Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects.
Title
Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects.
Creator
Bedoyan JK; Hage R; Shin HK; Linard S; Ferren E; Ducich N; Wilson K; Lehman A; Schillaci L; Manickam K; Mori Mari; Bartholomew D; DeBrosse S; Cohen B; Parikh S; Kerr D
Publisher
Jimd Reports
Date
2020
2020-11
Description
Pyruvate dehydrogenase complex deficiencies (PDCDs) and other mitochondrial disorders (MtDs) can (a) result in congenital lactic acidosis with elevations of blood alanine (Ala) and proline (Pro), (b) lead to decreased ATP production, and (c) result in high morbidity and mortality. With ~140,000 live births annually in Ohio and ~1 in 9,000 overall prevalence of MtDs, we estimate 2 to 3 newborns will have PDCD and 13 to 14 others likely will have another MtD annually. We compared the sensitivities of plasma amino acids (AA) Alanine (Ala), Alanine:Leucine (Ala:Leu), Alanine:Lysine and the combination of Ala:Leu and Proline:Leucine (Pro:Leu), in subjects with known primary-specific PDCD due to PDHA1 and PDHB mutations vs controls. Furthermore, in collaboration with the Ohio newborn screening (NBS) laboratory, we determined Ala and Pro concentrations in dried blood spot (DBS) specimens using existing NBS analytic approaches and evaluated Ala:Leu and Pro:Leu ratios from DBS specimens of 123,414 Ohio newborns in a 12-month period. We used the combined Ala:Leu ≥4.0 and Pro:Leu ≥3.0 ratio criterion from both DBS and plasma specimens as a screening tool in our retrospective review of newborn data. The screening tool applied on DBS and/or plasma (or serum) AA specimens successfully identified three unrelated females with novel de novo PDHA1 mutations, one male with a novel de novo X-linked HSD17B10 mutation, and a female with VARS2 mutations. This work lays the first step for piloting an NBS protocol in Ohio for identifying newborns at high risk for primary-specific PDCD and other MtDs who might benefit from neonatal diagnosis and early institution of known therapy and/or potential novel therapies for such disorders.
Subject
ketogenic diet; alanine; ketogenic amino acids; lactic acidosis; mitochondrial disorder; newborn screening; proline; pyruvate dehydrogenase complex deficiency
Identifier
Rights
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Format
journalArticle
URL Address
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Pages
70-81
Issue
1
Volume
56
ISSN
2192-8304 2192-8312 2192-8304
NEOMED College
NEOMED College of Medicine
NEOMED Department
Department of Pediatrics
Department of Integrative Medical Sciences
Update Year & Number
December 2020 List
Citation
Bedoyan JK; Hage R; Shin HK; Linard S; Ferren E; Ducich N; Wilson K; Lehman A; Schillaci L; Manickam K; Mori Mari; Bartholomew D; DeBrosse S; Cohen B; Parikh S; Kerr D, “Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects.,” NEOMED Bibliography Database, accessed April 19, 2024, https://neomed.omeka.net/items/show/11474.