Combined D-2- and L-2-Hydroxyglutaric Aciduria with Neonatal Onset Encephalopathy: A Third Biochemical Variant of 2-Hydroxyglutaric Aciduria?

Muntau, Ania C.; Röschinger, Wulf; Merkenschlager, Andreas; Knaap, Marjo S. van der; Jakobs, Cornelis; Durán, Marinus; Hoffmann, G. F.; Roscher, Adelbert A.

doi:10.1055/s-2000-7497

Cited by 65 publications

(54 citation statements)

References 15 publications

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“…Recently, the third biochemical variant of 2-HGA was described, which involves patients who have (moderate) increases in both D-2-HG and L-2-HG in different body fluids (7 ). These patients displayed a phenotype of neonatal onset metabolic encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Muntau et al (7 ) described a third 2-HGA variant; patients with this variant excrete moderately increased amounts of both D-2-HG and L-2-HG (7 ).…”

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confidence: 99%

“…Additional biochemical abnormalities include increased l-lysine in the CSF of L-2-HGA patients (9,10 ), regularly increased urinary Krebs cycle intermediates (especially succinate, 2-ketoglutarate, and citrate) in D-2-HGA (3,4 ), and increased excretion of 2-ketoglutarate in D/L-2-HGA (7 ).…”

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Disease-related Metabolites in Culture Medium of Fibroblasts from Patients with d-2-Hydroxyglutaric Aciduria, l-2-Hydroxyglutaric Aciduria, and Combined d/l-2-Hydroxyglutaric Aciduria

et al. 2003

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Background: d-2-Hydroxyglutaric aciduria (D-2-HGA), l-2-hydroxyglutaric aciduria (L-2-HGA), and the combined d/l-2-hydroxyglutaric aciduria (D/L-2-HGA) are poorly understood organic acidurias. To investigate the usefulness of cultured human skin fibroblasts for both diagnostic and research purposes, we measured disease-related metabolites in the cell culture medium. Methods: We measured d-2-hydroxyglutarate (D-2-HG), l-2-hydroxyglutarate (L-2-HG), succinate, 2-ketoglutarate, and citrate in fibroblast cell medium by stable-isotope-dilution gas chromatography–mass spectrometry and glutamine, glutamic acid, and lysine with an amino acid analyzer. We used six cell lines from patients with D-2-HGA, two from patients with L-2-HGA, three from patients with D/L-2-HGA, and seven control cell lines. Culture medium was analyzed after a 96-h incubation period. Results: Culture media from cell lines from D-2-HGA patients contained D-2-HG at concentrations 5- to 30-fold higher than media from controls, whereas the concentration of L-2-HG in media was not increased. Media from L-2-HGA cell lines showed a fivefold increase in L-2-HG compared with controls. Media containing fibroblasts from D/L-2-HGA patients contained moderately increased amounts of both D-2-HG and L-2-HG. For all cell lines, succinate concentrations in the blank medium were higher than after 96 h of incubation with the exception of two of three D/L-2-HGA cell lines. Media of D-2-HGA cell lines had 2-ketoglutarate concentrations that were 40% of that for controls. Glutamic acid concentrations in media of these cell lines were 60% lower than in controls. Conclusions: Cell culture media from fibroblasts from patients with D-2-HGA, L-2-HGA, or D/L-2-HGA contain increased amounts the corresponding 2-HGs, demonstrating the suitability of fibroblasts for both diagnosis of and research concerning 2-HGAs.

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Section: Discussionmentioning

confidence: 99%

“…Recently, Muntau et al (7 ) described a third 2-HGA variant; patients with this variant excrete moderately increased amounts of both D-2-HG and L-2-HG (7 ).…”

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confidence: 99%

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Disease-related Metabolites in Culture Medium of Fibroblasts from Patients with d-2-Hydroxyglutaric Aciduria, l-2-Hydroxyglutaric Aciduria, and Combined d/l-2-Hydroxyglutaric Aciduria

et al. 2003

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“…Chalmers et al 4 identificaram um paciente com acidúria D-2-hidroxiglutárica (D-2-HGA), enquanto Duran et al 5 descreveram um caso de acidúria L-2-hidroxiglutárica (L-2-HGA). A terceira variante bioquímica da acidúria 2-hidroxiglutárica foi descrita por Montau et al 6 , que relataram três pacientes com elevada excreção urinária de ácido D e L-2-hidroxiglutárico, denotada pelos autores como acidúria D,L-2-hidroxiglutárica (D,L-2-HGA). O ácido L-2-hidroxiglutárico (L-2-HG) ou o seu enantiômero, o ácido D-2-hidroxiglutárico (D-2-HG), apresentam concentrações muito elevadas nos tecidos e líquidos biológicos dos pacientes com L-2-HGA e D-2-HGA, respectivamente.…”

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Acidúrias D-2-hidroxiglutárica e L-2-hidroxiglutárica: uma revisão da literatura

Rodrigues¹,

Vargas²

2016

cbr

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RESUMOAs acidúrias D-2-hidroxiglutárica (D-2-HGA) e L-2-hidroxiglutárica (L-2-HGA) são raras doenças neurometabólicas que constituem um grupo de erros inatos do metabolismo. Essas doenças são causadas pela deficiência das atividades enzimáticas da D-2-hidroxiglutarato desidrogenase na D-2-HGA do tipo I ou isocitrato desidrogenase na D-2-HGA do tipo II, e da L-2-hidroxiglutarato desidrogenase na L-2-HGA. Os principais achados clínicos nos pacientes caracterizam-se por sintomas neurológicos, como convulsões, coma e atrofia cerebral. Também ocorrem lesões cerebrais nos gânglios da base (D-2-HGA, L-2-HGA) e cerebelo (L-2-HGA). Bioquimicamente, essas acidúrias caracterizam-se por acúmulo em tecidos e elevada excreção urinária dos ácidos D-2-hidroxiglutárico (na D-2-HGA) e L-2-hidroxiglutárico (na L-2-HGA). Ainda, uma terceira variante bioquímica da acidúria, a D,L-2-hidroxiglutárica (D,L-2-HGA), é caracterizada por excreção aumentada de ambos enantiômeros do ácido 2-hidroxiglutárico. Em modelo animal, estudos de toxicidade dos ácidos D e L-2-hidroxiglutárico mostraram injúria cerebral, mas não foi elucidado o mecanismo exato causador do dano. Além disso, altos níveis dos ácidos D e L-2-hidroxiglutárico foram encontrados em tumores cerebrais. No entanto, a relação entre a acidúria e o câncer ainda precisa ser esclarecida. Tendo em vista a gravidade da doença, este trabalho teve como objetivo fazer uma revisão bibliográfica acerca do tema, enfatizando as consequências do metabolismo, principalmente para o tecido cerebral, bem como apontar possíveis abordagens terapêuticas. Palavras-chave: ácido D-2-hidroxiglutárico; acidúria D-2-hidroxiglutárica; dano cerebral; ácido L-2-hidroxiglutárico; acidúria L-2-hidroxiglutárica; tumor ABSTRACTThe 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 seve...

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“…Additional signs such as pyramidal and extrapyramidal signs, afebrile seizure, macrocephaly, and cessation of development may be added to the picture. Psychiatric pictures such as behavioral changes, hyperactivity, attention and learning problems may be encountered before neurological signs (5,6).…”

Section: Introductionmentioning

confidence: 99%

Attention deficit hyperactivity disorder comorbidity in an adolescent diagnosed with L-2 hydroxyglutaric aciduria and response to atomoxetine treatment: a case report

Yektaş¹,

Tufan²

2016

Dusunen Adam

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Attention deficit hyperactivity disorder comorbidity in an adolescent diagnosed with L-2 hydroxyglutaric aciduria and response to atomoxetine treatment: a case report 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.Keywords: Atomoxetine, attention deficit hyperactivity disorder, L-2-hydroxyglutaric aciduria ÖZET L-2-hidroksi glutarik asidüri tanılı bir ergende dikkat eksikliği hiperaktivite bozukluğu eş tanısı ve atomoksetin tedavisine yanıt: Bir olgu sunumu L-2-hidroksi glutarik asidüri (L-2 HGA) nadir görülen, yavaş ilerleyen ve otozomal resesif kalıtılan nörodejeneratif metabolik bir hastalıktır. Hastalık mental retardasyon, davranış bozukluğu, ataksi, ekstrapiramidal bulgular ve epileptik nöbetlerle seyreder. Tanı; idrar, plazma ya da serebrospinal sıvıda L-2-hidroksiglutarik asid yüksekliği ile konulur. Bu yazıda nöbetler, mental retardasyon, dikkat eksikliği hiperaktivite bozukluğu (DEHB) belirtileri, okul başarısında sorunlarla belirti veren ve L-2 HGA tanısı konulan 13 yaşında bir erkek hastadan bahsedilmiş olup nadir görülen bu hastalığa eşlik eden DEHB semptomlarına atomoksetin tedavi yanıtı tartışılmıştır.

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Combined D-2- and L-2-Hydroxyglutaric Aciduria with Neonatal Onset Encephalopathy: A Third Biochemical Variant of 2-Hydroxyglutaric Aciduria?

Cited by 65 publications

References 15 publications

Disease-related Metabolites in Culture Medium of Fibroblasts from Patients with d-2-Hydroxyglutaric Aciduria, l-2-Hydroxyglutaric Aciduria, and Combined d/l-2-Hydroxyglutaric Aciduria

Disease-related Metabolites in Culture Medium of Fibroblasts from Patients with d-2-Hydroxyglutaric Aciduria, l-2-Hydroxyglutaric Aciduria, and Combined d/l-2-Hydroxyglutaric Aciduria

Acidúrias D-2-hidroxiglutárica e L-2-hidroxiglutárica: uma revisão da literatura

Attention deficit hyperactivity disorder comorbidity in an adolescent diagnosed with L-2 hydroxyglutaric aciduria and response to atomoxetine treatment: a case report

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