The biochemical hallmark of D-2-hydroxyglutaric aciduria is brain accumulation of D-2-hydroxyglutaric acid (D2HG). Patients present predominantly neurological manifestations, whose pathogenesis is still unknown. Thus, we examined the impact of elevated brain levels of D2HG, induced by intracerebral injection of this metabolite in juvenile rats, on redox and mitochondrial homeostasis and histochemical landmarks in the cerebral cortex. D2HG administration disrupted redox homeostasis by increasing the levels of reactive oxygen species and lipid peroxidation and the activities of superoxide dismutase, glutathione peroxidase, and glutathione reductase and decreasing reduced glutathione levels. Furthermore, the complex IV and mitochondrial creatine kinase activities, as well as the protein contents of voltage-dependent anion channel 1, translocase of outer mitochondrial membrane 20, and peroxisome proliferator-activated receptor-γ coactivator 1-α, were diminished by D2HG, indicating bioenergetics dysfunction and disrupted mitochondrial biogenesis. D2HG also reduced neuronal nuclear protein content and augmented cleaved caspase-3, S100 calcium-binding protein B, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule 1, indicating neuronal loss, apoptosis, astrogliosis, and microglial activation, respectively. The tumor necrosis factor alpha expression was also significantly augmented, reflecting an increased inflammatory response. We also evaluated whether bezafibrate (BEZ) pretreatment could prevent the alterations induced by D2HG. BEZ normalized most of the D2HG-induced deleterious effects. Therefore, bioenergetics and redox status disruption caused by D2HG, associated with neuronal death, glial reactivity, and increased inflammatory response, may potentially represent pathomechanisms of brain damage in D-2-HGA. Finally, it is proposed that BEZ may be potentially used as therapy for D-2-HGA.

Type II D-2-Hydroxyglutaric aciduria (T2D2HGA) is caused by a gain-of-function pathogenic variant in Isocitrate Dehydrogenase 2 (IDH2). Patients with T2D2HGA commonly present with developmental delay, seizures, cardiomyopathy, and arrhythmias. The recently approved IDH2-inhibitor Enasidenib targets the p.Arg140Gln pathogenic IDH2 variant and decreases production of D2HGA. We present a 7-year-old female with T2D2HGA due to the p.Arg140Gln variant. She was diagnosed at 3-years-old after presenting with global developmental delay, leukoencephalopathy, communicating hydrocephalus, seizures, and dilated cardiomyopathy. At age 3 years 11 months, 50 mg Enasidenib daily was initiated. Primary outcomes included seizure frequency, hospital admissions, development, and cardiac structure. Laboratories were monitored biweekly for common Enasidenib side effects. Our patient tolerated Enasidenib well. Urine 2-HGA decreased significantly from 244 mg/g creatinine to undetectable within 2 weeks of treatment. Inpatient admissions decreased from 8 during the 2 years preceding treatment to 1 during treatment. She has been seizure-free since Enasidenib initiation. Echocardiography showed improvement in dilated cardiomyopathy with normal left ventricular systolic function. Developmental assessment demonstrated improvements in gross motor, fine motor, language, and socialization domains. Treatment was complicated by mild elevations in alanine transaminase (118 IU/L, range 0-28) and creatine kinase (334 U/L, range 45-198) that resolved by decreasing Enasidenib dosing frequency to three times weekly. Enasidenib is a viable treatment for Type II D2HGA with benefits including developmental gains, fewer acute medical interventions, and cardiomyopathy improvement. While drug-induced hepatitis is a novel adverse effect of Enasidenib, it can be ameliorated by decreasing dose frequency.

Several underlying conditions of moyamoya syndrome (MMS) are well established, but so far, D-2-hydroxyglutaric aciduria (D-2-HGA) has not been mentioned. We are the first to describe a case of a patient suffering from D-2-HGA developing MMS. The co-occurrence of D-2-HGA and MMS in a patient is reported. Furthermore, we describe the neurosurgical revascularization procedure performed and report on the follow-up. A 7-year-old girl suffering from D-2-HGA developed two transient ischemic attacks (TIAs). Using MRI/MRA and invasive angiography MMS was diagnosed. We performed an encephalo-duro-arterio-myo-synangiosis (EDAMS) as an indirect revascularization procedure first on the right and 2 months later on the left hemisphere. We have followed her up until the age of 10. Since the second surgery, she has not suffered further TIAs and is in a better general medical condition. Even though children with D-2-HGA often suffer epileptic attacks, every new (transient) neurological deficit should be followed up by an MRI/MRA so as not to oversee a possible underlying MMS. After diagnosis, EDAMS in combination with acetylsalicylic acid (ASA) is recommended to prevent further ischemic events.