Inborn errors of metabolism in a neonatology unit: Impact and long‐term results

Couce, María L.; Bana, A.; Bóveda, M. Dolores; Pérez-Muñuzuri, Alejandro; Fernández-Lorenzo, José Ramón; Fraga, José M.

doi:10.1111/j.1442-200x.2010.03177.x

Cited by 23 publications

(21 citation statements)

References 18 publications

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“…1–7 There are more than 4300 genetic diseases of known causes. Collectively, they are the leading causes of infant mortality, particularly in neonatal intensive care units (NICUs), 4 and in paediatric intensive care units (PICUs).…”

Section: Introductionmentioning

confidence: 99%

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Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

Willig

Petrikin

Smith

et al. 2015

The Lancet Respiratory Medicine

331

447

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Summary Background Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants. Methods We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large children's hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq. Findings 20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0·0002). Median time to genome analysis was 5 days (range 3–153) and median time to STATseq report was 23 days (5–912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis. Interpretation In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.

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Section: Introductionmentioning

confidence: 99%

“…5,19,20,23,24,27–32 Although appropriate NICU treat ment is one of the most cost-effective methods of high-cost health care, patients’ long-term outcomes are diverse. 1,8,33,34 In genetic diseases with poor prognosis, rapid diagnosis might enable early discussions with parents about palliative care to minimise suffering. 8,34 …”

Section: Introductionmentioning

confidence: 99%

Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

Willig

Petrikin

Smith

et al. 2015

The Lancet Respiratory Medicine

331

447

View full text Add to dashboard Cite

show abstract

“…Indeed, NICU treatment is among the most cost-effective of high-cost health care, and the long-term outcomes of most NICU subpopulations are excellent (16–18). In genetic diseases for which treatments exist, rapid diagnosis is critical for timely delivery of interventions that lessen morbidity and mortality (14–17, 19, 20).…”

Section: Introductionmentioning

confidence: 99%

Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

et al. 2012

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Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling.

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“…21 Over the last years, the implementation of expanded newborn screening programs in several countries, as well as the availability of new specific therapies for some diseases and advanced supportive devices have contributed to modify some IMD's natural history and progression. 1,4 As shown in Couce series 22 about the incidence of IMD in a neonatal unit, not necessary related to ALF, the investment in an early neonatal screening can allow the early diagnosis and treatment in a group of patients in a pre-symptomatic period, avoiding severe clinical complications and hospital admission in a number of cases.…”

Section: Discussionmentioning

confidence: 99%

Acute liver failure related to inherited metabolic diseases in young children

Costa

Moinho

Ferreira

et al. 2018

Anales de Pediatría (English Edition)

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Inborn errors of metabolism in a neonatology unit: Impact and long‐term results

Abstract: Earlier diagnosis by expanded newborn screening and earlier treatment is essential in order to be able to prevent neurological sequelae.

Cited by 23 publications

References 18 publications

Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

Acute liver failure related to inherited metabolic diseases in young children

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