D‐2‐Hydroxyglutaric aciduria: Further clinical delineation

Abstract

It has recently been recognized that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with a severe and a mild phenotype. Whereas the clinical and neuroimaging findings of the severe phenotype were homogeneous among the patients, the findings in the mild phenotype were much more variable, leaving the clinical picture poorly defined. We were able to collect the clinical, biochemical and neuroimaging data on an additional 8 patients with D-2-hydroxyglutaric aciduria, 4 with the severe and 4 with the mild phenotype. With the new information, it becomes clear that the mild phenotype shares the essential characteristics of the severe phenotype. The most frequent findings, regardless of the clinical phenotype, are epilepsy, hypotonia and psychomotor retardation. Additional findings, mainly occurring in the severe phenotype, are episodic vomiting, cardiomyopathy, inspiratory stridor and apnoeas. The most consistent MRI finding is enlargement of the lateral ventricles, occipital more than frontal. Regardless of the clinical phenotype, early MRI shows in addition subependymal cysts and signs of delayed cerebral maturation. Later MRI may reveal multifocal cerebral white-matter abnormalities. Two patients had vascular abnormalities, but it is as yet unclear whether these are related to D-2-hydroxyglutaric aciduria or are incidental findings.

Progress in understanding 2‐hydroxyglutaric acidurias

“…D-2-HGA was recognized as a distinct neurometabolic disorder with mild and severe phenotypes in the late 1990s (Van der Knaap et al 1999a, b). The clinical phenotype encompassed epilepsy, hypotonia and psychomotor retardation as the primary features.…”

“…The clinical features in these undifferentiated patients included enlargement of the lateral ventricles, enlarged frontal subarachnoid spaces, subdural effusions, subependymal pseudocysts, signs of delayed cerebral maturation and multifocal cerebral white-matter abnormalities (Van der Knaap et al 1999a, b). An ongoing imaging study is underway in our laboratories to more accurately define the CNS abnormalities associated with the type I and II disorders.…”

“…*Undifferentiated (n = 43)DNA unavailable for D2HGDH and IDH2 sequencingChalmers et al 1980; Nyhan et al 1995; Sugita et al 1995; Baker et al 1997; Wagner et al 1998; Van der Knaap et al 1999a; b; Eeg-Olofsson et al 2000; Kwong et al 2002; Wang et al 2003; Mahfoud et al 200918 published pts.25 unpublished pts. *Unknown (n = 2)D-2-HGA type I and type II were excluded: no mutations detected in D2HGDH or IDH2 Kranendijk et al 2010bCombinedIncreased D-2-HG and L-2-HGWagner et al 1998; Amiel et al 1999; Van der Knaap et al 1999a; b; Muntau et al 2000; Wajner et al 2002; Read et al 2005D,L-2-HGA (n = 11)6 published pts.5 unpublished pts. *Skeletal dysplasia (n = 6)3 published pts.Talkhani et al 2000; Honey et al 2003; Bayar et al 20053 unpublished pts.…”

“…Currently, six cases of d,l -2-hydroxyglutaric aciduria (D,L-2-HGA) have been described, of which four were previously classified as D-2-HGA affected with a severe phenotype (Wagner et al 1998; Amiel et al 1999; Van der Knaap et al 1999a, b; Muntau et al 2000; Wajner et al 2002; Read et al 2005). D,L-2-HGA is biochemically characterized by moderately increased D-2-HG and L-2-HG in urine, mild increases of both metabolites in plasma, and a very slight elevation of D-2-HG in CSF and normal levels of L-2-HG (Table 8).…”

“…* Siblings; References: Controls -(Van der Knaap et al 1999a); A-(Wagner et al 1998) case2, (Van der Knaap et al 1999b) pat.8, (Muntau et al 2000) pat.3; B-(Amiel et al 1999) case2, (Van der Knaap et al 1999a) pat.4; C-(Muntau et al 2000) pat.1, (Van der Knaap et al 1999a) pat.1; D-(Muntau et al 2000) pat.2, (Van der Knaap et al 1999a) pat.2; E-(Wajner et al 2002); F-(Read et al 2005)…”