Abstract
Hydroxysteroid (17β) dehydrogenase 10 (HSD10) and mitochondrial acetoacetyl-CoA thiolase (β-KT) are two adjacent enzymes for the degradation of isoleucine, thus HSD10 and β-KT deficiencies are confusing at an early stage because of nearly the same elevation of typical metabolites in urine, such as 2-methyl-3-hydroxybutyric acid (2M3HBA) and tiglylglycine (TG). In order to better understand the differences between these two disorders, we described the clinical and molecular characteristics of two HSD10 deficiency patients and four β-KT deficiency patients. β-KT deficiency patients had a much more favorable outcome than that of HSD10 deficiency patients, indicating that the multifunction of HSD10, especially neurosteroid metabolic activity, other than only enzymatic degradation of isoleucine, is involved in the pathogenesis of HSD10 deficiency. Two different mutations, a novel mutation p.Ile175Met and a reported mutation p.Arg226Gln, were detected in the HSD17B10 gene of HSD10 deficiency patients. Six different mutations, including four known mutations: p.Ala333Pro, p.Thr297Lys, c.83_84delAT, c.1006-1G > C, and two novel mutations: p.Thr277Pro and c.121-3C > G were identified in the ACAT1 gene of β-KT deficiency patients. In general, DNA diagnosis played an important role in distinguishing between these two disorders.
Similar content being viewed by others
References
Chatfield KC et al (2015) Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing. Mitochondrion 21:1–10. https://doi.org/10.1016/j.mito.2014.12.005
Deutschmann AJ et al (2014) Mutation or knock-down of 17beta-hydroxysteroid dehydrogenase type 10 cause loss of MRPP1 and impaired processing of mitochondrial heavy strand transcripts. Hum Mol Genet 23:3618–3628. https://doi.org/10.1093/hmg/ddu072
Falk MJ et al (2016) A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression. RNA Biol 13:477–485. https://doi.org/10.1080/15476286.2016.1159381
Feldman AG, Sokol RJ, Hardison RM, Alonso EM, Squires RH, Narkewicz MR, Pediatric Acute Liver Failure Study G (2017) Lactate and lactate: pyruvate ratio in the diagnosis and outcomes of pediatric acute liver failure. J Pediatr 182(217–222):e213. https://doi.org/10.1016/j.jpeds.2016.12.031
Fukao T, Yamaguchi S, Orii T, Osumi T, Hashimoto T (1992) Molecular basis of 3-ketothiolase deficiency: identification of an AG to AC substitution at the splice acceptor site of intron 10 causing exon 11 skipping. Biochim Biophys Acta 1139:184–188
Fukao T, Yamaguchi S, Orii T, Hashimoto T (1995) Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme a thiolase gene. Hum Mutat 5:113–120. https://doi.org/10.1002/humu.1380050203
Fukao T et al. (1997) Identification of three novel frameshift mutations (83delAT, 754insCT, and 435 + 1G to A) of mitochondrial acetoacetyl-coenzyme A thiolase gene in two Swiss patients with CRM-negative beta-ketothiolase deficiency. Hum Mutat 9:277–279. https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<277::AID-HUMU11>3.0.CO;2-#
Fukao T, Scriver CR, Kondo N, t2 Collaborative Working G (2001) The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Mol Genet Metab 72:109–114. https://doi.org/10.1006/mgme.2000.3113
Fukao T, Horikawa R, Naiki Y, Tanaka T, Takayanagi M, Yamaguchi S, Kondo N (2010a) A novel mutation (c.951C>T) in an exonic splicing enhancer results in exon 10 skipping in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab 100:339–344. https://doi.org/10.1016/j.ymgme.2010.03.012
Fukao T et al (2010b) A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab 100:37–41. https://doi.org/10.1016/j.ymgme.2010.01.007
Fukao T et al (2012) Three japanese patients with beta-ketothiolase deficiency who share a mutation, c.431A>C (H144P) in ACAT1 : subtle abnormality in urinary organic acid analysis and blood acylcarnitine analysis using tandem mass spectrometry. JIMD Rep 3:107–115. https://doi.org/10.1007/8904_2011_72
Fukao T et al (2014) The first case in Asia of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) with atypical presentation. J Hum Genet 59:609–614. https://doi.org/10.1038/jhg.2014.79
Garcia-Villoria J et al (2009) Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis. Clin Biochem 42:27–33. https://doi.org/10.1016/j.clinbiochem.2008.10.006
He XY, Schulz H, Yang SY (1998) A human brain L-3-hydroxyacyl-coenzyme a dehydrogenase is identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease. J Biol Chem 273:10741–10746
He XY, Wegiel J, Yang SY (2005) Intracellular oxidation of allopregnanolone by human brain type 10 17beta-hydroxysteroid dehydrogenase. Brain Res 1040:29–35. https://doi.org/10.1016/j.brainres.2005.01.022
Kano M, Fukao T, Yamaguchi S, Orii T, Osumi T, Hashimoto T (1991) Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene. Gene 109:285–290
Korman SH (2006) Inborn errors of isoleucine degradation: a review. Mol Genet Metab 89:289–299. https://doi.org/10.1016/j.ymgme.2006.07.010
Masuno M et al (1992) Chromosome mapping of the human mitochondrial acetoacetyl-coenzyme A thiolase gene to 11q22.3----q23.1 by fluorescence in situ hybridization. Cytogenet Cell Genet 60:121–122
Nguyen KN et al (2017) Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years' experience of a medical center in northern Vietnam. J Inherit Metab Dis 40:395–401. https://doi.org/10.1007/s10545-017-0026-6
Olpin SE, Pollitt RJ, McMenamin J, Manning NJ, Besley G, Ruiter JP, Wanders RJ (2002) 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency in a 23-year-old man. J Inherit Metab Dis 25:477–482
Perez-Cerda C et al (2005) 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: an X-linked inborn error of isoleucine metabolism that may mimic a mitochondrial disease. Pediatr Res 58:488–491. https://doi.org/10.1203/01.pdr.0000176916.94328.cd
Poll-The BT, Wanders RJ, Ruiter JP, Ofman R, Majoie CB, Barth PG, Duran M (2004) Spastic diplegia and periventricular white matter abnormalities in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, a defect of isoleucine metabolism: differential diagnosis with hypoxic-ischemic brain diseases. Mol Genet Metab 81:295–299. https://doi.org/10.1016/j.ymgme.2003.11.013
Rauschenberger K et al (2010) A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO molecular medicine 2:51–62. https://doi.org/10.1002/emmm.200900055
Richards S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med J Am Coll Med Genet 17:405–424. https://doi.org/10.1038/gim.2015.30
Sarafoglou K, Matern D, Redlinger-Grosse K, Bentler K, Gaviglio A, Harding CO, Rinaldo P (2011) Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. Pediatrics 128:e246–e250. https://doi.org/10.1542/peds.2010-3918
Seaver LH et al (2011) A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability. PLoS One 6:e27348. https://doi.org/10.1371/journal.pone.0027348
Sutton VR, O'Brien WE, Clark GD, Kim J, Wanders RJ (2003) 3-Hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 26:69–71
Yang SY et al (2009) Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism. Proc Natl Acad Sci U S A 106:14820–14824. https://doi.org/10.1073/pnas.0902377106
Yang SY, Dobkin C, He XY, Philipp M, Brown WT (2013) A 5-methylcytosine hotspot responsible for the prevalent HSD17B10 mutation. Gene 515:380–384. https://doi.org/10.1016/j.gene.2012.12.064
Zhang GX et al (2004) Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with "mild" mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA. Pediatr Res 56:60–64. https://doi.org/10.1203/01.PDR.0000129657.48122.52
Zschocke J (2012) HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. J Inherit Metab Dis 35:81–89. https://doi.org/10.1007/s10545-011-9415-4
Acknowledgements
The study was supported by Health and Family planning Commission of Guangzhou Municipality Grant (20151A010048).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declared that they have no conflicts of interest to this work.
Rights and permissions
About this article
Cite this article
Su, L., Li, X., Lin, R. et al. Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene. Metab Brain Dis 32, 2063–2071 (2017). https://doi.org/10.1007/s11011-017-0097-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-017-0097-y