RESUMEN
BACKGROUND Influenza-associated acute necrotizing encephalopathy (IANE) can be lethal and disabling and have a sudden onset and deteriorate rapidly but lacks early diagnostic indicators. We aimed to examine the early clinical diagnostic indicators in children with IANE. MATERIAL AND METHODS Acute influenza patients were grouped according to their clinical manifestations: flu alone (FA), flu with febrile seizure (FS), influenza-associated encephalopathy (IAE), and IANE. The clinical features, biomarkers, neuroelectrophysiological results, and neuroimaging examination results were compared. RESULTS A total of 31 patients were included (FA (n=4), FS (n=8), IAE (n=14), and IANE (n=5)). The IANE group, whose mean age was 3.7 years, was more likely to show rapid-onset seizure, acute disturbance of consciousness (ADOC), Babinski's sign, and death/sequela. More patients in the IANE group required tracheal intubation mechanical ventilation and received intravenous immunoglobulins (IVIG) and glucocorticoids. The alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels in the IANE group were significantly higher than in the FS and IAE groups. The aquaporin-4 (AQP-4) antibody and malondialdehyde (MDA) levels in the serum and cerebrospinal fluid (CSF) were notably higher in IANE patients in the acute stage compared with FS and IAE patients. All patients in the IANE group had positive neuroimaging findings. CONCLUSIONS Early clinical warning factors for IANE include rapid-onset seizures in patients under 4 years of age, ADOC, and pathological signs. Increased AQP-4 antibodies and MDA levels in CSF might contribute to early diagnosis. Early magnetic resonance venography (MRV) and susceptibility-weighted imaging (SWI) sequences, or thrombelastography to identify deep vein thrombosis, might indicate clinical deterioration.
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Encefalopatías/diagnóstico , Gripe Humana/diagnóstico , Enfermedad Aguda , Alanina Transaminasa/sangre , Alanina Transaminasa/metabolismo , Acuaporinas/sangre , Acuaporinas/metabolismo , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Encefalopatías/sangre , Encefalopatías/metabolismo , Líquido Cefalorraquídeo/metabolismo , Preescolar , Femenino , Glucocorticoides/sangre , Glucocorticoides/metabolismo , Humanos , Inmunoglobulinas Intravenosas/sangre , Inmunoglobulinas Intravenosas/metabolismo , Gripe Humana/sangre , Gripe Humana/metabolismo , L-Lactato Deshidrogenasa/sangre , L-Lactato Deshidrogenasa/metabolismo , Masculino , Malondialdehído/sangre , Malondialdehído/metabolismo , Neuroimagen/métodos , Convulsiones/sangre , Convulsiones/diagnóstico , Convulsiones/metabolismoRESUMEN
Gaucher disease (GD) is a common lysosomal storage disorder caused by the deficiency of acid ß-glucosidase, due to mutations in the GBA gene. To explore the clinical and molecular characteristics of GD patients from Southern China, GBA gene were analyzed by nest PCR and direct Sanger-sequencing. Novel missense mutations were transiently transfected in COS-7 cells by plasmid system for functional verification. Among the 22 GD patients, 19 patients were classified as type 1 and three as type 2. Over 60% of the type 1 patient had the onset before two years of age and about 42% of them died before three years of age. Six type 1 patients with L444P homozygous genotype, presented with early onset and severe hepatosplenomegaly. Four novel mutations Y22C, F109L, L149F and c.983_990delCCCACTGG were identified. The GBA activities in vitro of novel mutants Y22C, F109L and L149F were 20.2%, 6.9% and 6.5% of the wild-type, respectively. L444P mutation accounted for 47.7% of the mutant alleles. Our results revealed that type 1 GD tends to present with a severe phenotype among southern Chinese. L444P was the most prevalent mutation and L444P homozygous genotype was associated with severe type 1 GD. Three novel missense mutations identified were pathogenic.
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Enfermedad de Gaucher/genética , Glucosilceramidasa/genética , Mutación , Adolescente , Adulto , Anciano , Animales , Pueblo Asiatico/genética , Células COS , Niño , Preescolar , China/epidemiología , Chlorocebus aethiops , Femenino , Enfermedad de Gaucher/epidemiología , Genotipo , Glucosilceramidasa/química , Homocigoto , Humanos , Lactante , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mutación Missense , Mutación Puntual , Conformación Proteica , Adulto JovenRESUMEN
Sandhoff disease (SD) is a rare autosomal recessive lysosomal storage disorder of sphingolipid metabolism resulting from the deficiency of ß-hexosaminidase (HEX). Mutations of the HEXB gene cause Sandhoff disease. In order to improve the diagnosis and expand the knowledge of the disease, we collected and analyzed relevant data of clinical diagnosis, biochemical investigation, and molecular mutational analysis in five Chinese patients with SD. The patients presented with heterogenous symptoms of neurologic deterioration. HEX activity in leukocytes was severely deficient. We identified seven different mutations, including three known mutations: IVS12-26G > A, p.T209I, p.I207V, and four novel mutations: p.P468PfsX62, p.L223P, p.Y463X, p.G549R. We also detected two different heterozygous mutations c.-122delC and c.-126C > T in the promoter which were suspected to be deleterious mutations. We attempted to correlate these mutations with the clinical presentation of the patients. Our study indicates that the mutation p.T209I and p.P468PfsX62 may link to the infantile form of SD. Our study expands the spectrum of genotype of SD in China, provides new insights into the molecular mechanism of SD and helps to the diagnosis and treatment of this disease.
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Mutación , Enfermedad de Sandhoff/diagnóstico , Cadena beta de beta-Hexosaminidasa/genética , Niño , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Masculino , Linaje , Regiones Promotoras Genéticas , Enfermedad de Sandhoff/genética , Enfermedad de Sandhoff/metabolismo , Evaluación de SíntomasRESUMEN
This article reported the clinical manifestations, steroid profiles and adrenal ultrasound findings in two unrelated Chinese girls with lipoid congenital adrenal hyperplasia (LCAH). Direct DNA sequencing and restriction fragment length polymorphism (RFLP) analysis were used to identify the mutations of steroidogenic acute regulatory protein (StAR) gene. The two patients with 46,XX karyotype, presented hyperpigmentation, growth retardation, and hyponatremia. Steroid profiles analysis revealed elevated plasma adrenocorticotrophic hormone levels, decreased or normal serum cortisol levels and low levels of androgens. Ultrasound examinations revealed that enlarged adrenals in patient 1 and normal adrenals in patient 2. Direct DNA sequencing of StAR gene showed a reported homozygous for c.772C>T(p.Q258X) in patient 1. Compound heterozygous for c.367G>A(p.E123K) and IVS4+2T>A (both novel mutations) were found in patient 2, inherited from her mother and father respectively. The amino acid of mutant position of the novel p.E123K was highly conserved in ten different species and was predicted to have impacts on the structure and function of StAR protein by the PolyPhen-2 prediction software. RFLP analysis revealed three bands (670, 423 and 247 bp) in patient 2 and her father and two bands (423 and 247 bp) in her mother and 50 controls. It is concluded that LCAH should be considered in girls with early onset of adrenal insufficiency and that steroid profiles, karyotype analysis, adrenal ultrasound and StAR gene analysis may be helpful for the definite diagnosis of LCAH.
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Hiperplasia Suprarrenal Congénita/genética , Trastorno del Desarrollo Sexual 46,XY/genética , Mutación , Fosfoproteínas/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Secuencia de Aminoácidos , Niño , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Femenino , Humanos , Lactante , Recién Nacido , Datos de Secuencia Molecular , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
OBJECTIVE: To explore the clinical features and molecular mutation of HEXB gene in a case with juvenile Sandhoff disease. METHOD: We retrospectively reviewed the clinical, neuroimaging and biochemical findings in this Chinese child with juvenile Sandhoff disease. Hexosaminidase A and hexosaminidase A & B activities were measured in blood leukocytes by fluorometric assay. HEXB gene molecular analysis was performed by PCR and direct sequencing. RESULT: The 9-year-old boy was admitted for psychomotor regression. He presented slowly progressive gait disorder and dysarthria during the last three years. Cranial MRI revealed a marked cerebellar atrophy with normal intensity in the thalamus and basal ganglia. Brain MRS showed normal in the thalamus and basal ganglia. Hexosaminidase A was 69.5 (mg·h) [normal controls 150-360 nmol/(mg·h)], hexosaminidase A & B activity was 119 nmol/(mg·h)[normal controls 600-3 500 nmol/(mg·h)], confirming the diagnosis of Sandhoff disease. The patient was a compound heterozygote for a novel deletion mutation c.1404delT (p. P468P fsX62) and a reported mutation c.1509-26G>A. CONCLUSION: The clinical features of juvenile Sandhoff disease include ataxia, dysarthria and cerebellar atrophy. The enzyme assay and molecular analysis of HEXB gene can confirm the diagnosis of Sandhoff disease. The novel mutation c.1404delT(p. P468P fsX62) is a disease-related mutation.
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Mutación , Enfermedad de Sandhoff/diagnóstico , Enfermedad de Sandhoff/genética , Cadena beta de beta-Hexosaminidasa/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/enzimología , Ataxia Cerebelosa/genética , Niño , Análisis Mutacional de ADN , Heterocigoto , Hexosaminidasa A/sangre , Hexosaminidasa A/metabolismo , Hexosaminidasa B/sangre , Hexosaminidasa B/metabolismo , Humanos , Leucocitos/enzimología , Imagen por Resonancia Magnética , Masculino , Radiografía , Estudios Retrospectivos , Enfermedad de Sandhoff/enzimologíaRESUMEN
OBJECTIVE: Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase B(ARSB), which is required in the degradation of dermatan sulfate and chondroitin sulfate. The deficiency of ARSB leads to an accumulation of dermatan sulfate and chondroitin sulfate in lysosomes and gross excretion in the urine.Few articles about clinical study and ARSB gene mutation analysis of Chinese MPS VI patients were published. This study aimed to explore the clinical features and characteristics of ARSB gene in Chinese children with MPS VI. METHOD: Thirteen children were diagnosed as MPS VI by ARSB enzyme activity determination during the period from 2009 to 2013. Their clinical features, radiological findings and urine glycosaminoglycan (GAG) levels were retrospectively reviewed. Direct sequencing was used to identify any mutation in the ARSB gene. RESULT: Thirteen children were diagnosed at the average age of (3.9 ± 2.2) years with 6 male and 7 female. All of these children presented with severe form and onset at an early age of (1.5 ± 0.8) years.Other clinical features included coarse facies, short stature, skeleton deformity, corneal clouding, hepatosplenomegaly with normal intelligence. The radiological findings in all children were characteristic of dysostosis multiplex, like abnormal development of vertebral bodies of the spine, campylorrhachia and paddle-shaped widened ribs. The MRI in case 2 showed cervical cord compression and multiple cysts degeneration in the corona radiate, cella lateralis and callosum.High urine GAG levels were detected, (307.10 ± 112.14) mg/L (Normally below 70 mg/L) and (722.28 ± 245.68) µg/mg creatinine. The ARSB enzyme activity in leukocytes was low, (13.29 ± 6.22) nmol/(mg×h) [Normal range (47-169) nmol/(mg×h)] by fluorogenic assay and (0.24 ± 0.18) U/g [Normal range (1.01-11.47) U/g] by colorimetric assay. A total of 11 mutations were identified by molecular analysis, including seven previously reported mutations (p.L72R, p.G167R, p.G303E, p.F399L, p. T442M, p.Y255X and p.R327X) and four novel mutations (p.Y175D, p.S403X, p.S464X and large deletion including ex. 2, 3). The c.1197C>G (p.F399L) mutation was the most common mutation in this study (31%). CONCLUSION: The severe form of MPS VI is characterized by early onset and rapid illness progression. Both the radiological findings and increased urine GAG are important clues to diagnose MPS VI.Large decrease or absence of ARSB activity is diagnostic for MPS VI.Four novel mutations of ARSB gene were identified. The reported mutation c.1197C>G (p.F399L) was the hot-spot mutation in this study.
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Mucopolisacaridosis VI/diagnóstico , Mucopolisacaridosis VI/genética , Mutación , N-Acetilgalactosamina-4-Sulfatasa/genética , N-Acetilgalactosamina-4-Sulfatasa/metabolismo , Huesos/diagnóstico por imagen , Huesos/patología , Encéfalo/patología , Niño , Preescolar , Exones/genética , Femenino , Glicosaminoglicanos/orina , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Mucopolisacaridosis VI/enzimología , Reacción en Cadena de la Polimerasa , Radiografía , Estudios Retrospectivos , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: 3ß- hydroxysteroid dehydrogenase deficiency (3ßHSD), a rare form of congenital adrenal hyperplasia (CAH) resulted from mutations in the HSD3B2 gene that impair steroidogenesis in both adrenals and gonads. We report clinical features and the results of HSD3B2 gene analysis of a Chinese pubertal girl with salt wasting 3ßHSD deficiency. METHOD: We retrospectively reviewed clinical presentations and steroid profiles of the patient diagnosed in Guangzhou Women and Children's Medical Center in 2013. PCR and direct sequencing were used to identify any mutation in the HSD3B2 gene. RESULT: A 13-year-old girl was diagnosed as CAH after birth because of salt-wasting with mild clitorimegaly and then was treated with glucocorticoid replacement. Breast and pubic hair development were normal, and menarche occurred at 12 yr, followed by menstrual bleeding about every 45 days. In the last one year laparoscopic operation and ovariocentesis were performed one after another for recurrent ovary cysts. Under corticoid acetate therapy, ACTH 17.10 pmol/L (normal 0-10.12), testosterone 1.31 nmol/L (normal <0.7), dehydroepiandrosterone sulfate 13.30 µmol/L (normal 0.95 - 11.67), cortisol 720 nmol/L (normal 130-772.8), androstenedione, 17-hydroxyprogesterone and progesterone were normal. Estradiol 461 pmol/L, follicle-stimulating hormone 3.04 IU/L, luteinizing hormone 8.52 IU/L in follicular phase. A pelvic ultrasound showed lateral ovaries cysts (58 mm × 50 mm × 35 mm) and a midcycle-type endometrium. A novel nonsense mutation c.73G >T (p.E25X) was identified in HSD3B2 gene. The girl was homozygous and her mother was heterozygous, while her father was not identified with this mutation. CONCLUSION: A classic 3ßHSD deficiency is characterized by salt wasting and mild virilization in female. Ovary cysts may be the one of features of gonad phenotype indicating ovary 3ßHSD deficiency. A novel homozygous mutation c.73G >T(p.E25X) was related to the classical phenotype.
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Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Mutación/genética , Quistes Ováricos/genética , Progesterona Reductasa/genética , 17-alfa-Hidroxiprogesterona , Adolescente , Androstenodiona , China , Codón sin Sentido , Diagnóstico Tardío , Femenino , Hormona Folículo Estimulante , Homocigoto , Humanos , Hidrocortisona , Hormona Luteinizante , Recurrencia , Estudios RetrospectivosRESUMEN
Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Molecular mutational analysis was performed by PCR product sequencing for fourteen exons and exon-intron boundaries of GALNS gene in 21 patients from 19 unrelated families with severe MPS IVA in South China. We identified fifteen different mutations, including 10 reported mutations (p.P125L, p.G290S, p.M318R, p.G340D, p.L366P, p.R386C, p.A392V, c.1243-1G>C, p.L440RfsX54 and p.X523E) and five novel mutations (p.N177S, p.G290R, p.F306S, p.W403_T404delinsCS, p.W520X). All five novel mutations were inherited from parents of the patients and not found in 100 normal control alleles. Three mutations, p.M318R, p.L366P and p.R386C were common, accounting for 36.8% of mutant alleles investigated. One patient homozygous of p.A392V and the other two unrelated patients homozygous of p.L366P presented classical disease course. The results show that the GALNS gene has a different mutational spectrum in South China as compared to other regions. The p.A392V and p.L366P mutations were associated with severe phenotype of MPS IVA.