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
Jirair K. Bedoyan,
Rosemary Hage,
Ha Kyung Shin,
Sharon Linard,
Edwin Ferren,
Nicole Ducich,
Kirkland Wilson,
April Lehman,
Lori‐Anne Schillaci,
Kandamurugu Manickam,
Mari Mori,
Dennis Bartholomew,
Suzanne DeBrosse,
Bruce Cohen,
Sumit Parikh,
Douglas Kerr
Affiliations
Jirair K. Bedoyan
Departments of Genetics and Genome Sciences Case Western Reserve University (CWRU) Cleveland Ohio USA
Rosemary Hage
Newborn Screening and Radiation Chemistry Ohio Department of Health Laboratory Columbus Ohio USA
Ha Kyung Shin
School of Medicine CWRU Cleveland Ohio USA
Sharon Linard
Newborn Screening and Radiation Chemistry Ohio Department of Health Laboratory Columbus Ohio USA
Edwin Ferren
Pediatrics CWRU Cleveland Ohio USA
Nicole Ducich
School of Medicine CWRU Cleveland Ohio USA
Kirkland Wilson
School of Medicine CWRU Cleveland Ohio USA
April Lehman
Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine Columbus Ohio USA
Lori‐Anne Schillaci
Departments of Genetics and Genome Sciences Case Western Reserve University (CWRU) Cleveland Ohio USA
Kandamurugu Manickam
Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine Columbus Ohio USA
Mari Mori
Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine Columbus Ohio USA
Dennis Bartholomew
Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine Columbus Ohio USA
Suzanne DeBrosse
Departments of Genetics and Genome Sciences Case Western Reserve University (CWRU) Cleveland Ohio USA
Bruce Cohen
Department of Pediatrics Akron Children's Hospital (ACH) Rebecca D. Considine Research Institute Akron Ohio USA
Sumit Parikh
The Cleveland Clinic Foundation (CCF), Neurosciences Institute Cleveland Ohio USA
Abstract 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.
