TY - JOUR
T1 - 3-Hydroxyisobutyric acid dehydrogenase deficiency
T2 - Expanding the clinical spectrum and quantitation of D- and L-3-Hydroxyisobutyric acid by an LC–MS/MS method
AU - Sasarman, Florin
AU - Ferdinandusse, Sacha
AU - Sinasac, David S.
AU - Fung, Ernest
AU - Sparkes, Rebecca
AU - Reeves, Melanie
AU - Rombough, Catherine
AU - Sass, J. rn Oliver
AU - Voit, Renate
AU - Ruiter, Jos P. N.
AU - Koster, Janet
AU - Waterham, Hans R.
AU - Pasquini, Elisabetta
AU - Donati, Maria A.
AU - Marquardt, Thorsten
AU - Wanders, Ronald J. A.
AU - Al-Hertani, Walla
N1 - Funding Information: J. O. Sass gratefully acknowledges financial support by the programs FH Zeit für Forschung (“KETOplus”, 005‐1703‐0016) and FH‐Struktur (“FunForGen”, 322‐08‐03‐04‐02) of the Ministry of Culture and Science of the German State of North Rhine‐Westphalia. We thank Dr. Claudia Till for skillful scientific assistance. Funding Information: J. O. Sass gratefully acknowledges financial support by the programs FH Zeit für Forschung (“KETOplus”, 005-1703-0016) and FH-Struktur (“FunForGen”, 322-08-03-04-02) of the Ministry of Culture and Science of the German State of North Rhine-Westphalia. We thank Dr. Claudia Till for skillful scientific assistance. Publisher Copyright: © 2022 SSIEM.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - A deficiency of 3-hydroxyisobutyric acid dehydrogenase (HIBADH) has been recently identified as a cause of primary 3-hydroxyisobutyric aciduria in two siblings; the only previously recognized primary cause had been a deficiency of methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately downstream of HIBADH in the valine catabolic pathway and is encoded by the ALDH6A1 gene. Here we report on three additional patients from two unrelated families who present with marked and persistent elevations of urine L-3-hydroxyisobutyric acid (L-3HIBA) and a range of clinical findings. Molecular genetic analyses revealed novel, homozygous variants in the HIBADH gene that are private within each family. Evidence for pathogenicity of the identified variants is presented, including enzymatic deficiency of HIBADH in patient fibroblasts. This report describes new variants in HIBADH as an underlying cause of primary 3-hydroxyisobutyric aciduria and expands the clinical spectrum of this recently identified inborn error of valine metabolism. Additionally, we describe a quantitative method for the measurement of D- and L-3HIBA in plasma and urine and present the results of a valine restriction therapy in one of the patients.
AB - A deficiency of 3-hydroxyisobutyric acid dehydrogenase (HIBADH) has been recently identified as a cause of primary 3-hydroxyisobutyric aciduria in two siblings; the only previously recognized primary cause had been a deficiency of methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately downstream of HIBADH in the valine catabolic pathway and is encoded by the ALDH6A1 gene. Here we report on three additional patients from two unrelated families who present with marked and persistent elevations of urine L-3-hydroxyisobutyric acid (L-3HIBA) and a range of clinical findings. Molecular genetic analyses revealed novel, homozygous variants in the HIBADH gene that are private within each family. Evidence for pathogenicity of the identified variants is presented, including enzymatic deficiency of HIBADH in patient fibroblasts. This report describes new variants in HIBADH as an underlying cause of primary 3-hydroxyisobutyric aciduria and expands the clinical spectrum of this recently identified inborn error of valine metabolism. Additionally, we describe a quantitative method for the measurement of D- and L-3HIBA in plasma and urine and present the results of a valine restriction therapy in one of the patients.
KW - 3-hydroxyisobutyrate dehydrogenase
KW - 3-hydroxyisobutyric acid dehydrogenase deficiency
KW - 3-hydroxyisobutyric aciduria
KW - HIBADH
KW - HIBADH deficiency
KW - valine catabolic pathway
UR - http://www.scopus.com/inward/record.url?scp=85125800785&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jimd.12486
DO - https://doi.org/10.1002/jimd.12486
M3 - Article
C2 - 35174513
SN - 0141-8955
VL - 45
SP - 445
EP - 455
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 3
ER -