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Case Reports
. 2020 Feb 3;6(1):a004705.
doi: 10.1101/mcs.a004705. Print 2020 Feb.

Mortality in a neonate with molybdenum cofactor deficiency illustrates the need for a comprehensive rapid precision medicine system

Stephen F Kingsmore  1 , Nanda Ramchandar  1   2 , Kiely James  1 , Anna-Kaisa Niemi  2 , Annette Feigenbaum  2 , Yan Ding  1 , Wendy Benson  1 , Charlotte Hobbs  1 , Shareef Nahas  1 , Shimul Chowdhury  1 , David Dimmock  1
Affiliations
Case Reports

Mortality in a neonate with molybdenum cofactor deficiency illustrates the need for a comprehensive rapid precision medicine system

Stephen F Kingsmore et al. Cold Spring Harb Mol Case Stud. .

Abstract

Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.

Keywords: congenital horizontal nystagmus; diffuse swelling of cerebral white matter; generalized tonic seizures; hypouricemia; infantile encephalopathy; poor suck; upper limb spasticity.

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Figures

Figure 1.
Figure 1.
Components of the proposed comprehensive system for delivery of newborn precision medicine.
See this image and copyright information in PMC

References

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