leigh/genética , Proteínas Mitocondriales/genética , Mutación , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Niño , Preescolar , Cognición , Femenino , Heterogeneidad Genética , Genotipo , Humanos , Lactante , Enfermedad de Leigh/mortalidad , Enfermedad de Leigh/patología , Masculino , Linaje , Fenotipo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/mortalidad , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/patología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores Sexuales , Tasa de Supervivencia
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