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2.
Am J Emerg Med ; 36(6): 1126.e1-1126.e4, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29598889

RESUMO

We describe the case of a previously healthy 33year-old male pilot recently arrived to the United States from Africa. The patient presented to our ED febrile and disoriented, with projectile coffee-ground emesis. He was later found to have severe malaria and cerebral parasitemia. Due to the severity of his illness, the patient received the anti-malarial medication Artesunate as well as several exchange transfusions. Within 48h his parasitic load was reduced from 42% to 0.4%. The following is an account of a collaborative effort that spans the specialties of emergency medicine, infectious disease, and critical care medicine.

3.
Prenat Diagn ; 38(1): 33-43, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29096039

RESUMO

OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.


Assuntos
Anormalidades Congênitas/genética , Doenças Genéticas Inatas/diagnóstico , Pais , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Exoma , Feminino , Genes Recessivos , Humanos , Masculino , Gravidez
4.
Am J Hum Genet ; 102(1): 27-43, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29276006

RESUMO

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

5.
Pediatr Transplant ; 21(6)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28639398

RESUMO

Prediction of PTLD after pediatric lung transplant remains difficult. Use of EBV VL in WB has been poorly predictive, while measurement of VL in BAL fluid has been suggested to have enhanced utility. The NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) prospectively obtained serial quantitative measurements of EBV PCR in both WB and BAL fluid after pediatric lung transplantation. Descriptive statistics, contingency analyses, and Kaplan-Meier analyses evaluated possible association between EBV and PTLD. Of 61 patients, 34 (56%) had an EBV+PCR (at least once in WB or BAL). EBV donor (D)+patients more often had a positive PCR (D+/recipient (R)-: 13/18; D+/R+: 14/23) compared to EBV D- patients (6/17). Several D-/R- (5/12) patients developed EBV, but none developed PTLD. All four PTLD patients were D+/R- with EBV+PCR. Neither the time to first EBV+PCR nor the CT for PCR positivity in BAL or WB was statistically different between those with and without PTLD. Having an EBV-seropositive donor was associated with increased risk of EBV+PCR in WB. EBV load in BAL was not predictive of PTLD.


Assuntos
Herpesvirus Humano 4/isolamento & purificação , Transplante de Pulmão , Transtornos Linfoproliferativos/virologia , Complicações Pós-Operatórias/virologia , Carga Viral , Adolescente , Líquido da Lavagem Broncoalveolar/virologia , Criança , Pré-Escolar , DNA Viral/análise , Feminino , Herpesvirus Humano 4/genética , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Reação em Cadeia da Polimerase , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
6.
J Am Soc Nephrol ; 28(8): 2529-2539, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28373276

RESUMO

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.


Assuntos
Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/genética , Mutação , Fosfotransferases (Fosfomutases)/genética , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/genética , Regiões Promotoras Genéticas/genética , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
7.
AIDS ; 28(10): 1463-72, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24681417

RESUMO

OBJECTIVE: The objective of the present study was to determine the diagnostic performance of the symptom-based tuberculosis (TB) screening questionnaire recommended by WHO for people living with HIV (PLWH) in resource-limited settings, among adults off and on antiretroviral therapy (ART). DESIGN: Cross-sectional study at two HIV clinics in South Africa. METHODS: A total of 825 PLWH completed the screening questionnaire and underwent investigations [chest radiography (CXR) and microbiologic testing of sputa]. A positive screen was defined as presence of cough, fever, night sweats, or weight loss. Pulmonary tuberculosis (PTB) was defined as sputum smear positive for acid-fast bacilli or growth of Mycobacterium tuberculosis. RESULTS: Of 737 participants with at least one diagnostic sputum specimen, PTB was diagnosed in 31 of 522 (5.9%) on ART, and 34 of 215 (15.8%) not on ART. The questionnaire missed 15 of 31 (48.4%) PTB cases on ART, and three of 34 (8.8%) not on ART. Among participants on ART, post-test probability of PTB diagnosis (95% confidence interval) was 6.8% (4.0-10.9%) if screening positive, and 5.2% (2.9-8.4%) if screening negative, whereas among participants not on ART, post-test probabilities were 20.3% (14.2-27.5%) and 4.8% (1.0-13.5%), respectively. Among participants diagnosed with PTB, those on ART were significantly less likely to screen positive (adjusted odds ratio 0.04, 95% confidence interval: 0.01-0.39). In both groups (ART and no ART), screening was more sensitive when CXR was incorporated. CONCLUSION: For case detection and exclusion of PTB, the WHO-recommended questionnaire performed adequately among PLWH not on ART, and poorly among those on ART. Further research is needed to identify feasible and effective TB screening strategies for PLWH in resource-limited settings.


Assuntos
Medicina Clínica/métodos , Infecções por HIV/complicações , Programas de Rastreamento/métodos , Tuberculose/diagnóstico , Tuberculose/patologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Estudos Transversais , Países em Desenvolvimento , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Microscopia/métodos , Pessoa de Meia-Idade , África do Sul , Inquéritos e Questionários , Tuberculose/microbiologia
8.
JIMD Rep ; 10: 103-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23430810

RESUMO

Autosomal recessive disorders affecting pyridoxine (vitamin B6) metabolism are a rare but well-recognized cause of neonatal seizures. Antiquitin deficiency, caused by mutations in ALDH7A1, is a disorder of the lysine degradation pathway causing accumulation of an intermediate that complexes with pyridoxal phosphate. Reports of long-term follow-up of neonatal pyridoxine-dependent seizures (PDS) remain scarce and prognostic information is varied. We report a case of PDS in a 47-year-old lady who originally presented shortly after birth in 1964. Pyridoxine replacement was successful and diagnostic confirmation was obtained later in life, initially by biochemical analysis of serum pipecolic acid. Subsequently we organized genetic analysis of ALDH7A1, which revealed compound heterozygous mutations. To our knowledge, this represents the longest duration of follow-up published to date.

10.
Diabetes ; 57(4): 1034-42, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18162506

RESUMO

OBJECTIVE: Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. RESEARCH DESIGN AND METHODS: The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes. RESULTS: We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K(+) channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant. CONCLUSIONS: We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.


Assuntos
Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/genética , Insulina/genética , Mutação , Adulto , Substituição de Aminoácidos , Criança , Humanos , Lactente , Recém-Nascido
11.
Am J Hum Genet ; 81(2): 375-82, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17668386

RESUMO

Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Diabetes Mellitus/congênito , Diabetes Mellitus/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio/genética , Receptores de Droga/genética , Estudos de Coortes , Genes Dominantes , Genes Recessivos , Heterozigoto , Humanos , Recém-Nascido , Insulina/metabolismo , Dados de Sequência Molecular , Linhagem , Receptores Sulfonilureia
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