L-2-Hydroxyglutaric Aciduria – Definition
L-2-hydroxyglutaric aciduria (L2HGA, OMIM #236792) is a neurometabolic genetic disorder caused by mutations in the L2HGDH gene. It is characterized by cerebellar ataxia, psychomotor retardation, epilepsy, and microcephaly of varying severity.
Synonym:
L-2-hydroxy glutaric acidemia
Gene:
L2HGDH (L-2-hydroxyglutarate dehydrogenase gene)
Gene product:
L2HGDH (L-2-hydroxyglutarate dehydrogenase)
Function:
L2HGDH catalyzes the conversion of L-2-hydroxyglutaric acid (L2HG) into 2 ketoglutarate. The function of L2HG is still unknown.
Pattern of inheritance:
Autosomal recessive
Prevalence:
<1:1.000.000
Genotype-phenotype correlation:
All in all, there are only a few phenotypical differences.
Urinary excretion of L2HG is considerably reduced in patients with a c.905C>T mutation than in patients with a c.530_533delinsATT mutation, although there are no apparent phenotypic differences.
Penetrance:
All patients exhibit an elevated level of L-2-hydroxyglutaric acid in the urine.
L-2-Hydroxyglutaric Aciduria – Diagnosis
Laboratory Chemical Diagnostics
Massively elevated levels of 2-L-hydroxyglutaric acid are evident in the urine, plasma, and CSF when screening for organic acids. Subsequent chimeric separation can then be used to biochemically verify the L2HGA diagnosis.
Imaging Diagnostics
Cranial CT and MRI usually detect subcortical leukoencephalopathy, subcortical and paraventricular intensity disorders, and cerebellar atrophy.
Genetic Diagnostics
The diagnosis of “L-2-hydroxyglutaric aciduria” is confirmed by the detection of a germline mutation in the L2HGDH gene through sequence analysis, PCR (polymerase chain reaction), or MLPA (multiplex ligation-dependent probe amplification).
Differential Diagnoses
- D-2-hydroxyglutaric aciduria
- Neurometabolic diseases caused by other factors
Clinical Presentation
L-2-hydroxyglutaric aciduria is usually clinically detected within the first year of life through psychomotor retardation, epileptic attacks, or cerebellar ataxia. Around half of the patients exhibit macrocephaly. Other symptoms are muscular hypotension (usually during the early stage of the disease), extrapyramidal symptoms, abnormal behavior, and spasticity (tending to occur later on in the progression). Overall, the progression of the disease is slow, with most affected individuals reaching 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 addition, L2HGA is associated with various brain tumors such as ependymomas, primitive neuroectodermal tumors, low and high-grade gliomas, medulloblastomas, and oligodendrogliomas. The exact risk of tumors is not yet known.
In laboratory chemical testing, L2HGA is characterized by high levels of L-2-hydroxyglutaric acid in the urine, plasma, and CSF.
Special Features of Treatment
No causal therapy exists to date, which is why treatment is limited to supportive, symptom-orientated therapies.
Diagnosis of L-2-Hydroxyglutaric Aciduria- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of L-2-Hydroxyglutaric Aciduria- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
Due to the increased risk of brain tumors, a clinical and neurological examination should be conducted every 3-6 months. In addition, an annual cranial MRI (initially with contrast agent and then without as long as no anomalies are identified) is recommended.
