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L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare disorder. The patients have psychomotor retardation, ataxia, macrocephaly, and epilepsy usually in childhood. We present a case of L-2-HGA who developed dystonia in the third decade of life. The family reported symptoms of progressive psychomotor regression since childhood. On assessment, the patient had mild impairment of higher mental functions, mild exotropia, and right-hand dystonia. Brain MRI revealed diffuse bilateral symmetrical subcortical white matter hyperintense signals. 2-Hydroxyglutaric acid in urine was elevated and the whole genome sequencing revealed a homogeneous pathogenic variant of the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. The prognosis was explained to the caregivers. Patients with mild phenotype L-2-HGA can remain undiagnosed until adulthood. Cases of dystonia even without complaints of epilepsy should be investigated by MRI -brain, urine test and genetic testing to rule out L-2-HGA. [ABSTRACT FROM AUTHOR]

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare autosomal recessive disease characterized by elevated levels of hydroxyglutaric acid in the body fluids and brain with abnormal white matter. We present two siblings with psychomotor retardation and quadriparesis. Their brain imaging showed diffuse bilateral symmetrical involvement of the cerebral cortex, white matter, basal ganglia and cerebellum. The whole exome sequence studies revealed a homozygous likely pathogenic variant on chromosome 14q22.1 (NM_024884.2: c.178G > A; pGly60Arg) in the gene encoding for L-2-hydroxyglutarate dehydrogenase (L2HGDH) (OMIM #236792). Therefore, using the L2HGDH gene study is beneficial for L2HGA diagnosis. [ABSTRACT FROM AUTHOR]

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare neurometabolic disorder characterized by accumulation of L2-hydroxyglutarate (L-2-HG) due to mutations in the L2HGDH gene. L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. Here, we present a 16-year-old girl with L-2-HGA who developed a tumor in the right cerebral hemisphere, which was discovered after left-sided neurological deficits of the patient. Histologically, the tumor had a high-grade diffuse glioma phenotype. DNA sequencing revealed the inactivating homozygous germline L2HGDH mutation as well as inactivating mutations in TP53, BCOR and NF1. Genome-wide DNA-methylation analysis was unable to classify the tumor with high confidence. More detailed analysis revealed that this tumor clustered amongst IDH-wildtype gliomas by methylation profiling and did not show the glioma CpG island methylator phenotype (G-CIMP) in contrast to IDH-mutant diffuse gliomas with accumulated levels of D-2-HG, the stereoisomer of L-2-HD. These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. Our final integrated histomolecular diagnosis of the tumor was diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Due to rapid tumor progression the patient died nine months after initial diagnosis. In this manuscript, we provide extensive molecular characterization of the tumor as well as a literature review focusing on oncogenetic considerations of L-2-HGA-associated CNS tumors.

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L-2-Hydroxyglutaric aciduria (L-2-HGA) is an inherited neurometabolic disorder caused by deficient activity of l-2-hydroxyglutarate dehydrogenase. l-2-Hydroxyglutaric acid (L-2-HG) accumulation in the brain and biological fluids is the biochemical hallmark of this disease. Patients present exclusively neurological symptoms and brain abnormalities, particularly in the cerebral cortex, basal ganglia, and cerebellum. Since the pathogenesis of this disorder is still poorly established, we investigated the short-lived effects of an intracerebroventricular injection of L-2-HG to neonatal rats on redox homeostasis in the cerebellum, which is mostly affected in this disorder. We also determined immunohistochemical landmarks of neuronal viability (NeuN), astrogliosis (S100B and GFAP), microglia activation (Iba1), and myelination (MBP and CNPase) in the cerebral cortex and striatum following L-2-HG administration. Finally, the neuromotor development and cognitive abilities were examined. L-2-HG elicited oxidative stress in the cerebellum 6 h after its injection, which was verified by increased reactive oxygen species production, lipid oxidative damage, and altered antioxidant defenses (decreased concentrations of reduced glutathione and increased glutathione peroxidase and superoxide dismutase activities). L-2-HG also decreased the content of NeuN, MBP, and CNPase, and increased S100B, GFAP, and Iba1 in the cerebral cortex and striatum at postnatal days 15 and 75, implying long-standing neuronal loss, demyelination, astrocyte reactivity, and increased inflammatory response, respectively. Finally, L-2-HG administration caused a delay in neuromotor development and a deficit of cognition in adult animals. Importantly, the antioxidant melatonin prevented L-2-HG-induced deleterious neurochemical, immunohistochemical, and behavioral effects, indicating that oxidative stress may be central to the pathogenesis of brain damage in L-2-HGA. [ABSTRACT FROM AUTHOR]

Objective: In this study, we performed analysis of brainstem reflexes and movement disorders using surface polymyogram in L-2-hydroxyglutaric aciduria (L2HGA). We also reviewed all cases in the literature with detailed clinical and radiological description to analyze the anatomical correlates of involuntary movements. Patients and method: We performed surface electromyography of appropriate muscles, long-loop reflexes, and somatosensory evoked potentials and analyzed the neuroimaging findings in patients with L2HGA and recorded blink reflex (BR), auditory startle response (ASR), and startle response after somatosensory stimuli (SSS) in patients and healthy subjects. We also performed a systematic literature search to identify the association of neuroimaging findings and movements disorders in previous patients with L2HGA. Results: Thirteen patients were enrolled in the study. Among them, ten had low-amplitude postural tremor with a frequency between 4 and 7 Hz. The tremor was predominant on distal parts of the upper extremities. Postural tremor was accompanied by negative myoclonus in one-third. The BR, ASR, and SSS, all, were hypoactive. There was a close association of postural tremor with cerebellar atrophy in patients who participated in this study and by the analysis of the previously reported patients. Conclusions: Low-amplitude postural tremor is common in L2HGA. It is related with cerebellar atrophy. Although the neuroimaging shows no overt lesions at the brainstem, there is a functional inhibition at this level. [ABSTRACT FROM AUTHOR]

Aim:L-2-hydroxyglutaric aciduria (L2HGA) which is autosomal recessive and characterized by psychomotor retardation, cerebellar ataxia, variable macrocephaly, and epilepsy is a rarely seen neurometabolic disease. The disease is biochemically identified by slightly increased L-2HGA levels in urine, cerebrospinal fluid, and plasma.Materials and Methods:A sensitive and rapid capillary electrophoretic technique was used for the determination of L2HGA in urine. Since the L2HGA lacks of chromophore, an indirect UV detection method was applied.Results:The running electrolyte consisted of 10 mmol/L 2,6-pyridinedicarboxylic acid (PDC) at pH 5.6 containing 0.1 mmol/L of cetyltrimethylammonium bromide (CTAB). PDC was chosen because of its good chromophoric property for indirect UV detection. CTAB was used as electro-osmotic flow (EOF) reversal. The method was well-validated in the selected conditions. The detection limit of the method L2HGA was 1.16 μmol/L. The migration time of L2HGA was less than 2.0 min.Conclusion:The developed method was applied to the urine samples collected from 16 patients who suffer from L-2-hydroxyglutaric aciduria and 4 healthy volunteers.

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly. Methods: In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools. Results: Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH. [ABSTRACT FROM AUTHOR]

L-2 Hydroxyglutaric aciduria is a rare metabolic disorder which is autosomal recessive in inheritance. It is characterised by the increased urinary excretion of L-2 hydroxyglutaric acid and the diagnosis is based on the increased levels of the L-2 hydroxy glutaric acid in the urine, serum & CSF. This is a neurometabolic disorder which is associated with slowly progressive psychomotor delay since childhood. We report a case of an 18 –year old female who presented at the emergency department with seizures, fever and on imaging show classic features.

Abstract Background L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare organic aciduria neurometabolic disease that is inherited as an autosomal recessive mode and have a variety of symptoms, such as psychomotor developmental retardation, epilepsy, cerebral symptoms as well as increased concentrations of 2-hydroxyglutarate (2-HG) in the plasma, urine and cerebrospinal fluid. The causative gene of L-2-HGA is L-2-hydroxyglutarate dehydrogenase gene (L2HGDH), which consists of 10 exons. Case presentation We presented a rare patient primary diagnosis of L-2-HGA based on the clinical symptoms, magnetic resonance imaging (MRI), and gas chromatography-mass spectrometry (GC-MS) results. Mutational analysis of the L2HGDH gene was performed on the L-2-HGA patient and his parents, which revealed two novel mutations in exon 3: a homozygous missense mutation (c.407 A > G, p.K136R) in both the maternal and paternal allele, and a heterozygous frameshift mutation [c.407 A > G, c.408 del G], (p.K136SfsX3) in the paternal allele. The mutation site p.K136R of the protein was located in the pocket of the FAD/NAD(P)-binding domain and predicted to be pathogenic. Conclusion We predicted the homozygous missense mutation (c.407 A > G, p.K136R) was considered as the pathogenic mutation of the patient. The study highlights the power of pedigree analysis in order to interpret novel mutations.

Aim:L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive encephalopathy caused by mutations in the L-2-hydroxyglutarate dehydrogenase gene.Materials and Methods:Here we discuss the clinical and molecular characteristics in patients with L2HGA.Results:There were eight patients with L2HGA. Their median age was 16 (9.5-37) years. Five of them were female and three of them were male. The main symptoms of the patients were psychomotor retardation (8/8), cerebellar ataxia (5/8), extrapyramidal symptoms (7/8) and seizures (4/8). All patients had behavioral problems. Elevated urinary L-2-hydroxy (L-2-OH) glutaric acid was detected and the median level of urine L-2-OH glutaric acid at diagnosis was 146 (60-1460 nmol/mol creat). Characteristic magnetic resonance imaging findings including subcortical cerebral white matter abnormalities with T2 hyperintensities of the dentate nucleus, globus pallidus and putamen were detected. Two patients had homozygous R335X, two patients had homozygous R282Q, two patients had homozygous R302L and one patient had compound heterozygous P302L/A64T mutation in L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene.Conclusion:Because of the slow progression of the disease, the diagnosis of the patients is usually belated. L2HGA must be considered in the differential diagnosis based on clinical findings and specific findings in cranial magnetic resonance imaging. In our study, one of our patients has a novel mutation.

Aim: L-2-hydroxyglutaric aciduria is a slowly progressive neurometabolic disorder caused by an enzymatic deficiency of L-2-hydroxyglutarate dehydrogenase. Here, we aimed to evaluate the clinical, neuroradiologic, and genotypic characteristics of patients with L-2-hydroxyglutaric aciduria who were followed in our outpatient clinic. Material and Methods: Twenty-five patients with L-2-hydroxyglutaric aciduria were enrolled in the study. Data regarding demographic, clinical, and neuroradiologic findings and molecular analysis were evaluated retrospectively. Results: The mean age of patients at the time of diagnosis was 12.09±8.02 years, whereas the mean age at the time of the first symptoms was 39.47±29.96 months. Diagnostic delay was found as 9.95±7.78 years. Developmental delay, decrease in school success, and seizures were the most common initial symptoms; however, behavioral problems and seizures became more prominent in the disease course. At the time of diagnosis, mental retardation and at least one pathologic cerebellar finding were detected in all symptomatic patients. Three patients developed brain tumors. The most common neuroimaging findings were subcortical white matter changes and cerebellar dentate nucleus involvement. In one patient, there was only isolated basal ganglia involvement without white matter lesions. Patients with similar genotypic features exhibited different clinical and radiologic findings. Conclusion: Although clinical symptoms appear early in L-2-hydroxyglutaric aciduria, there is approximately a ten-year delay in diagnosis. In subjects in whom brain tumor is detected in early childhood, L-2-hydroxyglutaric aciduria should be considered in the differential diagnosis in the presence of mental retardation accompanied by developmental delay, cerebellar and pyramidal findings, and behavior disorders in a wide spectrum ranging from autism spectrum disorder to psychosis. In patients with L-2-hydroxyglutaric aciduria, incipient headache, tinnitus, altered consciousness, and seizures can be indicative of brain tumors. [ABSTRACT FROM AUTHOR]

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder characterized by a slowly progressive clinical course, psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings. The diagnosis depends on the presentation of increased levels of L-2-hydroxyglutaric acid in the urine, plasma, and cerebrospinal fluids. Patients with L2HGA have an increased risk for the development of cerebral neoplasms which, though rarely, can be the initial presentation of the disease. Moreover, patients with L2HGA have an increased risk for the development of cerebral neoplasms. Cases presentation: Although psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings are the most common characteristics of the disease, we present two rare cases admitted with tumoral symptoms. Conclusion: Patients with L2HGA have an increased risk for the development of cerebral neoplasms. [ABSTRACT FROM AUTHOR]

Abstract Background L-2-hydroxyglutaric aciduria (L2HGA) is a progressive neurometabolic disease of brain caused by mutations of in L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. Cardinal clinical features include cerebellar ataxia, epilepsy, neurodevelopmental delay, intellectual disability, and other clinical neurological deficits. Case presentation We describe an index case of the family presented with generalised tonic-clonic seizure, developmental delay, intellectual disability, and ataxia. Initially, the differential diagnosis was difficult to be established and a SNP genome wide scan identified the candidate region on chromosome 14q22.1. DNA sequencing showed a novel homozygous mutation in the candidate gene L2HGDH (NM_024884.2: c.178G > A; p.Gly60Arg). The mutation p.Gly60Arg lies in the highly conserved FAD/NAD(P)-binding domain of this mitochondrial enzyme, predicted to disturb enzymatic function. Conclusions The combination of homozygosity mapping and DNA sequencing identified a novel mutation in Pakistani family with variable clinical features. This is second report of a mutation in L2HGDH gene from Pakistan and the largest family with L2HGA reported to date.

L-2 Hydroxyglutaric aciduria is a rare metabolic disorder which is autosomal recessive in inheritance. It is characterised by the increased urinary excretion of L-2 hydroxyglutaric acid and the diagnosis is based on the increased levels of the L-2 hydroxy glutaric acid in the urine, serum & CSF. This is a neurometabolic disorder which is associated with slowly progressive psychomotor delay since childhood. We report a case of an 18 –year old female who presented at the emergency department with seizures, fever and on imaging show classic features. [ABSTRACT FROM AUTHOR]

Objective: L-2-hydroxyglutaric aciduria is a genetic metabolic disorder. Its clinical features include elevated levels of hydroxyglutaric acid in body fluids and abnormal magnetic resonance imaging (MRI) in the subcortical white matter, which are affected by the accumulation of L-2-hydroxyglutaric acid.Method: A boy with psychomotor retardation and progressive ataxia accompanied by abnormal brain MRI findings was tested using whole-exome sequencing.Results: Next-generation sequencing (NGS) revealed two novel compound heterozygous frameshift mutations, c.407 del A (p.K136SfsTer3) and c.699_c700 ins A (p.D234RfsTer42), in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene, leading to premature termination codons and truncated FAD/NAD(P)-binding domain of L2HGDH protein. Further laboratory testing revealed an increase in the 2-hydroxyglutaric acid level in the urine.Conclusion: The results suggested that NGS could provide clues for identifying patients with abnormal neuroradiological findings in the subcortical white matter. [ABSTRACT FROM AUTHOR]

Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. L-2-HG markedly induced the generation of reactive oxygen species (increase of 2′,7′-dichloroflurescein-DCFH-oxidation), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione-GSH) and sulfhydryl content in the cerebral cortex. Alterations of the activities of various antioxidant enzymes were also observed in the cerebral cortex and striatum following L-2-HG administration. Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients. [ABSTRACT FROM AUTHOR]

Aim: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive encephalopathy caused by mutations in the L-2-hydroxyglutarate dehydrogenase gene. Materials and Methods: Here we discuss the clinical and molecular characteristics in patients with L2HGA. Results: There were eight patients with L2HGA. Their median age was 16 (9.5-37) years. Five of them were female and three of them were male. The main symptoms of the patients were psychomotor retardation (8/8), cerebellar ataxia (5/8), extrapyramidal symptoms (7/8) and seizures (4/8). All patients had behavioral problems. Elevated urinary L-2-hydroxy (L-2-OH) glutaric acid was detected and the median level of urine L-2-OH glutaric acid at diagnosis was 146 (60-1460 nmol/mol creat). Characteristic magnetic resonance imaging findings including subcortical cerebral white matter abnormalities with T2 hyperintensities of the dentate nucleus, globus pallidus and putamen were detected. Two patients had homozygous R335X, two patients had homozygous R282Q, two patients had homozygous R302L and one patient had compound heterozygous P302L/A64T mutation in L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. Conclusion: Because of the slow progression of the disease, the diagnosis of the patients is usually belated. L2HGA must be considered in the differential diagnosis based on clinical findings and specific findings in cranial magnetic resonance imaging. In our study, one of our patients has a novel mutation. [ABSTRACT FROM AUTHOR]

SLC25A1 mutations are associated with combined D,L‐2‐hydroxyglutaric aciduria (DL‐ 2HGA; OMIM #615182), characterized by muscular hypotonia, severe neurodevelopmental dysfunction and intractable seizures. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Only a single family with an SLC25A1 mutation has been described in which mitochondrial respiratory chain dysfunction was documented, specifically in complex IV. Five infants of two consanguineous Bedouin families of the same tribe presented with small head circumference and neonatal‐onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development culminating in early death. Ventricular septal defects (VSD) were demonstrated in three patients. Blood and CSF lactate were elevated with normal levels of plasma amino acids and free carnitine and increased 2‐OH‐glutaric acid urinary exertion. EEG was compatible with white matter disorder. Brain MRI revealed ventriculomegaly, thin corpus callosum with increased lactate peak on spectroscopy. Mitochondrial complex V deficiency was demonstrated in skeletal muscle biopsy of one infant. Homozygosity mapping and sequencing ruled out homozygosity of affected individuals in all known complex V‐associated genes. Whole exome sequencing identified a novel homozygous SLC25A1 c.713A>G (p.Asn238Ser) mutation, segregating as expected in the affected kindred and not found in 220 control alleles. Thus, SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects. [ABSTRACT FROM AUTHOR]

L-2-hydroxyglutaric aciduria (L-2 HGA) is a rare, neurodegenerative, slowly progressing and autosomal recessively inherited metabolic disorder. The disease progresses with mental retardation, behavioral disorder, ataxia, extrapyramidal signs and epileptic seizures. Diagnosis is made by detection of increased levels of L-2-hydroxyglutaric acid in urine, plasma or cerebrospinal fluid. In this report, we presented a 13 year old male patient diagnosed with L-2 HGA and had seizures, intellectual disability, attention deficit hyperactivity disorder (ADHD) symptoms and failure in school performance. Here we discussed this rare disease with ADHD symptoms and the response to atomoxetine treatment. [ABSTRACT FROM AUTHOR]

Background: L-2-Hydroxyglutaric aciduria is a rare slow progressive autosomal recessively inherited neurometabolic disease. Methods: In this study we describe the clinical genetic and magnetic resonance imaging findings of four Turkish patients from the same family. Results: All siblings were mentally retarded, had cerebellar symptoms and gait ataxia. The index patient presented with absences, generalized tonic clonic seizures and repeated nonconvulsive status epilepticus episodes before treatment. Their magnetic resonance images demonstrated subcortical white matter and basal ganglia alterations combined with cerebellar atrophy. In all patients the level of L-2-Hydroxyglutaric acid in urine and cerebrospinal fluid were found to be high which confirmed the diagnosis. One prominent feature regarding the course of the disease in our patients is that their neurological status remained more or less unchanged during the follow-up period lasting 20 years which is the longest described in the literature. Conclusion: Considering the autosomal recessive inheritance pattern of this disorder, and the high rate of consanguineous marriage in Turkey, one should bear in mind this rare disorder while confronted with patients suffering from a combination of progressive cerebellar syndrome, mental retardation and seizures. [ABSTRACT FROM AUTHOR]

The D-2-hydroxyglutaric (D-2-HGA) and L-2-hydroxyglutaric acidurias (L-2-HGA) are rare neurometabolic diseases that form a group of inborn errors of metabolism. They are caused by a deficiency on the enzyme activities of D-2-hydroxyglutarate dehydrogenase in D-2-HGA type I or isocitrate dehydrogenase in D-2-HGA type II, and L-2-hydroxyglutarate dehydrogenase in L-2-HGA. The main clinical findings in affected patients are related to neurological symptoms, such as convulsions, coma and brain atrophy. Brain injuries also occur in the basal ganglia (D-2-HGA, L-2-HGA) and cerebellum (L-2-HGA). These acidurias are biochemically characterized by the accumulation in tissues and increased urinary excretion of D-2-hydroxyglutaric acid (in D-2-HGA) and L-2-hydroxyglutaric acid (in L-2-HGA). Still, a third biochemical variant of aciduria, called D,L-2-hydroxyglutaric (D,L-2-HGA), is characterized by increased excretion of both enantiomers of 2-hydroxyglutaric acid. In an animal model, toxicity studies on D- and L-2-hydroxyglutaric acids showed brain injury, but the exact mechanism of brain damage was not elucidated. Furthermore, high levels of D- and L-2-hydroxyglutaric acids were found in brain tumors. However, the relationship between cancer and aciduria still needs to be clarified. In view of the severity of the disease, this study aimed to do a literature review on the topic, emphasizing metabolic consequences, particularly for the brain tissue, as well as to identify possible therapeutic approaches. [ABSTRACT FROM AUTHOR]

L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive, slowly progressive neurodegenerative disease characterized by psychomotor delay and cerebellar dysfunction. The biochemical hallmark is increased concentrations of L2HG in body fluids. Brain MRI exhibits characteristic centripetal extension of the white matter involvement that differentiates it from other leukodystrophies. The authors report two sisters from Pakistan with L2HGA with 4 years of follow-up. The authors have also compared the clinical outcome of our patients with 45 previously reported patients with L2HGA for whom treatment and clinical outcome was reported., Case Presentation: The authors report two sisters with L2HGA from Pakistan born to consanguineous parents. The 15- and 17-year-old girls presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. Both had normal anthropometric measurements for age. Exaggerated tendon reflexes and bilateral sustained ankle clonus were observed in addition to cerebellar signs. Urine organic acids analysis showed marked excretion of 2-hydroxyglutaric acid, chiral differentiation of 2-hydroxyglutaric acid showed it to be L2HGA. Brain MRI of the 15-year-old showed diffuse subcortical white matter changes evident by T2/FLAIR hyperintense signals bilaterally, particularly in the frontal region in the centripetal distribution with some diffusion restriction along involvement of globus pallidus. The characteristic MRI pattern raised the suspicion of L2HGA. Targeted L2HGDH sequencing identified a homozygous pathogenic variant, c.829C>T (p.Arg227*) in L2HGDH gene in both girls. Both parents were heterozygous carriers of the familial variant., Conclusion: Neuroradiological features of centripetal subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement are rather specific to L2HGA and should lead to further biochemical investigations to look for L2HGA and L2HGDH gene sequencing., Competing Interests: None.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article, (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: L-2-hydroxyglutaric aciduria is a rare autosomal recessive encephalopathy caused by mutations in the L-2-hydroxyglutarate dehydrogenase gene. We describe some novel clinical and molecular characteristics found in a boy with L-2-hydroxyglutaric aciduria. Case presentation: We report an 8-year-old Chinese boy, who had characteristic developmental delay, ataxia and acrocephaly as the main symptoms. He also complained of paroxysmal headache and palpitation. Brain image revealed a symmetrical, extensive subcortical white matter lesion. Urine test for organic acids showed a significantly increased level of 2-hydroxyglutaric acid (106.74 mmol/mol cre, normal range 0.6 ~ 5.9 mmol/mol cre), leading to the diagnosis of L-2-hydroxyglutaric aciduria. Genetic testing uncovered two heterozygous missense mutations in L-2-hydroxyglutarate dehydrogenase gene: c.169G > A in exon 2 and c.542G > T in exon 5, not hitherto been described. Conclusion: Novel gene mutation and associated clinical symptoms can contribute for the understanding and identification of this rare disease. Possible genotype-phenotype correlation waits for further study. [ABSTRACT FROM AUTHOR]

Patients affected by L- 2-hydroxyglutaric aciduria (L-2-HGA) are biochemically characterized by elevated L- 2-hydroxyglutaric acid (L-2-HG) concentrations in cerebrospinal fluid, plasma, and urine due to a blockage in the conversion of L-2-HG to α-ketoglutaric acid. Neurological symptoms associated with basal ganglia and cerebelar abnormalities whose pathophysiology is still unknown are typical of this neurometabolic disorder. In the present study we evaluated the early effects (30 min after injection) of an acute in vivo intrastriatal and intracerebellar L-2-HG administration on redox homeostasis in rat striatum and cerebellum, respectively. Histological analyses of these brain structures were also carried out 7 days after L-2-HG treatment (long-term effects). L-2-HG significantly decreased the concentrations of reduced (GSH) and total glutathione (tGS), as well as of glutathione peroxidase (GPx) and reductase (GR) activities, but did not change the activities of superoxide dismutase and catalase in striatum. Furthermore, the concentrations of oxidized glutathione (GSSG) and malondialdehyde (MDA), as well as 2′,7′-dichlorofluorescein (DCFH) oxidation and hydrogen peroxide (H 2 O 2 ) production, were increased, whereas carbonyl formation and nitrate plus nitrite concentrations were not altered by L-2-HG injection. It was also found that the melatonin, ascorbic acid plus α-tocopherol, and creatine totally prevented most of these effects, whereas N- acetylcysteine, the noncompetitive glutamate NMDA antagonist MK-801, and the nitric oxide synthase inhibitor L-NAME were not able to normalize the redox alterations elicited by L-2-HG in striatum. L-2-HG intracerebellar injection similarly provoked a decrease of antioxidant defenses (GSH, tGS, GPx, and GR) and an increase of the concentrations of GSSG, MDA, and H 2 O 2 in cerebellum. These results strongly indicate that the major accumulating metabolite in L-2-HGA induce oxidative stress by decreasing the antioxidant defenses and enhancing reactive oxygen species in striatum and cerebellum of adolescent rats. Regarding the histopathological findings, L-2-HG caused intense vacuolation, lymphocyte and macrophage infiltrates, eosinophilic granular bodies, and necrosis in striatum. Immunohistochemistry revealed that L-2-HG treatment provoked an increase of GFAP and a decrease of NeuN immunostaining, indicating reactive astroglyosis and reduction of neuronal population, respectively, in striatum. Similar macrophage infiltrates, associated with less intense vacuolation and lymphocytic infiltration, were observed in cerebellum. However, we did not observe necrosis, eosinophilic granular bodies, and alteration of GFAP and NeuN content in L-2-HG-teated cerebellum. From the biochemical and histological findings, it is presumed that L-2-HG provokes striatal and cerebellar damage in vivo possibly through oxidative stress induction. Therefore, we postulate that antioxidants may serve as adjuvant therapy allied to the current treatment based on a protein-restricted diet and riboflavin and L- carnitine supplementation in patients affected by L-2-HGA. [ABSTRACT FROM AUTHOR]

Background: L-2-hydroxyglutaric aciduria is a metabolic repair deficiency characterized by elevated levels of L-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid. Neurological signs associated with the disease in humans and dogs include seizures, ataxia and dementia. Case presentation: Here we describe an 8 month old Yorkshire terrier that presented with episodes of hyperactivity and aggressive behavior. Between episodes, the dog's behavior and neurologic examinations were normal. A T2 weighted MRI of the brain showed diffuse grey matter hyperintensity and a urine metabolite screen showed elevated 2-hydroxyglutaric acid. We sequenced all 10 exons and intron-exon borders of L2HGDH from the affected dog and identified a homozygous A to G transition in the initiator methionine codon. The first inframe methionine is at p.M183 which is past the mitochondrial targeting domain of the protein. Initiation of translation at p.M183 would encode an N-terminal truncated protein unlikely to be functional. Conclusions: We have identified a mutation in the initiation codon of L2HGDH that is likely to result in a nonfunctional gene. The Yorkshire terrier could serve as an animal model to understand the pathogenesis of L-2-hydroxyglutaric aciduria and to evaluate potential therapies. [ABSTRACT FROM AUTHOR]

l-2-Hydroxyglutaric aciduria ( l-2-HGA) is a neurometabolic disease characterized by the presence of elevated levels of 2-hydroxyglutaric acid in the plasma, cerebrospinal fluid and urine. Clinical features in this inherited condition consist of mental deterioration, ataxia and motor deficits with pyramidal and extrapyramidal symptoms and signs. l-2-HGA is caused by mutations in the l-2-HGDH gene which most probably encodes for a l-2-hydroxyglutarate dehydrogenase, a putative mitochondrial protein converting l-2-hydroxyglutarate to alphaketoglutarate. Here, we report a pathogenic nonsense mutation in the l-2-HGDH gene found for the first time in an Italian patient affected by l-2-HGA, reinforcing the previously described phenotype of this rare metabolic disease and confirming the data indicating that mutations in the l-2-HGDH gene cause l-2-HGA. [ABSTRACT FROM AUTHOR]

We report a male infant with L-2-hydroxyglutaric aciduria and Wilms tumor. L-2-hydroxyglutaric aciduria is a rare, autosomal-recessive, inborn error of metabolism characterized by a variable degree of progressive encephalopathy. Of the fewer than 100 cases reported in the literature, at least 9 patients have developed tumors of the central nervous system. To our knowledge, the present case is the 1st example of an extracranial tumor associated with L-2-hydroxyglutaric aciduria. This observation potentially widens the tumor spectrum in this metabolic disorder and may lead to further insight into the relationship between L-2-hydroxyglutaric acid and cellular transformation. [ABSTRACT FROM AUTHOR]

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We describe late diagnosis of an adult with L-2-hydroxyglutaric aciduria (MIM 236792) on the basis of characteristic metabolite data and mutation analysis in the L2HGDH gene. The patient lacked MRI abnormalities which have been purported to be constant or typical findings in this disease. We further report the genetic status of his parents and his one living sibling. Our observations underline the clinical heterogeneity of the syndrome of L-2-hydroxyglutaric aciduria. This report emphasizes the diagnostic benefit of the assessment of urinary organic acids not only in children, but also in adult patients with unexplained neurological symptoms. The patient was determined to be compound heterozygous for two novel missense mutations in exon 4 of the gene (c.418G>C, c.446T>G), resulting in amino acid exchanges from alanine to proline (p.Ala140Pro) and leucine to arginine (p.Leu149Arg), respectively. The mother of our patient was heterozygous for Ala140Pro, and the father heterozygous for Leu149Arg only. Mutation analysis of a healthy 49-year-old third son of the non-consanguineous parents revealed a normal exon 4. [ABSTRACT FROM AUTHOR]

Abstract: L-2-hydroxyglutaric aciduria (LHGuria) is a rare neurometabolic disorder, which has characteristic clinical and laboratory features. The recent findings imply that LHG dehydrogenase is responsible for the disease and is FAD-dependent. Therefore, it might be expected that riboflavin could enhance any residual activity. We present our observations from nearly 2-year-long riboflavin treatment in a 16-year-old boy with LHGuria. During riboflavin treatment of 100mg/d, partial improvement in his cognitive and motor performances was observed. Urinary LHG excretion decreased from 5990mmol/mol creatinine to 1490mmol/mol creatinine. Moreover, when riboflavin treatment was interrupted, significant disturbances in both symptoms and urinary LHG excretion (6360mmol/mol creatinine) occurred in the patient. After the resettlement of riboflavine treatment, the patient resumed to his previous clinical status in a week. The improvement went further minimally under the dose of 200mg/d, but no further improvement happened with 300mg/d. The present case suggests that riboflavin could be considered as a potential therapeutic approach in LHGuria until the optimal treatment of LHGuria is established. [Copyright &y& Elsevier]

Objective: To report the importance of a rare organic acid metabolic disorder, L-2-hydroxyglutaric aciduria, and its characteristic neuroimaging cerebral white matter abnormalities in a case of epilepsy. Subject and Methods: A 19-year-old male presented with an 11-year history consisting of school failures, intellectual deterioration and generalized tonic-clonic convulsions. Results: Neurological examination showed mental subnormality, mild dysarthria and bilateral pyramidal signs. Computed tomography and magnetic resonance imaging (MRI) of the brain showed characteristic white matter lesions, suggestive of L-2-hydroxyglutaric aciduria. The diagnosis of this disease was confirmed by elevated urinary concentrations of L-2-hydroxyglutaric acid. The epilepsy was partially controlled with antiepileptic drugs. Conclusion: This report indicates the importance of routine examination of urinary organic acids in children and young adults presenting with chronic encephalopathy and epilepsy with characteristic MRI white matter lesions. L-2-hydroxyglutaric aciduria should be considered as one of the differential diagnoses of epilepsy. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

L-2-Hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a rare autosomal recessive neurodegenerative disorder characterized by psychomotor delay, cerebellar and extrapyramidal signs and subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement. Mutations in the gene L2HGDH (C14orf160/duranin/) have been identified as causative for L-2-HGA. A feature disproportionally associated with L-2-HGA is the development of malignant brain tumors. In our cohort of 40 patients with L- 2-HGA, two developed medulloblastoma and glioblastoma multiforme during the course of the disease. Two missense mutations in two patients were identified in the L2HGDH gene in exon 3 (c.292C→T) and in exon 7 (c.887T→A). Both mutations were present in the homozygous state. Serial MR imaging findings as well as MR spectroscopy imaging is reported in a patient who developed glioblastoma multiforme. [ABSTRACT FROM AUTHOR]

Summary: l-2-Hydroxyglutaric aciduria (l-2-HGA) is a hereditary neurometabolic disorder reported in human beings and dogs. An 11-month-old Staffordshire bull terrier was suspected to have the disease, on the basis of clinical signs and magnetic resonance imaging findings. l-2-HGA was confirmed by urinary organic analysis and DNA testing and the dog was humanely destroyed. Post-mortem findings consisted only of microscopical lesions in the brain, characterized by marked spongiform changes and predominantly affecting the grey matter of the cerebral cortex, thalamus, cerebellum and brainstem. The spongiform changes were characterized by well-demarcated, clear vacuoles located at perineuronal and perivascular sites. Immunohistochemical and ultrastructural examination confirmed that the affected cells were astrocytes. [Copyright &y& Elsevier]

l-2-Hydroxyglutaric (l-2-HG) aciduria is a rare inherited metabolic disease usually observed in children. Patients present a very slowly progressive deterioration with cerebellar ataxia, mild or severe mental retardation, and various other clinical signs including extrapyramidal and pyramidal symptoms, and seizures. The disease is characterized by increased levels ofl-2-HG in body fluids such as urine and cerebrospinal fluid. We report on two sisters from consanguineous parents, in whoml-2-HG aciduria was diagnosed at an adult age. Although magnetic resonance imaging and spectroscopic findings were severely abnormal in both, they experienced a different clinical course. The older sister presented with severe mental retardation, recurrent epileptic seizures, and progressive deterioration in her ability to walk and to talk; she is now confined to a wheelchair with severe speech deficit. In contrast, the younger sister only had a few epileptic seizures in childhood and moderate mental retardation, is still able to walk, and performs manual work, and has a social life in a specialized institution for moderately mentally handicapped persons. For the two patients, a complete deletion of exon 9 was demonstrated in a gene located on chromosome 14q22.1, which most probably encodes for L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder could therefore be related to a toxic effect of L-2-hydroxyglutarate on the central nervous system, although the presence of other toxic metabolites cannot be excluded. [ABSTRACT FROM AUTHOR]

Abstract: The biochemical defect in l-2-hydroxyglutaric aciduria is still unknown, but the mutated gene has recently been identified on chromosome 14q22. Transfection of human embryonic kidney (HEK) cells with a cDNA encoding the product of the human gene led to a>15-fold increase in l-2-hydroxyglutarate dehydrogenase activity. The overexpressed enzyme had similar biochemical characteristics (including sensitivity to FAD and association with membranes) as the rat liver enzyme. Western blot analysis indicated that it is processed through the removal of a N-terminal ≈ 4 kDa fragment, in agreement with a mitochondrial localization. Transfection experiments indicated that the mutations (K81E, E176D, Δ-exon9) found in patients with l-2-hydroxyglutaric aciduria suppressed l-2-hydroxyglutarate dehydrogenase activity. Western blot analysis showed that the three mutated proteins were expressed to various degrees in HEK cells, but were abnormally processed. Taken together, these data indicate that l-2-hydroxyglutaric aciduria is due to a deficiency in l-2-hydroxyglutarate dehydrogenase. [Copyright &y& Elsevier]

Background L-2-Hydroxyglutaric aciduria is a rare, infantile-onset, autosomal recessive organic aciduria affecting exclusively the central nervous system. To our knowledge, only 1 complete report of the neuropathological findings in an adult has been published. Objective To present the clinical, neuroimaging, and neuropathological findings of L-2-hydroxyglutaric aciduria. Design Case report. Setting Complexo Hospitalario de Pontevedra, Pontevedra, Spain. Patient A 15-year-old boy who had early infantile-onset progressive psychomotor regression, mild choreodystonia affecting the distal part of the upper limbs, pyramidal signs, and epilepsy. Results The diagnosis of L-2-hydroxyglutaric aciduria was confirmed by the finding of highly elevated levels of L-2-hydroxyglutaric acid in the serum, urine, and cerebrospinal fluid. The neuroimaging findings showed striking confluent subcortical white matter lesions and minimal basal ganglia (pallidum, thalamic, and putaminal) abnormalities. The patient died of a spontaneous mesenteric thrombosis. The postmortem neuropathological findings showed spongiosis and cystic cavitations in subcortical white matter, with minimal abnormalities of the basal ganglia. The dentate nucleus, a structure usually affected in neuroimaging studies, showed minimal neuronal loss but was surrounded by important spongiosis and microvacuolation with astrocytic proliferation. Conclusions This case reaffirms that L-2-hydroxyglutaric aciduria is a spongiform type of leukoencephalopathy with cystic cavitations predominating in the subcortical areas. Although the neuroimaging findings are highly characteristic of the disease, in this patient cerebellar abnormalities were minimal and dentate signal abnormalities were not present. [ABSTRACT FROM AUTHOR]

l-2-Hydroxyglutaric aciduria is a rare inherited, neurometabolic disorder. The underlying metabolic defect and the pathophysiology of l-2-hydroxyglutaric aciduria have not yet been defined. We present MR spectroscopy and cranial MR imaging findings, including diffusion-weighted sequences in two male siblings (aged 10 and 12 years). MR spectroscopy revealed a multiplet at 2.10-2.50 ppm and two broad peaks at 0.9-1.6 ppm. The multiplet at 2.10-2.50 ppm might have been created by elevated glutamate and glutamine or l-2-hydroxyglutaric acid itself, which has a similar chemical structure to glutamate. Diffusion-weighted images demonstrated increased diffusion of water molecules in the white-matter lesions. [ABSTRACT FROM AUTHOR]

L-2-Hydroxyglutaric acid (LGA) accumulates and is the biochemical hallmark of the neurometabolic disorder L-2-hydroxyglutaric aciduria (LHGA). Although this disease is predominantly characterized by severe neurological findings and pronounced cerebral atrophy, the pathomechanisms of brain injury are virtually unknown. In the present study, we investigated the effect of LGA (0.1-1 mM) on various parameters of the glutamatergic system, namely the basal and potassium-induced release of L-[[sup3]H]glutamate by synaptosomal preparations, Na[sup+]-dependent L-[[sup3]H]glutamate uptake by synaptosomal preparations and Na[sup+]-independent L-[[sup3]H]glutamate uptake by synaptic vesicles, as well as of L-[[sup3]H]glutamate binding to synaptic plasma membranes from cerebral cortex of male adult Wistar rats. We observed that LGA significantly increased L-[[sup3]H]glutamate uptake into synaptosomes and synaptic vesicles, without altering synaptosomal glutamate release and glutamate binding to synaptic plasma membranes. Although more comprehensive studies are necessary to evaluate the exact role of LGA on neurotransmission, our findings do not support a direct excitotoxic action for LGA. Therefore, other abnormalities should be searched for to explain neurodegeneration of LHGA. [ABSTRACT FROM AUTHOR]