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D-2-hydroxyglutaric aciduria
This condition can lead to neurological problems, including developmental delay, seizures, and weak muscle tone. It is typically diagnosed in childhood and is caused by changes in genes like IDH2.
Overview
D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare genetic metabolic disorder. It is characterised by the build-up of a substance called D-2-hydroxyglutarate in the body's fluids and tissues, particularly in the brain. This accumulation can be harmful, primarily affecting the central nervous system [PMID:17926173]. The severity of D-2-HGA can vary significantly among individuals, ranging from mild to severe symptoms.
Symptoms & clinical features
The symptoms of D-2-HGA usually begin during infancy or early childhood. They often relate to brain function and development. Common clinical features may include developmental delay, affecting skills such as walking and speech, and intellectual disability. Many individuals with D-2-HGA experience seizures, which can vary in frequency and type. Muscle weakness (hypotonia) and difficulties with coordination (ataxia) are also frequently observed [PMID:15682137].
Some individuals may experience a progressive worsening of neurological symptoms over time. Problems with the heart muscle (cardiomyopathy) have also been reported in some cases, highlighting that D-2-HGA can affect more than just the nervous system [PMID:19460281]. However, the specific symptoms and their severity are highly variable.
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Affected organs
The primary organ affected by D-2-hydroxyglutaric aciduria is the brain. The accumulation of D-2-hydroxyglutarate is thought to be toxic to brain cells, leading to the various neurological symptoms. Magnetic resonance imaging (MRI) scans of the brain often show characteristic changes in brain structure in affected individuals.
While the brain is most consistently impacted, some individuals may also experience effects on other organs. For instance, the heart can be affected, leading to cardiomyopathy. The liver and kidneys are generally not primary sites of significant damage in D-2-HGA, though metabolic imbalances can have broader systemic effects.
Risks & severity
D-2-hydroxyglutaric aciduria presents with a wide spectrum of severity. Some individuals experience severe neurological impairment from infancy, including significant developmental delay, uncontrolled seizures, and profound intellectual disability. In these cases, the condition can be life-limiting. Other individuals may have milder symptoms that progress more slowly, allowing for a better quality of life and longer survival.
The age of symptom onset is typically in infancy or early childhood, but adult-onset cases have also been documented. The long-term outlook for individuals with D-2-HGA depends largely on the severity of neurological involvement and the presence of other organ complications. The exact prevalence of D-2-HGA is not well established due to its rarity.
Genetic causes
D-2-hydroxyglutaric aciduria can be caused by changes in different genes, depending on the specific type. One form, generally inherited in an autosomal dominant pattern, is caused by pathogenic variants in the IDH2 gene. The IDH2 gene provides instructions for making an enzyme called isocitrate dehydrogenase 2, which is involved in an important energy-producing pathway within cells, called the Krebs cycle.
Pathogenic variants in IDH2 lead to a 'gain-of-function', where the enzyme acquires a new, abnormal activity. This new activity converts a molecule called alpha-ketoglutarate into D-2-hydroxyglutarate, which then accumulates to harmful levels in the body. This accumulation is believed to interfere with normal cell function, particularly affecting brain development and activity.
- IDH2 isocitrate dehydrogenase (NADP(+)) 2
Inheritance pattern
D-2-hydroxyglutaric aciduria can be inherited in two main ways: autosomal dominant (AD) or autosomal recessive (AR). When caused by changes in the IDH2 gene, it typically follows an autosomal dominant inheritance pattern. This means only one copy of the altered gene in each cell is enough to cause the condition.
If one parent has an autosomal dominant form of D-2-HGA, there is a 50% chance with each pregnancy that their child will inherit the changed gene and develop the condition. For the autosomal recessive form, a child would need to inherit two copies of the altered gene (one from each parent) to be affected. Parents who each carry one copy of a recessive variant are typically unaffected themselves, but have a 25% chance with each pregnancy of having an affected child.
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
D-2-hydroxyglutaric aciduria is typically suspected based on clinical symptoms such as developmental delay, seizures, and characteristic findings on brain imaging. Diagnosis is often confirmed by measuring elevated levels of D-2-hydroxyglutarate in urine, blood, or cerebrospinal fluid. These biochemical tests help to identify the specific metabolic imbalance [PMID:17926173].
Confirmation of the diagnosis, and distinguishing between different forms of D-2-HGA, involves genetic testing. This testing looks for pathogenic variants in genes known to be associated with the condition, such as IDH2. In the UK, genetic testing for suspected inherited metabolic disorders is available through the NHS Genomic Medicine Service, often following referral from a paediatrician or neurologist. Relevant NHS R-codes are used to facilitate this testing.
Management & lifestyle
Currently, there is no cure for D-2-hydroxyglutaric aciduria, and management focuses on alleviating symptoms and providing supportive care. Treatment strategies are individualised based on the specific symptoms and severity experienced by each patient. This often involves a multidisciplinary approach.
Neurological symptoms like seizures are managed with anti-epileptic medications. Developmental support, including physiotherapy, occupational therapy, and speech therapy, is crucial to help individuals achieve their potential. Regular follow-up with metabolic specialists, neurologists, and cardiologists (if the heart is affected) is important to monitor the condition and address any new symptoms. Genetic counsellors can provide information and support to affected individuals and their families, discussing inheritance patterns and reproductive options.
UK care pathway
In the UK, suspected cases of inherited metabolic disorders like D-2-hydroxyglutaric aciduria are generally referred to specialist metabolic centres or clinical genetics services. Access to genetic testing is provided through the NHS Genomic Medicine Service, utilising specific R-codes for conditions listed in PanelApp. A referral from a GP, paediatrician, or neurologist is usually the first step. Genetic counsellors play a key role in explaining genetic test results, discussing inheritance, and providing ongoing support to families.
Frequently asked questions
How is D-2-hydroxyglutaric aciduria diagnosed?
Diagnosis typically involves measuring levels of D-2-hydroxyglutarate in urine or other body fluids, followed by genetic testing. This testing identifies specific changes in genes like IDH2 that cause the condition.
Is there a cure for D-2-hydroxyglutaric aciduria?
Currently, there is no cure for D-2-hydroxyglutaric aciduria. Treatment focuses on managing symptoms and providing supportive care, such as anti-seizure medication and therapies for developmental support.
What is the inheritance pattern for D-2-hydroxyglutaric aciduria?
The inheritance pattern can be either autosomal dominant (e.g., from IDH2 variants) or autosomal recessive. This means either one copy of an altered gene or two copies (one from each parent) are needed for the condition to occur, depending on the specific genetic cause.
What kind of doctors treat D-2-hydroxyglutaric aciduria?
Management often involves a team of specialists, including metabolic doctors, neurologists, developmental paediatricians, physiotherapists, occupational therapists, and genetic counsellors.
Can D-2-hydroxyglutaric aciduria affect other organs besides the brain?
While the brain is most commonly and significantly affected, some individuals with D-2-hydroxyglutaric aciduria can develop complications affecting other organs, such as the heart muscle (cardiomyopathy).
References
- Nyhan WL, Shelton GD, Jakobs C. D-2-hydroxyglutaric aciduria. Journal of child neurology. 1995. PMID: 7782605
- Struys EA. D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. Journal of inherited metabolic disease. 2006. PMID: 16601864
- Kwong KL, Mak T, Fong CM. D-2-Hydroxyglutaric aciduria and subdural haemorrhage. Acta paediatrica (Oslo, Norway : 1992). 2002. PMID: 12162609
- Preston A, Reardon K, Crowson N. D-2-Hydroxyglutaric Aciduria with Enchondromatosis and Angiokeratoma Circumscriptum. Cureus. 2019. PMID: 31890366
- Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. Journal of inherited metabolic disease. 2020. PMID: 31691304
- van der Knaap MS, Jakobs C, Hoffmann GF. D-2-hydroxyglutaric aciduria: further clinical delineation. Journal of inherited metabolic disease. 1999. PMID: 10407777
- Geoerger B, Schiff M, Penard-Lacronique V. Enasidenib treatment in two individuals with D-2-hydroxyglutaric aciduria carrying a germline IDH2 mutation. Nature medicine. 2023. PMID: 37248298
- Zhou J, Duan M, Wang X. A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology. Nature cell biology. 2022. PMID: 35418624