MSACL 2016 EU Abstract

Application of GC/MS and Untargeted Metabolomics for the Diagnosis of Transaldolase (TALDO) Deficiency

Qin Sun (Presenter)
Baylor College of Medicine

Bio: PhD. FACMG Co-Director, Biochemical Genetics Laboratory Assistant Professor, Department of Molecular and Human Genetics Director, The Analyte Center Baylor College of Medicine Phone: 713.798.6032 Fax: 713.798.6584

Authorship: Qin Sun, Leroy Hubert, Taraka R. Donti, V. Reid Sutton, and Sarah H. Elsea
Baylor Genetics and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

Short Abstract

Transaldolase (TALDO) deficiency is a rare disorder in pentose phosphate metabolism. Manifestations of TALDO deficiency include hepatomegaly, dysmorphic features and cardiac defects. Since first described in 2001, about a dozen additional have been published. Diagnosis is typically made by detecting urinary accumulation of intermediates in the pentose phosphate pathway, including erythritol, ribitol, arabitol and sedoheptulose. Here, we report diagnoses of two TALDO cases using GCMS for polyol analysis and DNA sequencing. Untargeted plasma metabolomic profiling also identified several pathognomonic biomarkers for the disorder. The results suggest that untargeted metabolomics may be an efficient screening tool for early diagnosis of TALDO deficiency.

Long Abstract

The pentose phosphate pathway (PPP) has two important cellular functions, 1) generating nicotinamide adenine dinucleotide phosphate (NADPH) as energy, and 2) producing ribose for nucleotide and nucleic acid synthesis. Transaldolase (TALDO) catalyzes a reversible reaction of the second function. TALDO deficiency (MIM 606003) is a rare autosomal recessive disorder first described in 2001; over a dozen TALDO deficiency cases have been reported since. Variable clinical symptoms include hepatomegaly, liver fibrosis/cirrhosis, dysmorphic features, cutis laxa and cardiac defects. Intrauterine growth retardation has also been reported. Diagnosis is achieved by detecting urinary accumulation of intermediates in pentose phosphate pathway, such as erythritol, ribitol and arabitol. In addition, 7 carbon sugars, sedoheptulose and sedoheptitol, are also elevated. Here, we report lab diagnoses of two TALDO deficient patients. Urinary polyols were determined by GCMS, which showed elevated arabitol, ribitol, xylitol and sedoheptulose. However, sedoheptitol concentrations were within normal range. Sanger sequencing of the TALDO1 gene demonstrated homozygous c. 574C>T (p.R193C) mutations in both patients. We have validated an untargeted metabolomic test which is capable of screening over 900 analytes. We have studied a wide variety of inborn errors of metabolism using this platform and are able to accurately identify most small molecule diseases, such as urea cycle disorders, amino acid disorders, organic acidemias, fatty acid oxidation disorders and certain peroxisomal and neurotransmitter disorders. Among over 500 clinical samples that we have analyzed to date, we have been able to make a potential diagnosis in about 5% of cases. Applying this technique to one TALDO case, we were able to identify elevations of ribitol, erythronate, ribonate and arabitol/xylitol in the metabolomics profile of a plasma sample. These results suggest that untargeted metabolomic profiling may be an efficient screening tool among patients with equivocal clinical indications and achieve diagnoses of a variety of metabolic disorders, including TALDO deficiency.


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