3‐Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase

Abstract

3-hydroxyisobutyric aciduria is an organic aciduria with a poorly understood biochemical basis. It has previously been assumed that deficiency of 3-hydroxyisobutyrate dehydrogenase (HIBADH) in the valine catabolic pathway is the underlying enzyme defect, but more recent evidence makes it likely that individuals with 3-hydroxyisobutyryic aciduria represent a heterogeneous group with different underlying mechanisms, including respiratory chain defects or deficiency of methylmalonate semialdehyde dehydrogenase. However, to date methylmalonate semialdehyde dehydrogenase deficiency has only been demonstrated at the gene level for a single individual. We present two unrelated patients who presented with developmental delay and increased urinary concentrations of 3-hydroxyisobutyric acid. Both children were products of consanguineous unions and were of European or Pakistani descent. One patient developed a febrile illness and subsequently died from a hepatoencephalopathy at 2 years of age. Further studies were initiated and included tests of the HIBADH enzyme in fibroblast homogenates, which yielded normal activities. Sequencing of the ALDH6A1 gene (encoding methylmalonate semialdehyde dehydrogenase) suggested homozygosity for the missense mutation c.785 C > A (S262Y) in exon 7 which was not found in 210 control alleles. Mutation analysis of the ALDH6A1 gene of the second patient confirmed the presence of a different missense mutation, c.184 C > T (P62S), which was also identified in 1/530 control chromosomes. Both mutations affect highly evolutionarily conserved amino acids of the methylmalonate semialdehyde dehydrogenase protein. Mutation analysis in the ALDH6A1 gene can reveal a cause of 3-hydroxyisobutyric aciduria, which may present with only slightly increased urinary levels of 3-hydroxyisobutyric acid, if a patient is metabolically stable.

Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

“…Of interest, aldh3a1 has been suggested to promote resistance to 4-HNE-induced oxidative damage in the cornea, and lowered levels of this protein may add to the level of oxidative stress in aldh5a1 −/− mice [34]. Aldh6a1 encodes methylmalonate semialdehyde dehydrogenase, an enzyme on the valine catabolic pathway, with mitochondrial location [35, 36]. The mitochondrial location of this protein, and its elevated levels, is consistent with data on SOD2 in relation to increased mitochondrial numbers in aldh5a1 −/− mice [1].…”

Adenine Binding Mode Is a Key Factor in Triggering the Early Release of NADH in Coenzyme A-dependent Methylmalonate Semialdehyde Dehydrogenase

“…In mammals, MSDH is a mitochondrial enzyme that participates in the distal portions of the valine and pyrimidine catabolic pathways (25). A possible correlation between organic acidemia and MSDH deficiency has been explored (26,27), and very recently, Sass et al (28) proposed that polymorphism in the human ALDH6A1 gene encoding MSDH is directly correlated with 3-hydroxybutyric aciduria, a severe metabolic disease. Detailed kinetic studies of the MSDH-catalyzed reaction have shown that (i) the rate constant associated with the acylation step is high (k ac Ͼ 1000 s Ϫ1 ), indicating that the position of the nicotinamide ring relative to the hemithioacetal allows efficient hydride transfer, and (ii) that NADH release occurs before the rate-limiting ␤-decarboxylation and CoA attack on the thioacylenzyme intermediate (22), thus supporting the ping-pong kinetic mechanism that has previously been reported for other CoA-dependent ALDHs (29,30).…”

Aldehyde dehydrogenases: From eye crystallins to metabolic disease and cancer stem cells

“…Mutations in ALDH4A1 gene are associated with type II hyperprolinemia [34], and mutations in ALDH5A1 cause γ-hydroxybutyric aciduria [35]. A deficiency in ALDH6A1 is associated with psychomotor delay and methylmalonic aciduria [75] and a mutation in the ALDH6A1 gene causes 3-hydroxyisobutyric aciduria [76]. Patients suffering from pyridoxine-dependent seizures have a wide spectrum of mutations in the ALDH7A1 gene [36].…”

“…HSCs possess high levels of ALDH catalytic activity [80,81], making them less vulnerable to the cytotoxic effects of the chemotherapeutic agent, cyclophosphamide. Aldefluor®, a fluorescent compound activated by ALDH activity, was found to identify and select for human HSCs as well as mature myeloid progenitors from bone marrow, placenta and peripheral blood and, consequently, has been used as a marker for counting the number of HSCs and myeloid progenitors in these tissues for blood and marrow transplant purposes [76,82–87]. Aldefluor® has also been used to study leukemia and leukemic stem cells (LSCs) and preliminary evidence suggests that levels of activity in these cells may correlate with response to treatment [88–90].…”