RARE DISEASE
L-2-hydroxyglutaric aciduria
L-2-hydroxyglutaric aciduria
L-2-hydroxyglutaric aciduria
Synonyms: L-2-HGA, L-2-hydroxyglutaric acidemia
Synonyms: L-2-HGA, L-2-hydroxyglutaric acidemia
Synonyms: L-2-HGA, L-2-hydroxyglutaric acidemia
Drug discovery
0
drugs
With orphan designations
Overview
L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the L2HGDH gene, leading to toxic accumulation of L-2-hydroxyglutarate. Clinically, it presents with psychomotor delay, cerebellar ataxia, seizures, macrocephaly, and progressive neurological deterioration. Diagnosis is confirmed by elevated urinary L-2-hydroxyglutaric acid via chiral separation and characteristic MRI findings of subcortical leukoencephalopathy with dentate nucleus involvement. No disease-modifying therapies exist; management focuses on symptomatic relief and supportive care, though riboflavin and levocarnitine may stabilize symptoms in some cases [1][3][13][16][19].
Burden
Clinical: Progressive disability with 100% developing intellectual deficits and 50% requiring mobility aids by adulthood [1][6][19].
Oncological: 5–10% risk of brain tumors linked to chronic L-2-HG accumulation [9][15][19].
Economic: Lifelong multidisciplinary care, compounded by delayed diagnosis due to nonspecific early symptoms [1][12][18].
Therapies
Symptomatic management: Antiepileptics for seizures, physical/occupational therapy for motor deficits [1][3][19].
Experimental adjuncts: Riboflavin (100–300 mg/day) and levocarnitine (1.5–3 g/day) to potentially reduce metabolite levels and stabilize neurological function [3][7][19].
Monitoring: Regular neuroimaging for early detection of cerebral neoplasms (5% prevalence) [9][15][19].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
38 drug discovery papers about L-2-hydroxyglutaric aciduria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
38 drug discovery papers about L-2-hydroxyglutaric aciduria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-26 | Clinical and Genetic Analysis of L-2-Hydroxyglutaric Aciduria Caused by a Novel L2HGDH Mutation with a Concurrent RYR1 Variant
Background/Objectives: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder marked by developmental delay, intellectual disability, and progressive movement abnormalities. Variants in RYR1 can cause congenital myopathies, but data on the co-occurrence of variants in populations are limited. The aim of this study was to characterize the clinical and genetic basis of the neurometabolic and neuromuscular abnormalities and to investigate the potential interaction between the identified variants. Methods: Patients with complex, previously undiagnosed clinical presentations underwent neurological evaluation, including brain magnetic resonance imaging, electromyography, biochemical testing, and whole-exome sequencing (WES). Identified variants were analyzed in silico and confirmed by Sanger sequencing in the patient and her parents. Three cases were reviewed, and one of these patients exhibited developmental delay, hypotonia, intellectual disability, and progressive motor dysfunction. Biochemical tests revealed markedly elevated urinary 2-hydroxyglutaric acid levels, consistent with L2HGA. Results: WES identified a homozygous likely pathogenic variant in L2HGDH (c.589_590insGGC, p.Q197insG), confirming the molecular diagnosis of L2HGA. In addition, a heterozygous missense variant in RYR1 (c.7268T>A, p.M2423K), classified as a variant of uncertain significance, was detected and was inherited from her mildly affected father. The L2HGDH variant explains the neurometabolic phenotype of the patient, whereas the RYR1 variant remains of uncertain significance, and its clinical contribution cannot be clearly established. Conclusions: To our knowledge, this case illustrates the co-occurrence of a likely pathogenic L2HGDH variant and a heterozygous RYR1 variant of uncertain significance. The findings expand the mutational spectrum of L2HGA and underscore the value of comprehensive genomic testing in complex neurometabolic and neuromuscular disorders.
2026-01-14 | 2-hydroxyglutaric aciduria in the practice of neonatologists and pediatricians: possibilities for early diagnosis and treatment
2-hydroxyglutaric aciduria (ICD-10 code E72.8: Other specified disorders of amino-acid metabolism) is a group of rare metabolic disorders resulting from the accumulation of α-ketoglutarate derivatives in mitochondria: D- and L-enantiomers of 2-hydroxyglutaric acid. This pathology is caused by a wide range of mutations in the genes of mitochondrial enzymes, which explains the existence of several subtypes of the disease in the described group. Over the 45 years since the first mention of 2-hydroxyglutaric aciduria, nearly 500 cases have been reported worldwide. 2-hydroxyglutaric aciduria leads to multisystemic disorders, primarily neurological, severe disability, or death, which determines the importance of early diagnosis. The disease is not included in neonatal screening, but certain similarities between its clinical and laboratory manifestations and various acidemias and other metabolic disorders, as well as their severe consequences and outcomes, necessitate further study and systematization of knowledge about this pathology. This article describes current approaches to the diagnosis and treatment of 2-hydroxyglutaric aciduria in newborns and young children. Key words: inherited metabolic disorders, aciduria, 2-hydroxyglutaric acid, 2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria types I and II, L-2-hydroxyglutaric aciduria
2025-12-25 | Successful Treatment of 2-Hydroxyglutaric Aciduria Diagnosed in Adulthood, Three Decades after the Onset: A Case Report and Literature Review.
2-Hydroxyglutaric aciduria is a rare genetic metabolic disorder, especially in Japan. Although magnetic resonance images show characteristic abnormalities in the subcortical white matter, some cases have been diagnosed in adulthood, namely many decades after onset. We herein report the case of a bedridden 37-year-old 2-hydroxyglutaric aciduria male patient who was diagnosed three decades after onset. Despite this, combination treatment with riboflavin and levocarnitine improved his condition, thus allowing him to walk by himself. Considering our case and the previous literature, we emphasize the importance of correctly diagnosing and treating patients with 2-hydroxyglutaric aciduria.
2025-06-04 | L‐2‐Hydroxyglutaric Aciduria Complicated by Cerebral Neoplasm
Data S1. Investigations of index patient. MRI (magnetic resonance imaging) brain of the index patient at the age of 15 years. Genetic report of the index patient. Data S2. Summary and neuroimaging of the affected younger sibling. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2025-05-17 | Riboflavin treatment in L-2-hydroxyglutaric aciduria: report on a pediatric patient and literature review.
L-2-hydroxyglutaric aciduria (L-2-HGA, #236,792) is an autosomal recessive neurodegenerative disorder caused by the deficiency of L-2-hydroxyglutarate dehydrogenase, a flavin adenine dinucleotide (FAD)-dependent enzyme, due to biallelic pathogenic variants in the L2HGDH gene. The present study described the patient with L2HGA presenting with a slight psychomotor delay, epilepsy from 5 years of age, non-progressive cerebellar ataxia, and mild to moderate intellectual disability during 10 years of follow-up. Two different heterozygous variants in the L2HGDH gene were identified in the patient: a known substitution c.829C > T(p.Arg277*) and a novel substitution c.1196 + 1G > A corresponding with significantly increased urinary L-2-hydroxyglutarate (L2HG) excretion. A 6-month period of treatment with riboflavin (100 mg/day) was implemented with no clinical nor biochemical effect.
small molecules
2026-06-26 | Clinical and Genetic Analysis of L-2-Hydroxyglutaric Aciduria Caused by a Novel L2HGDH Mutation with a Concurrent RYR1 Variant
Background/Objectives: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder marked by developmental delay, intellectual disability, and progressive movement abnormalities. Variants in RYR1 can cause congenital myopathies, but data on the co-occurrence of variants in populations are limited. The aim of this study was to characterize the clinical and genetic basis of the neurometabolic and neuromuscular abnormalities and to investigate the potential interaction between the identified variants. Methods: Patients with complex, previously undiagnosed clinical presentations underwent neurological evaluation, including brain magnetic resonance imaging, electromyography, biochemical testing, and whole-exome sequencing (WES). Identified variants were analyzed in silico and confirmed by Sanger sequencing in the patient and her parents. Three cases were reviewed, and one of these patients exhibited developmental delay, hypotonia, intellectual disability, and progressive motor dysfunction. Biochemical tests revealed markedly elevated urinary 2-hydroxyglutaric acid levels, consistent with L2HGA. Results: WES identified a homozygous likely pathogenic variant in L2HGDH (c.589_590insGGC, p.Q197insG), confirming the molecular diagnosis of L2HGA. In addition, a heterozygous missense variant in RYR1 (c.7268T>A, p.M2423K), classified as a variant of uncertain significance, was detected and was inherited from her mildly affected father. The L2HGDH variant explains the neurometabolic phenotype of the patient, whereas the RYR1 variant remains of uncertain significance, and its clinical contribution cannot be clearly established. Conclusions: To our knowledge, this case illustrates the co-occurrence of a likely pathogenic L2HGDH variant and a heterozygous RYR1 variant of uncertain significance. The findings expand the mutational spectrum of L2HGA and underscore the value of comprehensive genomic testing in complex neurometabolic and neuromuscular disorders.
2026-01-14 | 2-hydroxyglutaric aciduria in the practice of neonatologists and pediatricians: possibilities for early diagnosis and treatment
2-hydroxyglutaric aciduria (ICD-10 code E72.8: Other specified disorders of amino-acid metabolism) is a group of rare metabolic disorders resulting from the accumulation of α-ketoglutarate derivatives in mitochondria: D- and L-enantiomers of 2-hydroxyglutaric acid. This pathology is caused by a wide range of mutations in the genes of mitochondrial enzymes, which explains the existence of several subtypes of the disease in the described group. Over the 45 years since the first mention of 2-hydroxyglutaric aciduria, nearly 500 cases have been reported worldwide. 2-hydroxyglutaric aciduria leads to multisystemic disorders, primarily neurological, severe disability, or death, which determines the importance of early diagnosis. The disease is not included in neonatal screening, but certain similarities between its clinical and laboratory manifestations and various acidemias and other metabolic disorders, as well as their severe consequences and outcomes, necessitate further study and systematization of knowledge about this pathology. This article describes current approaches to the diagnosis and treatment of 2-hydroxyglutaric aciduria in newborns and young children. Key words: inherited metabolic disorders, aciduria, 2-hydroxyglutaric acid, 2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria types I and II, L-2-hydroxyglutaric aciduria
2025-12-25 | Successful Treatment of 2-Hydroxyglutaric Aciduria Diagnosed in Adulthood, Three Decades after the Onset: A Case Report and Literature Review.
2-Hydroxyglutaric aciduria is a rare genetic metabolic disorder, especially in Japan. Although magnetic resonance images show characteristic abnormalities in the subcortical white matter, some cases have been diagnosed in adulthood, namely many decades after onset. We herein report the case of a bedridden 37-year-old 2-hydroxyglutaric aciduria male patient who was diagnosed three decades after onset. Despite this, combination treatment with riboflavin and levocarnitine improved his condition, thus allowing him to walk by himself. Considering our case and the previous literature, we emphasize the importance of correctly diagnosing and treating patients with 2-hydroxyglutaric aciduria.
2025-06-04 | L‐2‐Hydroxyglutaric Aciduria Complicated by Cerebral Neoplasm
Data S1. Investigations of index patient. MRI (magnetic resonance imaging) brain of the index patient at the age of 15 years. Genetic report of the index patient. Data S2. Summary and neuroimaging of the affected younger sibling. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2025-05-17 | Riboflavin treatment in L-2-hydroxyglutaric aciduria: report on a pediatric patient and literature review.
L-2-hydroxyglutaric aciduria (L-2-HGA, #236,792) is an autosomal recessive neurodegenerative disorder caused by the deficiency of L-2-hydroxyglutarate dehydrogenase, a flavin adenine dinucleotide (FAD)-dependent enzyme, due to biallelic pathogenic variants in the L2HGDH gene. The present study described the patient with L2HGA presenting with a slight psychomotor delay, epilepsy from 5 years of age, non-progressive cerebellar ataxia, and mild to moderate intellectual disability during 10 years of follow-up. Two different heterozygous variants in the L2HGDH gene were identified in the patient: a known substitution c.829C > T(p.Arg277*) and a novel substitution c.1196 + 1G > A corresponding with significantly increased urinary L-2-hydroxyglutarate (L2HG) excretion. A 6-month period of treatment with riboflavin (100 mg/day) was implemented with no clinical nor biochemical effect.
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