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L-2-hydroxyglutaric aciduria
This condition causes progressive neurological problems, often starting in childhood, including developmental delay, seizures, and difficulties with movement. It is a rare disorder that is inherited in an autosomal recessive pattern.
Overview
L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited metabolic disorder characterised by the accumulation of a substance called L-2-hydroxyglutaric acid in various bodily fluids, especially in the brain. This build-up is thought to be toxic to brain cells, leading to a range of neurological problems [PMID:33671217]. The condition typically presents during infancy or childhood, although symptoms can sometimes emerge later.
Over time, L-2-HGA can lead to a progressive deterioration of neurological function. Individuals with the condition often experience challenges with development and movement. It is considered a white matter disorder, meaning it primarily affects the 'white matter' of the brain, which consists of nerve fibres that connect different brain regions [PMID:21727787].
Symptoms & clinical features
The symptoms of L-2-HGA can vary among individuals but generally involve neurological impairment. Common features include developmental delay, affecting milestones like walking and speech. Muscle weakness (hypotonia) or stiffness (spasticity) can be present, leading to problems with coordination and balance, known as ataxia [PMID:33671217].
Many individuals with L-2-HGA experience seizures, which can vary in type and severity. Intellectual disability is also a common feature. Over time, the neurological issues can worsen, leading to a decline in abilities. Some individuals may develop macrocephaly (an abnormally large head size) [PMID:21727787].
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Affected organs
L-2-hydroxyglutaric aciduria primarily affects the brain. The accumulation of L-2-hydroxyglutaric acid is particularly damaging to the central nervous system. This can lead to structural changes in the brain that are visible on imaging scans, such as abnormalities in the white matter and deep grey matter structures like the basal ganglia and cerebellum.
Risks & severity
L-2-HGA is a progressive condition, meaning its symptoms tend to worsen over time. The age of onset can vary, but symptoms typically begin in early childhood, often between birth and six years of age. The severity of the condition and the rate of progression can differ significantly between affected individuals. While some may experience a more gradual decline, others might have a more rapid progression of neurological issues.
The condition generally leads to a significant impact on neurological function and quality of life. The exact prevalence of L-2-HGA is not well established due to its rarity, but it is considered a very uncommon disorder worldwide.
Genetic causes
L-2-hydroxyglutaric aciduria is caused by changes (variants) in specific genes. These genes provide instructions for making proteins involved in the metabolism (processing) of L-2-hydroxyglutaric acid. When these genes have pathogenic variants, the body cannot properly break down this acid, leading to its accumulation.
While specific causative genes are not detailed in this dataset, research indicates that variants in genes encoding enzymes responsible for L-2-hydroxyglutarate dehydrogenase activity are implicated. This enzyme is crucial for converting L-2-hydroxyglutarate to alpha-ketoglutarate, a step that prevents its build-up. Disruptions in this pathway cause the toxic accumulation observed in the condition.
Inheritance pattern
L-2-hydroxyglutaric aciduria is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered gene - one from each parent - to develop the condition. People who have only one copy of the altered gene are called carriers; they typically do not show symptoms of L-2-HGA themselves but can pass the gene on to their children.
If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two altered copies of the gene and develop L-2-HGA. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of L-2-hydroxyglutaric aciduria often begins with clinical suspicion based on the neurological symptoms and developmental profile. Blood and urine tests can detect elevated levels of L-2-hydroxyglutaric acid. Magnetic Resonance Imaging (MRI) scans of the brain typically reveal characteristic abnormalities, particularly in the white matter [PMID:21727787].
Genetic testing is used to confirm the diagnosis by identifying pathogenic variants in the causative genes. This testing is often performed through NHS Genomic Medicine Service (GMS) pathways, typically following a referral from a specialist paediatrician or neurologist. Relevant R-codes for genetic testing may include those for metabolic disorders or white matter conditions, allowing access to comprehensive genomic analysis.
Management & lifestyle
Currently, there is no cure for L-2-hydroxyglutaric aciduria, and management focuses on supportive care to help manage symptoms and improve quality of life. This can include medications to control seizures, physical therapy to address movement difficulties, and occupational therapy to assist with daily living activities. Speech therapy may also be beneficial for communication challenges.
Some dietary interventions, such as a low-lysine and low-tryptophan diet, have been explored as a potential way to reduce L-2-hydroxyglutarate levels, but their effectiveness is not definitively established, and they are typically only used under strict medical supervision [PMID:33671217]. Regular follow-up with a neurologist and other specialists within the NHS framework is crucial to monitor the progression of the condition and adjust management strategies as needed. Genetic counselling is also an important part of care, offering information and support to families regarding inheritance and future planning.
UK care pathway
In the UK, individuals suspected of having rare genetic conditions like L-2-hydroxyglutaric aciduria would typically be referred to a specialist within the NHS, such as a paediatric neurologist or a metabolic specialist. If a genetic condition is suspected, they may then be referred to a Clinical Genetics service. Genetic counselling is available to discuss the condition, inheritance patterns, and testing options.
Diagnostic genetic testing, often through the NHS Genomic Medicine Service (GMS), can be accessed via specific R-codes for inherited metabolic disorders or neurological conditions. These codes facilitate access to advanced genomic investigations needed to confirm the diagnosis.
Frequently asked questions
What does 'autosomal recessive inheritance' mean?
Autosomal recessive inheritance means a person must inherit two copies of the altered gene - one from each parent - to have the condition. Parents who each carry one copy of the altered gene are typically healthy themselves but can pass the condition on to their children.
Can L-2-hydroxyglutaric aciduria be cured?
Currently, there is no cure for L-2-hydroxyglutaric aciduria. Treatment focuses on managing the symptoms and providing supportive care to improve the individual's quality of life. This includes therapies, medications for seizures, and ongoing medical supervision.
How is L-2-hydroxyglutaric aciduria diagnosed?
Diagnosis typically involves identifying characteristic symptoms, finding elevated levels of L-2-hydroxyglutaric acid in urine and blood tests, and observing specific brain abnormalities on MRI scans. The diagnosis is confirmed through genetic testing that identifies the underlying gene changes.
What kind of doctors treat L-2-hydroxyglutaric aciduria?
Individuals with L-2-hydroxyglutaric aciduria are typically cared for by a team of specialists, including paediatric neurologists, metabolic specialists, physiotherapists, occupational therapists, and speech and language therapists. Genetic counsellors also play a key role in supporting families.
Is L-2-hydroxyglutaric aciduria a common condition?
No, L-2-hydroxyglutaric aciduria is a very rare condition. Its exact prevalence is not precisely known, but it is considered an uncommon disorder globally.
References
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- Chakrabarty RP, Van Vranken JG, Aoi Y. Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite. Nature. 2026. PMID: 42162436
- Coşkun T. L-2-hydroxyglutaric aciduria and brain tumors. Journal of pediatric hematology/oncology. 2010. PMID: 20421813
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- Kamath SD, Bhat MD, Santhosh V. L-2-Hydroxyglutaric Aciduria: An Ever-Expanding Phenotypic Spectrum. Annals of Indian Academy of Neurology. 2023. PMID: 37970304
- Cordier F, Wesseling P, Tops BBJ. Malignant glioma in L-2-Hydroxyglutaric Aciduria: thorough molecular characterization of a case and literature review. Free neuropathology. 2024. PMID: 38716347