Abstract
Analyses of 19 amino acids, 38 acylcarnitines, and 3 creatine analogues (https://clir.mayo.edu) were implemented to test the hypothesis that succinic semialdehyde dehydrogenase deficiency (SSADHD) could be identified in dried bloodspots (DBS) using currently available newborn screening methodology. The study population included 17 post‐newborn SSADHD DBS (age range 0.8‐38 years; median, 8.2 years; 10 M; controls, 129‐353 age‐matched individuals, mixed gender) and 10 newborn SSADHD DBS (including first and second screens from 3 of 7 patients). Low (informative) markers in post‐newborn DBS included C2‐ and C4‐OH carnitines, ornithine, histidine and creatine, with no gender differences. For newborn DBS, informative markers included C2‐, C3‐, C4‐ and C4‐OH carnitines, creatine and ornithine. Of these, only creatine demonstrated a significant change with age, revealing an approximate 4‐fold decrease. We conclude that quantitation of short‐chain acylcarnitines, creatine, and ornithine provides a newborn DBS profile with potential as a first tier screening tool for early detection of SSADHD. This first tier evaluation can be readily verified using a previously described second tier liquid chromatography‐tandem mass spectrometry method for γ‐hydroxybutyric acid in the same DBS. More extensive evaluation of this first/second tier screening approach is needed in a larger population.
Highlights
Treatment for Succinic semialdehyde dehydrogenase deficiency (SSADHD) remains symptomatic, yet an expanding therapeutic preclinical pipeline strongly suggests that targeted and effective therapies for SSADHD are on the horizon.[13]
These survey data provide a measurable perspective on the disease burden for SSADHD families who have to wait 3 years to achieve a diagnosis, as well as the public health and societal impact of delayed diagnosis. To address these unmet healthcare needs, we examined the hypothesis that an integrated screen of 19 amino acids, 38 acylcarnitines, and 3 creatine analogues could be used to potentially identify a metabolomic pattern that could be used as an first-tier screening tool for SSADHD using dried bloodspots (DBS), an approach that has been successful in a number of inborn errors of metabolism.[16,17,18]
Short-chain acylcarnitine species were informative in both post-newborn and newborn SSADHD DBS, encompassing C2- and C4-OH carnitine in the post-newborn samples and C2, C3, C4, and C4-OH in newborn SSADHD DBS. This may not be surprising in view of the accumulation of both GHB and succinic semialdehyde in SSADHD,[13,34] which may interfere with short chain fatty acid metabolism
Summary
Under current circumstances (with a median age at diagnosis of 3 years), any natural history study of SSADHD would not include patients diagnosed in the early newborn period, representing a major confound from the neurodevelopmental perspective of a disease manifesting a prominent neurological phenotype These survey data provide a measurable perspective on the disease burden for SSADHD families who have to wait 3 years to achieve a diagnosis, as well as the public health and societal impact of delayed diagnosis.
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