Characterization and outcome of 41 patients with beta‐ketothiolase deficiency: 10 years’ experience of a medical center in northern Vietnam

Abstract

Beta-ketothiolase (T2) deficiency is an inherited disease of isoleucine and ketone body metabolism caused by mutations in the ACAT1 gene. Between 2005 and 2016, a total of 41 patients with T2 deficiency were identified at a medical center in northern Vietnam, with an estimated incidence of one in 190,000 newborns. Most patients manifested ketoacidotic episodes of varying severity between 6 and 18 months of age. Remarkably, 28% of patients showed high blood glucose levels (up to 23.3 mmol/L). Ketoacidotic episodes recurred in 43% of patients. The age of onset, frequency of episodes, and identified genotype did not affect patient outcomes that were generally favorable, with the exception of seven cases (five died and two had neurological sequelae). Custom-tailored acute and follow-up management was critical for a positive clinical outcome. Two null mutations, c.622C>T (p.Arg208*) and c.1006-1G>C (p.Val336fs), accounted for 66% and 19% of all identified ACAT1 mutant alleles, respectively. Most patients showed characteristic biochemical abnormalities. A newborn screening program could be expected to have a high yield in Vietnam. Investigation findings of haplotypes linked to the most common ACAT1 mutation (c.622C>T) are consistent with an ancient common founder of mutation-bearing chromosomes belonging to the Kinh ethnic population. The direct management and long-term follow-up of a large number of T2-deficient patients enabled us to study the natural history of this rare disease.

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

“…It has been detected in 28 families, most of which are Vietnamese. This variant accounts for 66% of all ACAT1 variant alleles identified in Vietnamese patients with T2 deficiency (Nguyen et al, ). Recent evidence indicates that the c.622C>T variant has been introduced by an ancient common founder to Vietnamese Kinh ethnic population 1900–2500 years ago (Nguyen et al, ).…”

“…This variant accounts for 66% of all ACAT1 variant alleles identified in Vietnamese patients with T2 deficiency (Nguyen et al, ). Recent evidence indicates that the c.622C>T variant has been introduced by an ancient common founder to Vietnamese Kinh ethnic population 1900–2500 years ago (Nguyen et al, ). This highly conserved residue is changed into glutamine (c.623G>A, p.Arg208Gln) in two other families (Sakurai et al, ).…”

“…Furthermore, five large deletions/insertions/duplications have been reported in the ACAT1 gene. g.20623_29833delinsGTAA includes deletion of exons 6–11 (Nguyen et al, ). c.731–46_752del (a 68‐bp deletion) involves the splice acceptor site of intron 7, causing exon 8 skipping (Fukao, Song, et al, ).…”

“…Since Daum, Lamm, Mamer, and Scriver (1971), for the first time, characterized T2 deficiency, at least 159 patients (Supporting Information Table) with the disease have been confirmed (through enzyme assay and/or genetic analysis) worldwide without ethnic preference. The incidence of T2 deficiency has been estimated in some regions, as one per 232,000 newborns in Minnesota, one per 190,000 newborns in northern Vietnam, and one per 111,000 newborns in Hyderabad (India) (Abdelkreem, Akella, et al, 2017;Nguyen et al, 2017;Sarafoglou et al, 2011).…”

“…Disease-associated ACAT1 variants are found in every exon ( Figure 4). Exon 11 contains the highest number (n = 15), followed by exon 6 (n = 11), exon 5 (n = 9), and exons 7 and 9 (each = 8 (Nguyen et al, 2017). This highly conserved residue is changed into glutamine (c.623G>A, p.Arg208Gln) in two other families (Sakurai et al, 2007).…”