RESUMO
Short-chain enoyl-coA hydratase (SCEH) deficiency due to biallelic pathogenic ECHS1 variants was first reported in 2014 in association with Leigh syndrome (LS) and increased S-(2-carboxypropyl)cysteine excretion. It is potentially treatable with a valine-restricted, high-energy diet and emergency regimen. Recently, Simon et al. described four Samoan children harbouring a hypomorphic allele (c.489G > A, p.Pro163=) associated with reduced levels of normally-spliced mRNA. This synonymous variant, missed on standard genomic testing, is prevalent in the Samoan population (allele frequency 0.17). Patients with LS and one ECHS1 variant were identified in NZ and Australian genomic and clinical databases. ECHS1 sequence data were interrogated for the c.489G > A variant and clinical data were reviewed. Thirteen patients from 10 families were identified; all had Pacific ancestry including Samoan, Maori, Cook Island Maori, and Tokelauan. All developed bilateral globus pallidi lesions, excluding one pre-symptomatic infant. Symptom onset was in early childhood, and was triggered by illness or starvation in 9/13. Four of 13 had exercise-induced dyskinesia, 9/13 optic atrophy and 6/13 nystagmus. Urine S-(2-carboxypropyl)cysteine-carnitine and other SCEH-related metabolites were normal or mildly increased. Functional studies demonstrated skipping of exon four and markedly reduced ECHS1 protein. These data provide further support for the pathogenicity of this ECHS1 variant which is also prevalent in Maori, Cook Island Maori, and Tongan populations (allele frequency 0.14-0.24). It highlights the need to search for a second variant in apparent heterozygotes with an appropriate phenotype, and has implications for genetic counselling in family members who are heterozygous for the more severe ECHS1 alleles. SYNOPSIS: Short-chain enoyl-CoA hydratase deficiency is a frequent cause of Leigh-like disease in Maori and wider-Pacific populations, due to the high carrier frequency of a hypomorphic ECHS1 variant c.489G > A, p.[Pro163=, Phe139Valfs*65] that may be overlooked by standard genomic testing.
Assuntos
Enoil-CoA Hidratase , Doença de Leigh , Humanos , Enoil-CoA Hidratase/genética , Enoil-CoA Hidratase/deficiência , Masculino , Feminino , Lactente , Austrália/epidemiologia , Doença de Leigh/genética , Pré-Escolar , Criança , Mutação , Nova Zelândia , Alelos , Frequência do GeneRESUMO
BACKGROUND: The term severe acute respiratory infection (SARI) encompasses a heterogeneous group of respiratory illnesses. Grading the severity of SARI is currently reliant on indirect disease severity measures such as respiratory and heart rate, and the need for oxygen or intensive care. With the lungs being the primary organ system involved in SARI, chest radiographs (CXRs) are potentially useful for describing disease severity. Our objective was to develop and validate a SARI CXR severity scoring system. METHODS: We completed validation within an active SARI surveillance project, with SARI defined using the World Health Organization case definition of an acute respiratory infection with a history of fever, or measured fever of ≥ 38 °C; and cough; and with onset within the last 10 days; and requiring hospital admission. We randomly selected 250 SARI cases. Admission CXR findings were categorized as: 1 = normal; 2 = patchy atelectasis and/or hyperinflation and/or bronchial wall thickening; 3 = focal consolidation; 4 = multifocal consolidation; and 5 = diffuse alveolar changes. Initially, four radiologists scored CXRs independently. Subsequently, a pediatrician, physician, two residents, two medical students, and a research nurse independently scored CXR reports. Inter-observer reliability was determined using a weighted Kappa (κ) for comparisons between radiologists; radiologists and clinicians; and clinicians. Agreement was defined as moderate (κ > 0.4-0.6), good (κ > 0.6-0.8) and very good (κ > 0.8-1.0). RESULTS: Agreement between the two pediatric radiologists was very good (κ = 0.83, 95% CI 0.65-1.00) and between the two adult radiologists was good (κ = 0.75, 95% CI 0.57-0. 93). Agreement of the clinicians with the radiologists was moderate-to-good (pediatrician:κ = 0.65; pediatric resident:κ = 0.69; physician:κ = 0.68; resident:κ = 0.67; research nurse:κ = 0.49, medical students: κ = 0.53 and κ = 0.56). Agreement between clinicians was good-to-very good (pediatrician vs. physician:κ = 0.85; vs. pediatric resident:κ = 0.81; vs. medicine resident:κ = 0.76; vs. research nurse:κ = 0.75; vs. medical students:κ = 0.63 and 0.66). Following review of discrepant CXR report scores by clinician pairs, κ values for radiologist-clinician agreement ranged from 0.59 to 0.70 and for clinician-clinician agreement from 0.97 to 0.99. CONCLUSIONS: This five-point CXR scoring tool, suitable for use in poorly- and well-resourced settings and by clinicians of varying experience levels, reliably describes SARI severity. The resulting numerical data enables epidemiological comparisons of SARI severity between different countries and settings.
Assuntos
Radiografia Torácica/normas , Infecções Respiratórias/diagnóstico por imagem , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
Anaerobic meningitis in infants is rare, therefore a high index of clinical suspicion is essential as routine methods for processing cerebrospinal fluid (CSF) do not detect anaerobes and specific antimicrobial therapy is required. We present an infant with Escherichia coli meningitis where treatment-resistance developed in association with culture negative purulent CSF. These features should have alerted us to the presence of anaerobes, prompting a search for the causes of polymicrobial meningitis in infants.
Assuntos
Infecções por Bacteroides/diagnóstico , Bacteroides fragilis/isolamento & purificação , Coinfecção/diagnóstico , Meningites Bacterianas/diagnóstico , Meningite devida a Escherichia coli/complicações , Infecções por Bacteroides/complicações , Escherichia coli/isolamento & purificação , Humanos , Lactente , Masculino , Meningites Bacterianas/complicaçõesRESUMO
Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant lifelong improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5' UTR and minimal promoter region. This deletion is the smallest promoter deletion reported to date, further defining the minimal promoter region of SLC19A3 Unfortunately, one of the siblings died prior to diagnosis, but the other is showing significant improvement after commencement of therapy. This case demonstrates the power of whole-genome sequencing for the identification of structural variants and subsequent diagnosis of rare neurodevelopmental disorders.
Assuntos
Doenças dos Gânglios da Base/genética , Proteínas de Membrana Transportadoras/genética , Regiões 5' não Traduzidas/genética , Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/diagnóstico , Biotina/genética , Biotina/metabolismo , Encéfalo/metabolismo , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Mutação , Regiões Promotoras Genéticas/genética , Irmãos , Tiamina/metabolismo , Adulto JovemRESUMO
INTRODUCTION: Clinically occult fractures from non-accidental injury (NAI) are best detected on radiographic skeletal survey. However, there are regional variations regarding the views included in such surveys. We undertook a systematic review of the evidence supporting skeletal survey protocols to design a protocol that could be implemented across New Zealand. METHODS: In June 2013, we searched Medline, Google Scholar, the Cochrane database, UpToDate and relevant reference lists for English-language publications on skeletal survey in NAI from 1946. We included publications that contained a protocol or reported evidence supporting including, or excluding, specific views in a skeletal survey. All included publications were critically appraised. Based on this systematic review, a draft protocol was developed and presented to an Australian and New Zealand Society for Paediatric Radiology NAI symposium in October 2013. Feedback from the symposium and later discussions was incorporated into the final protocol. RESULTS: We identified 2 guidelines for skeletal survey, 13 other protocols and 15 articles providing evidence for inclusion of specific images in a skeletal survey. The guidelines scored poorly on critical appraisal of several aspects of their methods. We found no studies that validate any of the protocols or compare their performance. Evidence supporting inclusion in a skeletal survey is limited to ribs, spine, pelvis, hands and feet, and long bone views. Our final protocol is a standardised, two-tiered protocol consisting of between 17 and 22 views. CONCLUSION: A standardised protocol for radiographic skeletal survey protocol has been developed in New Zealand. We present it here for consideration by others.