What is L-2-hydroxyglutaric aciduria?

L-2-hydroxyglutaric aciduria (L2HGA) is a metabolic disease that affects the nervous system. It is caused by mutations – or genetic alterations – in the L2HGDH gene, and is characterized by coordination disorders resulting from damage to the cerebellum, developmental delays, epilepsy, and an above-average head circumference to varying degrees.

How is L-2-hydroxyglutaric aciduria diagnosed?

Laboratory Chemical Diagnostics

Massively elevated levels of L-2-hydroxyglutaric acid are evident in the urine, blood, and cerebral fluid when screening for organic acids. Subsequent laboratory tests can then be used to confirm the L2HGA diagnosis biochemically.

Imaging Diagnostics

A CT and an MRI of the head reveal a combination of findings typical of L2HGA, including a smaller cerebellum.

Genetic Diagnostics

The “L-2-hydroxyglutaric aciduria” diagnosis is confirmed by the detection of a mutation – or genetic change – in the L2HGDH gene.

What is the risk of cancer?

Patients with L-2-hydroxyglutaric aciduria have an increased risk of various brain tumors (ependymomas, primitive neuroectodermal tumors, low and high-grade gliomas, medulloblastomas, and oligodendrogliomas). It has not yet been possible to put an exact figure on the risk level.

Clinical L2HGA usually manifests within the first year of life with developmental delays, epileptic seizures, or coordination disorders. Around half of the patients have an above-average head circumference. Other symptoms are muscular weakness (usually during the early stage of the disease), movement pattern disorders, abnormal behavior, and spasticity (muscle cramps, tending to occur later on in the progression). Overall, the progression of the disease is slow, and most people affected reach adulthood. However, it may eventually lead to the complete loss of motor skills (e.g. loss of the ability to walk) and speech problems.

In laboratory chemical testing, L2HGA is characterized by high levels of L-2-hydroxyglutaric acid in the urine, blood, and spinal fluid.

What causes L-2-hydroxyglutaric aciduria?

L-2-hydroxyglutaric aciduria is caused by mutations – or genetic changes – in the L2HGDH gene. This gene encodes for the L-2-hydroxyglutarate dehydrogenase protein, which is involved in metabolic processes in the brain, among other things.

Now if the L2HGDH gene is altered, the corresponding protein will not be produced correctly, and will no longer be able to perform its normal function. Consequently, an accumulation of L-2-hydroxyglutaric acid occurs, resulting in brain damage.

L2HGA is a very rare disease with an incidence of < 1:1.000.000, and it can be passed on by parents to their children. Heredity is autosomal recessive, which is why the disease occurs much more frequently in children of parents who are blood relatives than in the general population.

Is there a treatment?

No causal therapy is known to date, which is why treatment is limited to supportive, symptom-orientated therapy.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Due to the increased risk of brain tumors, a clinical and neurological examination should be conducted every 3-6 months. In addition, an annual MRI of the head (initially with contrast agent and then without as long as no anomalies are detected) is recommended.

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as changes in movement or coordination, speech disorders, or epileptic seizures occur. Moreover, delays in development should be noted and reported to a doctor as well. You should also see a doctor right away if you notice any other newly occurring anomalies or symptoms, such as headaches, nausea, or dizziness.

Support Groups and Additional Information