View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector J Inherit Metab Dis (2012) 35:571–587 DOI 10.1007/s10545-012-9462-5 METABOLIC DISSERTATION Progress in understanding 2-hydroxyglutaric acidurias Martijn Kranendijk & Eduard A. Struys & Gajja S. Salomons & Marjo S. Van der Knaap & Cornelis Jakobs Martijn Kranendijk Received: 13 December 2011 /Revised: 25 January 2012 /Accepted: 30 January 2012 /Published online: 6 March 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Abstract The organic acidurias D-2-hydroxyglutaric acidu- D2HGDH gene encoding D-2-hydroxyglutarate ria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), dehydrogenase and combined D,L-2-hydroxyglutaric aciduria (D,L- L-2-HG L-2-hydroxyglutaric acid 2-HGA) cause neurological impairment at young age. L-2-HGA L-2-hydroxyglutaric aciduria Accumulation of D-2-hydroxyglutarate (D-2-HG) and/or L- L-2-HGDH L-2-hydroxyglutarate dehydrogenase 2-hydroxyglutarate (L-2-HG) in body fluids are the bio- enzyme chemical hallmarks of these disorders. The current review L2HGDH gene encoding L-2-hydroxyglutarate describes the knowledge gathered on 2-hydroxyglutaric dehydrogenase acidurias (2-HGA), since the description of the first patients D,L-2-HGA combined D,L-2-hydroxyglutaric aciduria in 1980. We report on the clinical, genetic, enzymatic and IDH2 gene encoding isocitrate dehydrogenase 2 metabolic characterization of D-2-HGA type I, D-2-HGA 2-KG 2-ketoglutaric acid type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA HOT hydroxyacid-oxoacid transhydrogenase type I and type II novel clinical information is presented enzyme which was derived from questionnaires. L-malDH L-malate dehydrogenase enzyme Abbreviations MIM Mendelian Inheritance in Man 2-HG 2-hydroxyglutaric acid CSF cerebrospinal fluid (undifferentiated for chiral D-orL-form) 2-HGA 2-hydroxyglutaric aciduria D-2-HG D-2-hydroxyglutaric acid D-2-HGA D-2-hydroxyglutaric aciduria Introduction D-2-HGDH D-2-hydroxyglutarate dehydrogenase enzyme Gregersen et al (1977) were the first to identify enantiomeric D- and L-2-hydroxyglutaric acids (D-2-HG and L-2-HG) as Communicated by: K. Michael Gibson normal constituents of human urine. Three years later, two novel inborn errors of metabolism were simulta- Competing interest: None declared. : : : neously reported in the Journal of Inherited Metabolic M. Kranendijk E. A. Struys G. S. Salomons C. Jakobs (*) Disease.Chalmersetal(1980) identified a patient with Metabolic Unit - Department of Clinical Chemistry, VU University Medical Center, D-2-hydroxyglutaric aciduria (D-2-HGA), while Duran et Amsterdam, The Netherlands al (1980) described a case of L-2-hydroxyglutaric aciduria e-mail: [email protected] (L-2-HGA), landmark publications that identified the meta- bolic hallmarks (D- and L-2-HG) in these disorders. Muntau M. S. Van der Knaap Paediatric Neurology, VU University Medical Center, et al (2000) described a third biochemical variant of 2- Amsterdam, The Netherlands hydroxyglutaric aciduria (2-HGA) when they reported three 572 J Inherit Metab Dis (2012) 35:571–587 patients with elevated urinary D- and L-2-HG, denoted by these authors as “combined D,L-2-hydroxyglutaric aciduria” (D,L-2-HGA). Major milestones in research on these disor- ders came with gene discovery: D2HGDH encoding D-2- hydroxyglutarate dehydrogenase (D-2-HGDH)(Achouri et al 2004)andL2HGDH encoding L-2-hydroxyglutarate dehydro- genase (L-2-HGDH)(Rzem et al 2004; Topcu et al 2004). In Fig. 2 Enantiomers D- and L-2-hydroxyglutaric acid (D-2-HG and L- many D-2-HGA, and the majority of L-2-HGA patients, 2-HG, systemic IUPAC names included) genetic characterization revealed pathogenic mutations in these genes (Struys et al 2005b; Steenweg et al 2010). None- theless, in fully one-half of D-2-HGA patients no mutations in transhydrogenase (HOT) activity in human liver and fibro- D2HGDH were detected (Kranendijk et al 2010a). Subse- blasts, representing the first demonstration of a human en- quently, we described gain-of-function mutations in isocitrate zyme whose catalytic function was production of D-2-HG dehydrogenase 2 (IDH2) which proved causative for the D-2- (Struys et al 2005c). HOT catalyzes the conversion of γ- HG accumulation in previously unclassified D-2-HGA hydroxybutyrate (GHB) to succinic semialdehyde (SSA) with patients (Kranendijk et al 2010b). In sum, the preceding a stoichiometric production of D-2-HG from 2-KG (Fig. 3). decade has provided tremendous advances in our under- Similarly, pilot studies of L-2-HGA lymphoblasts incubated 13 2 standing of the inborn 2-hydroxyglutaric acidurias, which will with [ C6]glucose and [ H5]glutamic acid further delineated undoubtedly provide a solid foundation from which to develop that mitochondrial 2-KG is the precursor of L-2-HG (Struys et novel and effective treatment strategies. al 2007). Currently, the only enzyme known to generate L-2- This Review evaluates metabolic, enzymatic, genetic and HG from 2-KG in human is L-malate dehydrogenase (L- clinical progress in our understanding of the rare inborn malDH) (Fig. 3), whose primary catalytic function is the organic acidurias D-2-HGA, L-2-HGA and D,L-2-HGA. interconversion of L-malate to oxaloacetate (Rzem et al 2007). Future research and therapeutic perspectives are also briefly discussed. The diagnosis of 2-hydroxyglutaric aciduria Enantiomeric D,L-2-hydroxyglutaric acid and its origin The differential diagnosis of 2-hydroxyglutaric aciduria begins with the clinical evaluation of a patient with unex- The five-carbon dicarboxylic acid 2-hydroxyglutaric acid plained developmental delay and/or other neurological dys- (2-HG) possesses a hydroxyl group at the second carbon function of unknown etiology, raising suspicion for a (Fig. 1) which yields a chiral center. Accordingly, two three- metabolic disorder. Provisional diagnosis of the disorder is dimensional (3D) structures exist, including D-2-HG and L- occasionally suggested by abnormal brain MRI findings. 2-HG, which represent “non-superimposable” mirror Urinary organic acid screening with gas chromatography- images (Fig. 2). Systemic names are (R)-2-hydroxypentane- mass spectrometry (GC-MS), performed in multiple metabolic dioic acid and (S)-2-hydroxypentanedioic acid, respectively, centers, can reveal increased 2-HG, but the chiral con- for D- and L-2-HG. Whereas enantiomers share identical figuration remains to be determined. Although the clin- chemical and physical properties (melting point, mass, solu- ical presentation often can suggest either D-2-HGA or bility and pKa), their differing 3D-structures result in consid- erable differences in enzymatic and molecular properties. 13 Pilot studies employing stable isotope labeled [ C6]glu- 2 cose or [ H5]glutamic acid with D-2-HGA lymphoblast cell cultures revealed that mitochondrial 2-ketoglutarate (2-KG), a tricarboxylic acid (TCA) cycle intermediate, can be metabolized to D-2-HG (Struys et al 2004b). Subsequent studies documented the existence of hydroxyacid-oxoacid Fig. 3 Enzymes L-malDH and HOT are responsible for production of Fig. 1 2-hydroxyglutaric acid with a chiral center at the 2nd carbon (*) D-2-HG and L-2-HG from 2-KG J Inherit Metab Dis (2012) 35:571–587 573 L-2-HGA, chiral differentiation performed with GC-MS Herein we present novel clinical features in 14 type I and or liquid chromatography-tandem mass spectrometry 19 type II patients based on clinical questionnaires. The age (LC-MS/MS) is mandatory for the correct differential of onset for type I patients is generally within the first six diagnosis (Gibson et al 1993a; Struys et al 2004a). years, whereas for type II the age of onset was within two Additionally, amino acid analysis in plasma and/or ce- years (Table 1). Cardinal clinical manifestations for both rebrospinal fluid (CSF) may identify elevated lysine in disorders include developmental delay, hypotonia and seiz- L-2-HGA. Subsequently, enzymatic and genetic charac- ures, although seizures occur with higher frequency in type terization can confirm L-2-HGA, as well as differentiate II patients (Table 1). All type II patients were developmen- between the type I or II form of D-2-HGA, representing tally delayed, and the delays were more severe than those important information for genetic counseling and future observed in type I patients. In 9 of 19 type II patients prenatal diagnosis (Steenweg et al 2010;Kranendijket cardiomyopathy (primarily dilated, but in one case hypertro- al 2010a, b). While elevated L-2-HG levels are specific phic) was observed, a feature absent from the type I phenotype. for L-2-HGA and are also detected in D,L-2-HGA, D-2- The course of the type II disease is primarily progressive, but a HG can be elevated in a number of other disorders in static disease, or even improvement have been reported in a addition to D-2-HGA type I and type II, discussed in a limited number. Life expectancies for type II patients may separate section of this Review. Some authors have range from several months to early adulthood (Table 1). Con- suggested that a potential false positive diagnosis of versely, for type I patients the life expectancy remains unde- D- or L-2-HGA may occur with improperly preserved fined. One patient died in the third week of life with a diagnosis urine samples linked either to nonenzymatic conversion of necrotizing enterocolitis at post mortem examination, while of 2-KG to D/L-2-HG, or via excretion of D/L-2-HG three others are currently 5-12 years of age. from bacterial or fungal growth in the urine specimen The disorders appear panethnic, and consanguinity is (Kumps et al 2002).