RESUMEN
Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.
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Trastornos de Impronta , Síndrome de Silver-Russell , Recién Nacido , Femenino , Embarazo , Humanos , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patología , Metilación de ADN/genética , Fenotipo , Disomía Uniparental/genéticaRESUMEN
Background: 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome exhibiting significant clinical phenotype variability. This study aimed to investigate the clinical features, immune profiles, and cognitive abilities of 22q11.2DS patients receiving treatment at MacKay Memorial Hospital in Taipei, Taiwan. Methods: This is a cross-sectional analysis between January 2001 and December 2022. We recruited 27 patients with 22q11.2DS using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). Our evaluation included patient history, physical examination, laboratory analysis, and cardiac and cognitive assessment. Results: We included 27 patients with 22q11.2DS, 7 (25.9%) of whom were female. The median age of the patients was 17.9 yr. Ninety-three percent of the patients exhibited the characteristic facial features associated with the syndrome. A family history of 22q11.2DS was found in 11.1% of the patients. Furthermore, 74.1% of the patients had a congenital heart defect, the most common of which was tetralogy of Fallot (40.7%). Hypocalcemia was observed in 40.7% of the patients. A low T-cell count was observed in 66.7% of the patients, whereas 18.5% had low immunoglobulin levels. Cognitive assessments revealed that four out of six evaluated patients (66.7%) had an intellectual disability, as evidenced by intellectual quotient scores less than 70. The remaining two patients (33.3%) had a borderline intellectual function. Conclusion: Tetralogy of Fallot, hypocalcemia, immunologic defects, and cognitive impairment were common among our patients. To address the potential multisystem involvement, we recommend that all affected individuals undergo a comprehensive evaluation by a multidisciplinary care team.
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Síndrome de DiGeorge , Cardiopatías Congénitas , Hipocalcemia , Tetralogía de Fallot , Humanos , Femenino , Masculino , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/diagnóstico , Tetralogía de Fallot/genética , Hipocalcemia/genética , Hibridación Fluorescente in Situ , Taiwán/epidemiología , Estudios Transversales , Hibridación Genómica Comparativa , Cardiopatías Congénitas/genética , Sistema Inmunológico , Deleción CromosómicaRESUMEN
Background: Fabry disease is an inherited lysosomal storage disease affecting multiple organs with complications, including cardiomyopathy such as left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) has been the main treatment for Fabry patients since 2001. However, the indications of ERT are not clearly defined. We performed a meta-analysis according to previous studies to review the benefit of ERT for LVH improvement in Fabry patients. Methods: We performed a literature search from the National Center for Biotechnology Information (NCBI) and PubMed database without restriction of years for systematic review purposes. We performed a systematic review of clinical cohort studies and trials using a pooled analysis of proportions. We calculated the pooled proportions and the confidence intervals (CI) for left ventricular mass index (LVMI) for both ERT treatment and ERT treatment-naïve groups. The results for before ERT treatment and after ERT treatment are also investigated. Results: A total of 5 cohort studies and 2 randomized controlled trials (RCTs), involving a total of 552 participants (267 on ERT treatment versus 285 on naïve treatment), met the inclusion criteria. The pooled proportions analysis showed that the difference in means of LVMI between the ERT treatment group and the ERT treatment-naïve group was -0.149 [95% CI: -0.431, 0.132]. Effect differences favored the ERT treatment group over the ERT treatment-naïve group (p = 0.034). Another analysis included 3 cohort studies and 1 RCT with 442 participants (228 on before ERT and 214 on 4 years after ERT). The pooled proportions analysis showed that the difference in means of LVMI between the before ERT treatment group and the after ERT treatment group was -0.448 [95% CI: -0.787, -0.108]. It favored the 4 years after ERT group over the before ERT group (p = 0.037). Conclusions: Based on the currently available data, our meta-analysis showed that there are beneficial effects on LVH improvement with ERT in Fabry disease patients. It is better to start ERT as soon as we have diagnoses in female carriers and atypically affected males. Further research is needed to investigate the role of ERT in LVH improvement.
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Terapia de Reemplazo Enzimático , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/etiología , Femenino , Humanos , MasculinoRESUMEN
The present study included the first case of mucopolysaccharidosis (MPS) type VII in Taiwan. During pregnancy, the patient was diagnosed with hydrops fetalis and had ascites aspiration 4 times. In the following years, she presented gradually with chronic lung disease, developmental delay, short stature, dysmorphic features of coarse face, macroglossia and pigeon chest with scoliosis. Upon referral at age 4 years, she had corneal clouding, mild limitation of range of motion (ROM) and hepatosplenomegaly. X-ray showed paddle ribs and dysplastic vertebral bodies. MPS was suspected and urine glycosaminoglycans (GAGs) elevated were noted. The leukocyte enzymatic analyses for MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI were all normal. Afterward, the molecular analysis showed two heterozygous genetic variants of c.104C > A and c.1454C > T in trans in the GUSB gene (NM_000181.4) which were the causes for MPS VII. Then, we checked the leukocyte ß-glucuronidase activity for MPS VII and showed extremely low, therefore confirmed the diagnosis. Clinicians should increase the awareness on the early signs of MPS to have a prompt diagnosis and offer the correct treatment like enzyme replacement therapy (ERT) as early as possible.
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Mucopolisacaridosis VII , Preescolar , Femenino , Humanos , Mucopolisacaridosis VII/diagnóstico , Mucopolisacaridosis VII/genética , Mucopolisacaridosis VII/terapia , Embarazo , Radiografía , Rango del Movimiento Articular , TaiwánRESUMEN
Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by genetic defects that result in deficiency of one specific enzyme activity, consequently impairing the stepwise degradation of glycosaminoglycans (GAGs). Except for MPS II, the other types of MPS have autosomal recessive inheritance in which two copies of an abnormal allele must be present in order for the disease to develop. In this study, we present the status of variant alleles and biochemistry results found in infants suspected of having MPS I, II, IVA, and VI. A total of 324 suspected infants, including 12 for MPS I, 223 for MPS II, 72 for MPS IVA, and 17 for MPS VI, who were referred for MPS confirmation from newborn screening centers in Taiwan, were enrolled. In all of these infants, one specific enzyme activity in dried blood spot filter paper was lower than the cut-off value in the first blood sample, as well asin a second follow-up sample. The confirmatory methods used in this study included Sanger sequencing, next-generation sequencing, leukocyte enzyme fluorometric assay, and GAG-derived disaccharides in urine using tandem mass spectrometry assays. The results showed that five, nine, and six infants had MPS I, II, and IVA, respectively, and all of them were asymptomatic. Thus, a laboratory diagnosis is extremely important to confirm the diagnosis of MPS. The other infants with identified nucleotide variations and reductions in leukocyte enzyme activities were categorized as being highly suspected cases requiring long-term and intensive follow-up examinations. In summary, the final confirmation of MPS depends on the most powerful biomarkers found in urine, i.e., the quantification of GAG-derived disaccharides including dermatan sulfate, heparan sulfate, and keratan sulfate, and analysis of genetic variants can help predict outcomes and guide treatment.
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Mucopolisacaridosis , Mucopolisacaridosis II , Mucopolisacaridosis I , Disacáridos , Glicosaminoglicanos/genética , Humanos , Lactante , Recién Nacido , Mucopolisacaridosis/diagnóstico , Mucopolisacaridosis/genética , Espectrometría de Masas en Tándem/métodosRESUMEN
Background: Osteogenesis imperfecta (OI) is a rare disease characterized by increased bone fragility and susceptibility for fractures. Only few studies have compared the management for femoral fractures in children with OI. Nevertheless, no cohort studies have described the treatment for femoral fractures in adults with OI in Taiwan. This study aimed to investigate and compare the incidence of union and non-union femoral fractures and the best treatment options to avoid non-union fractures. Methods: We enrolled 72 patients with OI who were older than 18 years at MacKay Memorial Hospital between January 2010 and December 2018. Femoral fracture incidence, non-union rate, and treatment modality were analyzed. Results: Of 72 patients with OI, 11 patients had femoral fractures and 4 patients of them had >1 femoral fracture. The incidence for all types of femoral fractures was 651 fractures per 100,000 person-years annually. In 15 total fractures, 4 fractures resulted in non-union, and patients with type 4 OI mostly had shaft fractures. The best outcomes for non-union shaft fracture is achieved by surgical treatment. Conclusion: Adults with OI tended to develop femoral fractures and non-unions. Adults with type 4 OI were particularly at high risk for non-unions in shaft fractures with conservative treatment.
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Fracturas del Fémur/epidemiología , Osteogénesis Imperfecta/complicaciones , Adulto , Conservadores de la Densidad Ósea/uso terapéutico , Tratamiento Conservador/métodos , Femenino , Fracturas del Fémur/etiología , Fracturas del Fémur/terapia , Fijación de Fractura/estadística & datos numéricos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Taiwán/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
Background: Mucopolysaccharidoses (MPSs) are lysosomal storage disorders wherein glycosaminoglycans accumulate because the enzymes that degrade them are insufficient. The earliest symptoms, which are the main reasons for seeking consultation, are otorhinolaryngological and commonly occur in MPS I, II, IV, and VI. This retrospective study aimed to determine the occurrence of otorhinolaryngological manifestations in MPS patients in Taiwan and to analyze the prognosis of surgical intervention, including its effect on symptoms. Methods: We reviewed 42 patients (30 males and 12 females), with a median age of 20.5 years, who had MPS (16.7% type I, 35.7% type II, 19.0% type IIIB, 21.4% type IVA, and 7.2% type VI). The following otorhinolaryngological manifestations were collected: annual number of upper respiratory tract infections (URTIs) and otitis media with effusion (OME) episodes, adenoid size, tonsillar size, and apnea-hypopnea index (AHI). Results: Among 42 patients, we found recurrent otitis media in 42.9% of the patients, hearing loss in 83.3% (mixed: 52.4%, conductive: 21.4%, and sensorineural: 9.5%), frequent URTIs in 47.6%, and obstructive sleep apnea syndrome in 35.7%. Moreover, 76% of the patients underwent ear, nose, and throat (ENT) surgery, including adenoidectomy, tonsillectomy, tympanostomy with ventilation tube insertion, tracheotomy, and supraglottoplasty. Conclusions: MPS patients had a high incidence of ENT problems. ENT surgery reduced the severity of hearing loss, degree of symptoms related to upper airway obstruction, and severity of respiratory tract and otological infections of patients with MPS.
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Mucopolisacaridosis/complicaciones , Enfermedades Otorrinolaringológicas/epidemiología , Procedimientos Quirúrgicos Otorrinolaringológicos/estadística & datos numéricos , Femenino , Pérdida Auditiva/epidemiología , Pérdida Auditiva/etiología , Humanos , Masculino , Otitis Media con Derrame/epidemiología , Otitis Media con Derrame/etiología , Enfermedades Otorrinolaringológicas/etiología , Enfermedades Otorrinolaringológicas/cirugía , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/etiología , Estudios Retrospectivos , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/etiología , Taiwán/epidemiología , Adulto JovenRESUMEN
Background and Objectives: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNVs) and is recommended for the initial genetic testing of patients with autism spectrum disorder (ASD). This study aims to determine the diagnostic yield of array comparative genomic hybridization (array-CGH) in ASD patients from a cohort of Chinese patients in Taiwan. Materials and Methods: Enrolled in this study were 80 ASD children (49 males and 31 females; 2-16 years old) followed up at Taipei MacKay Memorial Hospital between January 2010 and December 2020. The genomic DNA extracted from blood samples was analyzed by array-CGH via the Affymetrix GeneChip Genome-Wide Human single nucleotide polymorphism (SNP) and NimbleGen International Standards for Cytogenomic Arrays (ISCA) Plus Cytogenetic Arrays. The CNVs were classified into five groups: pathogenic (pathologic variant), likely pathogenic (potential pathologic variant), likely benign (potential normal genomic variant), benign (normal genomic variant), and uncertain clinical significance (variance of uncertain significance), according to the American College of Medical Genetics (ACMG) guidelines. Results: We identified 47 CNVs, 31 of which in 27 patients were clinically significant. The overall diagnostic yield was 33.8%. The most frequently clinically significant CNV was 15q11.2 deletion, which was present in 4 (5.0%) patients. Conclusions: In this study, a satisfactory diagnostic yield of array-CGH was demonstrated in a Taiwanese ASD patient cohort, supporting the clinical usefulness of array-CGH as the first-line testing of ASD in Taiwan.
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Trastorno del Espectro Autista , Adolescente , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , TaiwánRESUMEN
RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible.
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Discapacidades del Desarrollo/genética , Cardiopatías Congénitas/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Síndrome de Costello/genética , Síndrome de Costello/fisiopatología , Estudios Transversales , Discapacidades del Desarrollo/clasificación , Discapacidades del Desarrollo/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatología , Facies , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/fisiopatología , Femenino , Cardiopatías Congénitas/fisiopatología , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/fisiopatología , Humanos , Síndrome LEOPARD/genética , Síndrome LEOPARD/fisiopatología , Masculino , Síndrome de Noonan/fisiopatología , Estudios Retrospectivos , Proteínas ras/genéticaRESUMEN
Hunter syndrome (mucopolysaccharidosis II; MPS II) is caused by a defect of the iduronate-2-sulfatase (IDS) gene. Few studies have reported integrated mutation data of Taiwanese MPS II phenotypes. In this study, we summarized genotype and phenotype correlations of confirmed MPS II patients and asymptomatic MPS II infants in Taiwan. Regular polymerase chain reaction and DNA sequencing were used to identify genetic abnormalities of 191 cases, including 51 unrelated patients with confirmed MPS II and 140 asymptomatic infants. IDS activity was analyzed in individual novel IDS variants using in vitro expression studies. Nineteen novel mutations were identified, in which the percentages of IDS activity of the novel missense mutations c.137A>C, c.311A>T, c.454A>C, c.797C>G, c.817C>T, c.998C>T, c.1106C>G, c.1400C>T, c.1402C>T, and c.1403G>A were significantly decreased (p < 0.001), c.254C>T and c.1025A>G were moderately decreased (p < 0.01), and c.851C>T was slightly decreased (p < 0.05) comparing with normal enzyme activity. The activities of the other six missense mutations were reduced but were insignificant. The results of genomic studies and their phenotypes were highly correlated. A greater understanding of the positive correlations may help to prevent the irreversible manifestations of Hunter syndrome, particularly in infants suspected of having asymptomatic MPS II. In addition, urinary glycosaminoglycan assay is important to diagnose Hunter syndrome since gene mutations are not definitive (could be non-pathogenic).
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Glicoproteínas/metabolismo , Mucopolisacaridosis II , Mutación Missense , Pueblo Asiatico , Femenino , Glicoproteínas/genética , Humanos , Lactante , Masculino , Mucopolisacaridosis II/enzimología , Mucopolisacaridosis II/genética , Mucopolisacaridosis II/orina , Análisis de Secuencia de ADN , TaiwánRESUMEN
Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) has a variable age of onset and variable rate of progression. However, information regarding the natural history of this disorder in Asian populations is limited. A retrospective analysis was carried out for 28 patients with MPS III (types IIIA [n = 3], IIIB [n = 23], and IIIC [n = 2]; 15 males and 13 females; median age, 8.2 years; age range, 2.7-26.5 years) seen in six medical centers in Taiwan from January 1996 through October 2017. The median age at confirmed diagnosis was 4.6 years. The most common initial symptom was speech delay (75%), followed by hirsutism (64%) and hyperactivity (54%). Both z scores for height and weight were negatively correlated with age (r = -.693 and -0.718, respectively; p < .01). The most prevalent clinical manifestations were speech delay (100%) and intellectual disability (100%), followed by hirsutism (93%), hyperactivity (79%), coarse facial features (68%), sleep disorders (61%), and hepatosplenomegaly (61%). Ten patients (36%) had epilepsy, and the median age at the first seizure was 11 years. Thirteen patients (46%) experienced at least one surgical procedure. At the time of the present study, 7 of the 28 patients had passed away at the median age of 13.0 years. Molecular studies showed an allelic heterogeneity without clear genotype and phenotype correlations. MPS IIIB is the most frequent subtype among MPS III in the Taiwanese population. An understanding of the natural history of MPS III may allow early diagnosis and timely management of the disease facilitating better treatment outcomes.
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Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis III/etiología , Acetilglucosaminidasa/genética , Acetilglucosaminidasa/metabolismo , Adolescente , Adulto , Biomarcadores , Niño , Preescolar , Análisis Mutacional de ADN , Electroencefalografía , Activación Enzimática , Femenino , Estudios de Asociación Genética , Humanos , Estimación de Kaplan-Meier , Masculino , Mucopolisacaridosis III/metabolismo , Mucopolisacaridosis III/mortalidad , Imagen Multimodal/métodos , Mutación , Fenotipo , Estudios Retrospectivos , Evaluación de Síntomas , Taiwán , Adulto JovenRESUMEN
Prader-Willi syndrome (PWS) is a genetic disorder with obesity, developmental delay, short stature, and behavioral abnormalities. The study aimed to assess the functional independence in children with PWS. The Functional Independence Measure for Children (WeeFIM) was used to evaluate 81 children with PWS (44 boys and 37 girls) with a median age of 11 years 1 month (range 2 years 8 months to 20 years 2 months) were recruited between January 2013 and December 2016. The mean total WeeFIM score was 103.8 (maximum 126). Sixty-five patients (80%) had deletion type PWS, 16 (20.0%) had nondeletion type. The scores were 103.6 ± 18.5 for deletion and 104.8 ± 18.3 for nondeletion type (p = .405), 104.8 ± 19.3 in boys and 102.6 ± 17.3 in girls (p = .293). The mean self-care, mobility, and cognition scores were 47 (maximum 56), 33 (maximum 35), and 24 (maximum 35), respectively. All total scores and 18 subscores in the three functional domains were positively correlated with age (p < .05). Most children required assistance in problem-solving, comprehension, and expression. The WeeFIM identified the strengths and limitations of children with PWS and confirmed that support and supervision were needed in cognitive and self-care tasks.
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Actividades Cotidianas , Cognición/fisiología , Síndrome de Prader-Willi/etiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Síndrome de Prader-Willi/fisiopatología , Autocuidado , Encuestas y Cuestionarios , Taiwán , Adulto JovenRESUMEN
OBJECTIVES: To investigate a near-infrared-to-blue luminescence upconversion curing method for polymerizing resin cements under zirconia discs. METHODS: Lava zirconia discs of different thicknesses (0.5-2.0 mm) were manufactured. First, the transmittances of the NIR and two blue lights (BLs) (LED and halogen lights) through these discs were measured. Second, NaYF4:Yb3+/Tm3+ upconversion phosphor (UP) powder was milled into 0.5-µm particle sizes. A light-curable resin cement VariolinkII base was chosen as the control (UP0), and an experimental cement (UP5) was prepared by adding 5 % UPs. These two cements were examined using multiphoton excitation microscopy for particle distribution. UP5 and UP0 were polymerized with or without zirconia shielding then subjected to a microhardness test. A multifold analysis was performed to examine the effects of zirconia thickness, curing protocols (pure BL or combined BL and NIR curing), and cement type. RESULTS: The transmittance of NIR was superior to that of BL through zirconia discs of all thicknesses. UP particles were homogeneously distributed in UP5 and emitted blue luminescence under 980-nm NIR excitation. UP5 showed higher microhardness values than UP0 under any curing protocol or zirconia shielding condition. The combination of 20-s BL and 40-s NIR curing yielded the highest microhardness in uncovered UP5. However, combining 40-s BL and 20-s NIR curing surpassed the other groups when the zirconia discs were thicker than 0.5 mm. SIGNIFICANCE: NIR exhibits higher transmission through zirconia than BL. UP particles work as strengthen fillers and photosensitizers in cements. NIR upconversion curing could be a new strategy for polymerizing resin cements under thick zirconia restorations.
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Ensayo de Materiales , Polimerizacion , Cementos de Resina , Circonio , Circonio/química , Cementos de Resina/química , Luminiscencia , Dureza , Rayos Infrarrojos , Curación por Luz de Adhesivos Dentales , Luces de Curación Dental , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Background: Muscular dystrophies and congenital myopathies encompass various inherited muscular disorders that present diagnostic challenges due to clinical complexity and genetic heterogeneity. Methods: This study aimed to investigate the use of whole exome sequencing (WES) in diagnosing muscular disorders in pediatric patients in Taiwan. Out of 161 pediatric patients suspected to have genetic/inherited myopathies, 115 received a molecular diagnosis through conventional tests, single gene testing, and gene panels. The remaining 46 patients were divided into three groups: Group 1 (multiplex ligation-dependent probe amplification-negative Duchenne muscular dystrophy) with three patients (6.5%), Group 2 (various forms of muscular dystrophies) with 21 patients (45.7%), and Group 3 (congenital myopathies) with 22 patients (47.8%). Results: WES analysis of these groups found pathogenic variants in 100.0% (3/3), 57.1% (12/21), and 68.2% (15/22) of patients in Groups 1 to 3, respectively. WES had a diagnostic yield of 65.2% (30 patients out of 46), detecting 30 pathogenic or potentially pathogenic variants across 28 genes. Conclusion: WES enables the diagnosis of rare diseases with symptoms and characteristics similar to congenital myopathies and muscular dystrophies, such as muscle weakness. Consequently, this approach facilitates targeted therapy implementation and appropriate genetic counseling.
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BACKGROUND: We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7. METHODS: Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents. RESULTS: The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH. CONCLUSION: Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.
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Canales de Cloruro , Humanos , Masculino , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Mutación con Ganancia de Función , Osteopetrosis/genética , Osteopetrosis/patología , Fenotipo , PreescolarRESUMEN
Congenital heart defects (CHDs) affect a substantial proportion of patients with Kabuki syndrome. However, the prevalence and type of CHD and the genotype-phenotype correlations in Asian populations are not fully elucidated. This study performed a retrospective analysis of 23 Taiwanese patients with molecularly confirmed Kabuki syndrome. Twenty-two patients presented with pathogenic variants in the KMT2D gene. Comprehensive clinical assessments were performed. A literature review was conducted to summarize the spectrum of CHDs in patients with Kabuki syndrome. In total, 16 (73.9%) of 22 patients with pathogenic KMT2D variants had CHDs. The most common types of CHD were atrial septal defects (37.5%), ventricular septal defects (18.8%), coarctation of the aorta (18.8%), bicuspid aortic valve (12.5%), persistent left superior vena cava (12.5%), mitral valve prolapse (12.5%), mitral regurgitation (12.5%), and patent ductus arteriosus (12.5%). Other cardiac abnormalities were less common. Further, there were no clear genotype-phenotype correlations found. A literature review revealed similar patterns of CHDs, with a predominance of left-sided obstructive lesions and septal defects. In conclusion, the most common types of CHDs in Taiwanese patients with Kabuki syndrome who presented with KMT2D mutations are left-sided obstructive lesions and septal defects.
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Osteogenesis imperfecta (OI) is a group of rare genetic disorders that affect bone formation. Patients with OI present mainly with increased bone fragility and bone deformities. Twenty-seven Taiwanese children between 2 and 21 years of age with OI and their parents were recruited at MacKay Memorial Hospital from January 2013 to December 2019. We used the Functional Independence Measure for Children (WeeFIM) questionnaire to assess the functional independence of the children and describe any functional limitations or additional burden of daily care. Out of a potential score of 126, the mean total WeeFIM score was 113.7. There was a statistically significant difference between the scores of type I, type III and type IV OI (121.88 [SD 7.01] vs. 80.8 [SD 26.25] vs. 119.17 [SD 10.89]; p < 0.001). There were no statistically significant differences between the scores in different age groups, the male and female participants, and patients with pathogenic variants in COL1A1 and COL1A2. The mean scores for the self-care, mobility, and cognition domains were 48.78 (maximum 56, mean quotient 91.14%), 30.44 (maximum 35, mean quotient 87.12%), and 34.44 (maximum 35, mean quotient 99.05%), respectively. The best performance was in the cognition domain (mean quotient 99.05%), and the worst was in the mobility domain (mean quotient 87.12%). There were no statistically significant correlations between WeeFIM scores and age, or age when symptoms began. The total WeeFIM score and 13 subscores for the self-care and mobility domains were all positively correlated with body height (p < 0.01). The correlation was lowest for bowel and walking/wheelchair tasks, and the highest for bathing and dressing-upper tasks. For tasks in bathing, over 40% of the patients needed help. For tasks in the cognition domain, most patients required no help. For the Taiwanese children with OI, some support and supervision were required for self-care and mobility tasks, and the functional independence in these two domains was correlated with body height and disease types. The WeeFIM questionnaire may be a useful tool to assess the functional strengths and weaknesses of children with OI.
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Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive disorder and is one of the lysosomal storage diseases. Patients with MPS IVA have a striking skeletal phenotype but normal intellect. The phenotypic continuum of MPS IVA ranges from severe and rapid progress to mild and slow progress. The diagnosis of MPS IVA is usually suspected based on abnormal bone findings and dysplasia on physical examination and radiographic investigation in the preschool years. In the past, only supportive care was available. Due to the early and severe skeletal abnormalities, the orthopedic specialist was usually the main care provider. However, patients need aggressive monitoring and management of their systemic disease. Therefore, they need an interdisciplinary team for their care, comprising medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. After the US Food and Drug Administration approved elosulfase alfa in 2014, patients older than 5 years could benefit from this treatment. Clinical trials showed clinically meaningful improvements with once-a-week intravenous dosing (2.0 mg/kg per week), significantly improving the 6min walk test, the 3min stair climb test, and respiratory function when compared with placebo. Elosulfase alfa is well-tolerated, and there is a good response indicated by decreasing urine glycosaminoglycans.
Asunto(s)
Condroitinsulfatasas/uso terapéutico , Mucopolisacaridosis IV/tratamiento farmacológico , Terapia de Reemplazo Enzimático , Humanos , FenotipoRESUMEN
Small supernumerary marker chromosomes (sSMCs) derived from the chromosome 6 short arm are rare and their clinical significance remains unknown. No case with sSMC(6) without centromeric DNA has been reported. Partial trisomy and tetrasomy of distal 6p is a rare but clinically distinct syndrome. We report on a de novo mosaic sSMC causing partial tetrasomy for 6p23-p25.3 in a male infant with symptoms of being small for gestational age, microcephaly, facial dysmorphism, congenital eye defects, and multi-system malformation. Conventional cytogenetic analysis revealed a karyotype of 47,XY,+mar [25]/46,XY [22]. Array comparative genomic hybridization (aCGH) revealed mosaic tetrasomy of distal 6p. This is the first case of mosaic tetrasomy 6p23-p25.3 caused by an inverted duplicated neocentric sSMC with characteristic features of trisomy distal 6p. Comparison of phenotypes in cases with trisomy and tetrasomy of 6p23-p25.3 could facilitate a genotype-phenotype correlation and identification of candidate genes contributing to their presentation. The presentation of anterior segment dysgenesis and anomaly of the renal system suggest triplosensitivity of the FOXC1 gene. In patients with microcephaly growth retardation, and malformation of the cardiac and renal systems, presentation of anterior segment dysgenesis might be indicative of chromosome 6p duplication, and aCGH evaluation should be performed for associated syndromic disease.
RESUMEN
Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by GALNS gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were -0.260, -0.102, -0.182, -0.360, -0.408, -0.587, -0.293, -0.311, and -0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.