Clinical OMICS

MAY-JUN 2019

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com May/June 2019 Clinical OMICs 25 ysis. In both the mice and cells, metabolic abnormalities similar to those described in the patient were observed. This study has provided incredibly important informa- tion to the patient and her family. Beyond that, DeBerardinis notes that "the next time there is a patient who gets WES without the metabolomic workup, and a mutation is found in the LIPT1 gene, it will be easy for the lab to say that this is the cause of the problem." "One of the most exciting parts of this study is that it allowed us to build a research platform using advanced genomics and metabolomics technologies together with experimental assays, to identify the disease cause of a rare IEM" noted Min Ni, Ph.D., assistant professor at the CRI and first author on the paper. This is particularly important because, as Ni asserted, "effi- cient diagnosis of IEMs is always challenging." There are more than 400 known IEMs that share the commonality of abnormal metabolism. Caused by having a mutation in an enzyme that catalyzes one of the steps in the biochemical network, some can be diagnosed by a phenotypic change caused by the shift in metabolites. But, for many others, a diagnosis requires sleuth- ing around in non-specific symptoms with limited means of molecular or biochemical testing. Therefore, many remain largely undiagnosed. However, if the underlying metabolic defect can be understood, a workaround of the metabolic block may be developed—fixing the broken step in the pathway. Ni said she was "very surprised" that a single-point muta- tion in a gene, such as the one they found in LIPT1, could lead to the remarkable alterations of multiple metabolic pathways. Because LIPT1 activates multiple other enzymes, this patient actually has defects in multiple different enzymes in the Kreb's Cycle. Although this complexity makes it more challenging to find a workaround, the results of the study have prompted the team to think about adding the dietary supplements to replenish those that have been depleted in the patient's diet. DeBerardinis noted that "the generosity of this family to par- ticipate in this study means that the next time we encounter a patient with LIPT1 deficiency, we could potentially start diets that could be helpful to these patients earlier in life." Ni added that their hope is that this work reaches beyond LIPT1. She noted that "the workflow could be readily applied to study of many other IEMs." DeBerardinis agrees, noting that "implementing metabolomics in a clinical setting is not impossible." Mass spectrometry is already present in clinical labs, so "we hope to convince people that this is something that could be broadly implemented." Min Ni (second from right) lead author of the Cell Reports paper "Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans" discusses lab results with other researchers at the Children's Medical Center Research Institute at UT Southwestern Medical Center Researchers led by Ralph DeBerardinis, M.D., Ph.D., chief of the division of pediatric genetics and metabolism at the Children's Medical Center Research Institute at UT Southwestern Medical Center are combining genomics and metabolomics to identify genes that, when mutated, give rise to metabolic diseases in children.

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