Inborn errors of metabolism refuse to stay-at-home: Experiences of a state-wide biochemical genetics service during the COVID-19 pandemic.

AIM: The New South Wales (NSW) biochemical genetics (BG) service in Australia developed business continuity plans (BCPs) in response to the COVID-19 pandemic to ensure the essential service remained operational. This article aims to discuss the effects of the COVID-19 BCPs on the NSW BG service and patient care. METHODS: BCPs were developed that included charting of NSW BG service workflow and services against staff resources and clinical impact on patients. The effect of the BCPs was analysed quantitatively by reviewing key performance indicators (result turnaround time, frequency and severity of clinical incidents and laboratory nonconformities) and qualitatively from staff feedback generated by a BG laboratory-wide survey. RESULTS: Alternative BCPs were implemented during the pre-defined period March 2020 to November 2021 (inclusive), to reflect changes in COVID-19 community transmission, vaccination rates; and health orders. Operation of our essential pathology service was maintained, with no significant difference observed in key performance indicators when compared to pre-COVID. During the pre-defined period of the COVID-19 pandemic, staff reported increased levels of both work- and out-of-work-related stress. CONCLUSION: The successful continuation of the BG service, with no statistically significant impact on patient care and delivery of essential services, can be attributed to strategic planning and timely implementation of these BCPs. In conjunction with the resilient and robust attitude of the staff during this ever-changing situation, this experience has served as an invaluable tool for future disaster management planning.

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

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.