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2.
Am J Med Genet A ; 179(7): 1276-1286, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31124279

RESUMO

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.

4.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

5.
JIMD Rep ; 39: 45-54, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28726122

RESUMO

Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase) deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization that predisposes to episodic ketoacidosis. It results from biallelic pathogenic variants in the ACAT1 gene, encoding mitochondrial beta-ketothiolase. We report two cases of beta-ketothiolase deficiency presenting with acute ketoacidosis and "metabolic stroke." The first patient presented at 28 months of age with metabolic acidosis and pallidal stroke in the setting of a febrile gastrointestinal illness. Although 2-methyl-3-hydroxybutyric acid and trace quantities of tiglylglycine were present in urine, a diagnosis of glutaric acidemia type I was initially suspected due to the presence of glutaric and 3-hydroxyglutaric acids. A diagnosis of beta-ketothiolase deficiency was ultimately made through whole exome sequencing which revealed compound heterozygous variants in ACAT1. Fibroblast studies for beta-ketothiolase enzyme activity were confirmatory. The second patient presented at 6 months of age with ketoacidosis, and was found to have elevations of urinary 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. Sequencing of ACAT1 demonstrated compound heterozygous presumed causative variants. The patient exhibited choreoathethosis 2 months after the acute metabolic decompensation. These cases highlight that, similar to a number of other organic acidemias and mitochondrial disorders, beta-ketothiolase deficiency can present with metabolic stroke. They also illustrate the variability in clinical presentation, imaging, and biochemical evaluation that make screening for and diagnosis of this rare disorder challenging, and further demonstrate the value of whole exome sequencing in the diagnosis of metabolic disorders.

6.
Oncologist ; 21(4): 514-20, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26975868

RESUMO

UNLABELLED: We report a case of a 31-year-old man with metastatic fibrolamellar hepatocellular carcinoma (FLHCC) treated with gemcitabine and oxaliplatin complicated by hyperammonemic encephalopathy biochemically consistent with acquired ornithine transcarbamylase deficiency. Awareness of FLHCC-associated hyperammonemic encephalopathy and a pathophysiology-based management approach can optimize patient outcome and prevent serious complications. A discussion of the management, literature review, and proposed treatment algorithm of this rare metabolic complication are presented. IMPLICATIONS FOR PRACTICE: Pathophysiology-guided management of cancer-associated hyperammonemic encephalopathy can improve patient outcome and prevent life-threatening complications. Community and academic oncologists should be aware of this serious metabolic complication of cancer and be familiar with its management.


Assuntos
Encefalopatias/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Hiperamonemia/patologia , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Encefalopatias/induzido quimicamente , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Humanos , Hiperamonemia/induzido quimicamente , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Masculino , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Doença da Deficiência de Ornitina Carbomoiltransferase/induzido quimicamente , Doença da Deficiência de Ornitina Carbomoiltransferase/patologia , Oxaliplatina
7.
Am J Hum Genet ; 97(3): 483-92, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26320891

RESUMO

Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.


Assuntos
Opacidade da Córnea/genética , Opacidade da Córnea/patologia , Cútis Laxa/genética , Cútis Laxa/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto/genética , Ornitina-Oxo-Ácido Transaminase/genética , Sequência de Aminoácidos , Sequência de Bases , Genes Dominantes/genética , Humanos , Dados de Sequência Molecular , Linhagem , Prolina/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA , Pele/patologia , Especificidade da Espécie
9.
Curr Opin Endocrinol Diabetes Obes ; 21(1): 39-44, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24275619

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize recent information that has had a significant impact on the laboratory diagnosis and clinical management of newborns with congenital hypothyroidism and congenital adrenal hyperplasia (CAH). RECENT FINDINGS: An approximate doubling of the incidence rate of congenital hypothyroidism in many parts of the world has been attributed to increased detection of infants with mild disease, delayed thyroid stimulating hormone elevations and demographic changes. A substantial number of children with modest thyroid stimulating hormone elevations on screening have permanent disease. Circulating levels of thyroxine may vary among hypothyroid children who are given identical dosages of medication. Treated infants should be monitored every 1-2 months during the first year of life. Although, generic and brand name thyroxine preparations may not be bioequivalent, children can be well controlled on generic formulations.Enzyme linked immunoassay assay for 17-hydroxyprogesterone is associated with a high rate of false positive specimens. In attempts to minimize this problem, some programs have resorted to two-tier screening of the initial specimen with steroid profiling as the second tier. Several programs are routinely testing second specimens in an effort to reduce the incidence of missed CAH cases. SUMMARY: This review explains the uptick in incidence rate of congenital hypothyroidism and underscores issues in management that can affect developmental outcome. One specimen two-tier testing for CAH resulted in an increased false negative rate without significantly reducing the false positive rate. The benefit of collecting second specimens for CAH screening is problematic. Optimal treatment of CAH continues to pose a challenge.


Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Hipotireoidismo Congênito/diagnóstico , Hormônio do Crescimento/uso terapêutico , Triagem Neonatal/métodos , Tiroxina/uso terapêutico , 17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Técnicas de Laboratório Clínico , Hipotireoidismo Congênito/tratamento farmacológico , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Triagem Neonatal/tendências , Sensibilidade e Especificidade
10.
Am J Med Genet A ; 161A(11): 2762-76, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24123776

RESUMO

Sensenbrenner syndrome, also known as cranioectodermal dysplasia, is a rare multiple anomaly syndrome with distinctive craniofacial appearance, skeletal, ectodermal, connective tissue, renal, and liver anomalies. Dramatic advances with next-generation sequencing have expanded its phenotypic variability and molecular heterogeneity. We review 39 patients including two new patients, one with compound heterozygous novel mutations in WDR35 and a previously unreported multisutural craniosynostosis that may be a part of Sensenbrenner syndrome. In 14 of 25 (56.0%) patients pathogenic mutations have been identified in 4 different genes that regulate (intraflagellar) cilia transport. We compared Sensenbrenner syndrome to asphyxiating thoracic dystrophy-Jeune syndrome (ATD-JS) and other ciliopathies. Our analyses showed that the high anterior hairline, forehead bossing and dolichocephaly (accompanied by sagittal craniosynostosis in more than half of the patients) occur in almost all patients with Sensenbrenner syndrome. Metaphyseal dysplasia with narrow thorax, proximal limb shortness, and short fingers are typical of Sensenbrenner syndrome and ATD-JS. Respiratory complications have been reported in both syndromes, usually less severe with Sensenbrenner syndrome. Proposed diagnostic criteria for Sensenbrenner syndrome include the distinctive craniofacial appearance, ubiquitous brachydactyly and ectodermal anomalies, and sagittal craniosynostosis. Mild heart defects have been noted, but there have been no atrioventricular canal or heterotaxy defects that are common in Ellis-Van Creveld syndrome. We anticipate that the steady identification of molecularly defined patients may allow correlation of phenotype and genotype. Additional natural history data will improve genetic counseling and current guidelines.


Assuntos
Osso e Ossos/anormalidades , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Humanos , Lactente , Recém-Nascido , Cariotipagem , Masculino , Fenótipo
11.
Clin Biochem ; 46(7-8): 681-4, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23462696

RESUMO

OBJECTIVE: The objective of this study is to develop an isotope dilution liquid chromatography tandem mass spectrometry assay to screen for hepatorenal tyrosinemia (HT) from newborn filter paper samples using pooled extracts to increase high throughput screening. DESIGN AND METHODS: Succinylacetone (SUAC), the marker for HT, was extracted from dried blood spots with the formation of the hydrazone derivative of SUAC; up to eight sample extracts were pooled and the SUAC-derivative was analyzed by mass spectrometry methods with an injection-to-injection time of one minute. If any pooled sample extract screened positive, then the samples comprising the pooled sample were assayed individually. RESULTS: Two newborn infants were identified with high levels of SUAC (7 & 23µM) and later confirmed to have HT. Three older children whose initial filter paper samples were taken at 195days to 614days of age with elevated SUAC (range 4.9-5µM) were identified; one of the three had clinical signs of HT and was placed on treatment (diagnosis of the other two are unavailable). CONCLUSION: MS/MS analysis of pooled dried blood sample extracts permits sensitive, reduced instrumental analytical time and increase high throughput screening for HT.


Assuntos
Heptanoatos/sangue , Triagem Neonatal/métodos , Tirosinemias/diagnóstico , Cromatografia Líquida/métodos , Humanos , Lactente , Recém-Nascido , Espectrometria de Massas em Tandem/métodos , Tirosinemias/sangue
12.
Clin Endocrinol (Oxf) ; 75(6): 806-10, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21623857

RESUMO

OBJECTIVE: The incidence of congenital hypothyroidism (CH) detected by newborn screening in the US has increased significantly since the early 1990s. We defined the characteristics associated with the increased incidence. PATIENTS: A cohort of children with CH born during an earlier period of low incidence (1991-94) was compared with a cohort born during a later period when the incidence of CH had doubled (2001-04). MEASUREMENTS: Screening was performed with T4 as the primary marker and thyroid stimulating hormone (TSH) on selected specimens. Follow-up on hypothyroid children determined whether they had permanent or transient hypothyroidism. Cases were classified based on laboratory results: initial TSH ≥100 mU/l was 'severe,' initial TSH <100 mU/l but ≥20 mU/l was 'mild' and initial TSH <20 mU/l with subsequent abnormal TSH was 'delayed'. RESULTS: The overall incidence of CH almost doubled between the two time periods, from 1:3010 to 1:1660. Excess cases were found in the mild and delayed categories, with no increase in severe cases. The proportion of transient cases was <5% in severe cases, 40% in mild cases and 70% among delayed cases. There was no difference in the proportion of transient case between the two time periods. Modifications to the T4/TSH testing protocol between the two time periods resulted in substantially increased numbers of specimens in the younger cohort being selected for TSH testing in both initial and repeat specimens. CONCLUSION: The rising incidence of CH in Massachusetts is confined to mild and delayed cases. Our findings suggest that this rise is attributable to enhanced detection rather than an absolute increase in numbers.


Assuntos
Hipotireoidismo Congênito/epidemiologia , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Massachusetts/epidemiologia , Triagem Neonatal , Índice de Gravidade de Doença , Regulação para Cima
14.
Indian J Pediatr ; 78(8): 953-60, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21416125

RESUMO

OBJECTIVE: To estimate the prevalence of the Inborn Errors of Metabolism (IEM), evaluate biomarker distributions and determine benefits of screening for the inborn errors of metabolism in Andhra Pradesh, India, using Tandem Mass Spectrometry (MS/MS). METHODS: The 4,946 newborns born during the period 2006-2008 in four major Government Maternity Hospitals in a rural district in Andhra Pradesh, India, were screened at an established newborn screening laboratory in the US using their previously established norms. RESULTS: Forty-seven neonates had out-of-range results (5 high probability; 28 low probability; 14 indeterminate). Two infants with disorders (carnitine uptake disorder and isovaleric aciduria) identified by screening are currently doing well. One infant with presumed glutaric aciduria type II, was deceased at the time of reporting. Another infant, with glutaric aciduria type I, became symptomatic and died at the age of 1 year despite early detection and treatment. A comparison of the concentrations of biomarkers among babies born in India and those born in Massachusetts, US, was also undertaken and significant differences were noted. CONCLUSIONS: A high prevalence of disorders was observed, but to estimate the true extent of the IEM in India larger studies are required. This study also illustrates challenges encountered in disease management highlighting the importance of considering the access to confirmatory testing and continuing clinical care before implementing any large-scale NBS for conditions with resource-intensive health needs such as the IEM detected by MS/MS.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem , Feminino , Humanos , Índia , Recém-Nascido , Masculino , Projetos Piloto
16.
Genet Med ; 12(12 Suppl): S220-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21150368

RESUMO

To fulfill the purpose of newborn screening, comprehensive newborn screening programs must ensure that infants and children with newborn screening conditions are not only diagnosed but also they maintain engagement in appropriate lifespan and family-centered care for best outcomes. To ensure success, monitoring and care-coordination requires a systems-based approach to streamline the significant surveillance activities, which must not overburden the critical core functions of newborn screening nor the health care delivery system. Furthermore, treatment and care can only be improved by translating reliable knowledge into changes in practice, a process that requires evaluations of outcomes that are confirmable at the local level and translatable into a larger, e.g., national data set. We describe a sustainable public health systems approach to long-term follow-up, built on existing comprehensive newborn screening infrastructure and compatible with national endeavors. We also describe early experience with implementation of a centralized public-health tracking model and show that a significant proportion of cases detected through newborn screening do not continue with subspecialty care as they get older.


Assuntos
Doenças Genéticas Inatas/terapia , Implementação de Plano de Saúde , Triagem Neonatal , Garantia da Qualidade dos Cuidados de Saúde , Criança , Medicina Baseada em Evidências , Seguimentos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Implementação de Plano de Saúde/normas , Humanos , Lactente , Recém-Nascido , New England , Prática de Saúde Pública
18.
Mol Genet Metab ; 101(1): 33-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20580581

RESUMO

INTRODUCTION: Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is the most frequent of the fatty acid oxidation disorders (FAOD), a group caused by defects in the mitochondrial B-oxidation of fatty acids. Fatty acid oxidation is critical in supplying energy during periods when glucose is limited or when energy needs are increased beyond the availability of glucose. In MCADD, this energy shortage can result in acute metabolic episodes or sudden death. The prevention of sudden death from MCADD served as the primary impetus to expand newborn screening. However, we have experienced sudden death in four children with MCADD despite their detection by newborn screening. The purpose of this report is to alert others to the danger of sudden death in MCADD even when it is detected by newborn screening, to identify the clinical symptoms that precede sudden death, and to examine the relationship between the newborn screening result and the risk for sudden death. METHODS: We describe these children and their metabolic findings with emphasis on their newborn screening octanoylcarnitine (C8) level, the primary marker for newborn detection of MCADD. We also performed a literature search of cases of sudden death in MCADD in which the clinical status preceding death is described. RESULTS: The newborn screening C8 levels in our four cases were markedly elevated, ranging from 8.4 to 24.8micromol/L (cut off<0.8micromol/L). Only two of the children were homozygous for the common c.985A>G MCAD mutation; the other two were heterozygous for this mutation. Similarly, among the eight reported cases which included MCAD genotypes, five were homozygous for the c.985A>G mutation, while two were heterozygous and one was homozygous for a splice site mutation. Vomiting 12-24h before sudden death was present in all four of our cases, and the review of reported cases of sudden death in MCADD disclosed vomiting as a frequent symptom. CONCLUSION: We suggest that in MCADD (1) a newborn screening C8 level of 6micromol/L or greater represents particular risk of sudden death; (2) that MCAD genotypes other than homozygosity for the c.985A>G mutation are also associated with sudden death; (3) that vomiting is a frequent symptom preceding sudden death; and (4) social support and medical follow-up of these families are crucial in reducing the occurrence of sudden death.


Assuntos
Morte Súbita , Erros Inatos do Metabolismo Lipídico , Triagem Neonatal , Acil-CoA Desidrogenase/sangue , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Pré-Escolar , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/metabolismo , Masculino , Mutação
19.
J Inherit Metab Dis ; 33(Suppl 2): S273-81, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20490925

RESUMO

Severe combined immunodeficiency (SCID) is a Primary Immune Deficiency that is under consideration for population-based newborn screening (NBS) by many NBS programs, and has recently been recommended for inclusion in the US uniform panel of newborn screening conditions. A marker of SCID, the T cell receptor excision circle (TREC), is detectable in the newborn dried blood spot using a unique molecular assay as a primary screen. The New England Newborn Screening Program developed and validated a multiplex TREC assay in which both the TREC analyte and an internal control are acquired from a single punch and run in the same reaction. Massachusetts then implemented a statewide pilot SCID NBS program. The authors describe the rationale for a pilot SCID NBS program, a comprehensive strategy for successful implementation, the screening test algorithm, the screening follow-up algorithm and preliminary experience based on statewide screening in the first year. The Massachusetts experience demonstrates that SCID NBS is a program that can be implemented on a population basis with reasonable rates of false positives.


Assuntos
Triagem Neonatal , Imunodeficiência Combinada Severa/diagnóstico , Algoritmos , Coleta de Amostras Sanguíneas , DNA/sangue , Reações Falso-Positivas , Genes Codificadores dos Receptores de Linfócitos T , Humanos , Recém-Nascido , Massachusetts , Triagem Neonatal/métodos , Projetos Piloto , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Indicadores de Qualidade em Assistência à Saúde , Reprodutibilidade dos Testes , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/imunologia
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