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

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.

Solvent accessibility of E1α and E1β residues with known missense mutations causing pyruvate dehydrogenase complex (PDC) deficiency: Impact on PDC‐E1 structure and function

“…The frequency of PDCD due to PDHA1 calculated from the gnomAD database, which favors adult subjects, is lower than that determined from a pilot PDCD newborn screening protocol limited to newborns in Ohio, USA, where the observed frequency of newborns with PDCD due to PDHA1 during a 12-month study period was 1 in 41 138. 17 With 141 456 subject entries (both male and female) in gnomAD and 9 pathogenic or likelypathogenic PDHB variants (missense, nonsense, splice site, and/or indels) identified, we estimate a frequency of 1 in 25 million subjects with PDCD due to PDHB.…”

“…11 Clinically PDC deficiency (PDCD) is highly variable ranging from fatal congenital lactic acidosis and congenital brain abnormalities, to progressive neurological and neuromuscular degradation and dysfunction with significant global developmental delay, to relatively mild ataxia or neuropathy with normal cognitive function and long survival. 3,[12][13][14][15][16] The estimated overall incidence of PDCD is between 1:50 000 and 1:75 000 live births annually in North America, 17 with a prevalence of 1 in 790 000 also reported. 4 Based on the genetic etiology of the deficiency, PDCDs are subclassified into at least three groups, primary-specific, primary-generalized, and secondary.…”

“…4 Based on the genetic etiology of the deficiency, PDCDs are subclassified into at least three groups, primary-specific, primary-generalized, and secondary. [17][18][19] Mutations in at least 38 genes are associated with PDCD but the majority (70%-90%) of genetically resolved PDCD are due to primary-specific PDC genes (PDHA1, PDHB, DLAT, PDHX, and PDP1), with those due to the X-linked PDHA1 constituting 82%-88% of primary-specific PDCD cases. 12,17,18,20 Dysregulation of the ubiquitin-proteasome system can result in E1β subunit instability leading to PDCD without any molecular defect in PDHB 21 and so further investigations of ubiquitin-proteasome system-related genes affecting PDCD are needed.…”

“…[17][18][19] Mutations in at least 38 genes are associated with PDCD but the majority (70%-90%) of genetically resolved PDCD are due to primary-specific PDC genes (PDHA1, PDHB, DLAT, PDHX, and PDP1), with those due to the X-linked PDHA1 constituting 82%-88% of primary-specific PDCD cases. 12,17,18,20 Dysregulation of the ubiquitin-proteasome system can result in E1β subunit instability leading to PDCD without any molecular defect in PDHB 21 and so further investigations of ubiquitin-proteasome system-related genes affecting PDCD are needed. Patients with pathogenic PDHA1 variants in exons 10 and 11 generally have severe clinical phenotype with low PDC activity in blood lymphocytes.…”

“…The estimated overall incidence of PDCD is between 1:50 000 and 1:75 000 live births annually in North America, 17 with a prevalence of 1 in 790 000 also reported 4 . Based on the genetic etiology of the deficiency, PDCDs are subclassified into at least three groups, primary‐specific, primary‐generalized, and secondary 17‐19 . Mutations in at least 38 genes are associated with PDCD but the majority (70%‐90%) of genetically resolved PDCD are due to primary‐specific PDC genes ( PDHA1 , PDHB , DLAT , PDHX , and PDP1 ), with those due to the X‐linked PDHA1 constituting 82%‐88% of primary‐specific PDCD cases 12,17,18,20 .…”