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Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning

Authors :
Mona Sajeev
Sharon Chin
Gladys Ho
Bruce Bennetts
Bindu Parayil Sankaran
Bea Gutierrez
Beena Devanapalli
Adviye Ayper Tolun
Veronica Wiley
Janice Fletcher
Maria Fuller
Shanti Balasubramaniam
Source :
International Journal of Neonatal Screening, Vol 7, Iss 2, p 25 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A>G (p. Tyr122Cys) in the DBT gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics.

Details

Language :
English
ISSN :
2409515X
Volume :
7
Issue :
2
Database :
Directory of Open Access Journals
Journal :
International Journal of Neonatal Screening
Publication Type :
Academic Journal
Accession number :
edsdoj.979438ed99754cd6b70d5292626f35db
Document Type :
article
Full Text :
https://doi.org/10.3390/ijns7020025