3‐Hydroxyisobutyrate dehydrogenase (HIBADH) deficiency—A novel disorder of valine metabolism

Abstract

3-Hydroxyisobutyric acid (3HiB) is an intermediate in the degradation of the branched-chain amino acid valine. Disorders in valine degradation can lead to 3HiB accumulation and its excretion in the urine. This article describes the first two patients with a new metabolic disorder, 3-hydroxyisobutyrate dehydrogenase (HIBADH) deficiency, its phenotype and its treatment with a low-valine diet. The detected mutation in the HIBADH gene leads to nonsense-mediated mRNA decay of the mutant allele and to a complete lossof-function of the enzyme. Under strict adherence to a low-valine diet a rapid decrease of 3HiB excretion in the urine was observed. Due to limited patient numbers and intrafamilial differences in phenotype with one affected and one unaffected individual, the clinical phenotype of HIBADH deficiency needs further evaluation.

3‐Hydroxyisobutyric acid dehydrogenase deficiency: Expanding the clinical spectrum and quantitation of D‐ and L‐3‐Hydroxyisobutyric acid by an LC–MS/MS method

“…Clinical and biochemical findings, as well as diagnostic investigations performed on the patients described here and previously 2 are summarized in Table 1.…”

“…With respect to treatment, valine restriction and a low-protein diet resulted in lower levels of 3HIBA in plasma and/or urine in Patient 1 and Patient 4, the symptomatic patient described previously. 2 Upon valine restriction in Patient 1, plasma levels of L-3HIBA were quantified with a novel LC-MS/MS method and found to be directly proportional with plasma valine levels; a finding that brings forth an easily accessible monitoring parameter. Whether this treatment resulted in an improvement of the clinical parameters is less clear.…”

“…Recently, it has been demonstrated that in addition to a deficiency of MMSDH [MIM: 614105], primary 3‐hydroxyisobutyric aciduria can result from a deficiency of HIBADH 2 ; 3‐hydroxyisobutyric aciduria is also a recognized secondary finding in a subgroup of mitochondrial diseases. Pathogenic variants in ALDH6A1 [MIM: 603178] encoding MMSDH have been identified to date in five patients presenting with highly variable clinical phenotypes that range from severe developmental delays and MRI findings to virtually asymptomatic, and abnormal metabolites including markedly elevated urinary 3HIBA, milder but variable elevations of 3‐hydroxypropionic acid, beta‐aminoisobutyric acid, beta‐alanine and methylmalonic acid 3–6 .…”

“…Pathogenic variants in ALDH6A1 [MIM: 603178] encoding MMSDH have been identified to date in five patients presenting with highly variable clinical phenotypes that range from severe developmental delays and MRI findings to virtually asymptomatic, and abnormal metabolites including markedly elevated urinary 3HIBA, milder but variable elevations of 3‐hydroxypropionic acid, beta‐aminoisobutyric acid, beta‐alanine and methylmalonic acid 3–6 . A deficiency of HIBADH resulting from a homozygous pathogenic variant in HIBADH [MIM: 608475] has been recently described in two siblings with increased urinary excretion of 3HIBA, one of whom presented with psychomotor retardation and low average total IQ values, while the other was asymptomatic 2 …”

Differential proteomics of placentas reveals metabolic disturbance and oxidative damage participate yak spontaneous miscarriage during late pregnancy

“…Diseases associated with BCAT1 include hypervalinemia. HIBADH that plays a critical role in the catabolism of valine [ 31 ] also reduced its expression level. Therefore, the decline of BCAT1 and HIBADH might contribute to the abnormal alanine level.…”