2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either

autosomal recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

Presentation

The signs/symptoms of this condition are consistent with the following: *

Intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...

, *Muscular

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

Encephalitis Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations ...

Seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

Aphasia Aphasia is an inability to comprehend or formulate language because of damage to specific brain regions. The major causes are stroke and head trauma; prevalence is hard to determine but aphasia due to stroke is estimated to be 0.1–0.4% in ...

Cause

Mutation in several genes can lead to different types of 2-hydroxyglutaric aciduria. For example, the D2HGDH and L2HGDH genes provide instructions for making enzymes that are found in

mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

- in which these

enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

break down D-2-hydroxyglutarate and L-2-hydroxyglutarate, respectively, as a part of normal reaction series that generate energy for cell activities. Any

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

occur in either of these genes would interrupt the functional enzymes and allow both 2-hydroxyglutarates to accumulate in cells, which cause 2-hydroxyglutaric aciduria type I. Moreover, it is known that type II for L-2-hydroxyglutaric aciduria and a mixed type for both 2-hydroxyglutarates come from mutations in IDH2 gene and SLC25A1 gene, respectively.

Diagnosis

Classification

2-hydroxyglutaric aciduria is an organic aciduria, and because of the stereoisomeric property of 2-hydroxyglutarate different variants of this disorder are distinguished:

L-2-hydroxyglutaric aciduria

The L-2 form is more common, severe, and mainly affects the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. The basal ganglia are affected, and cystic cavitations in the white matter of the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

are common, beginning in infancy. This form is chronic, with early symptoms such as

, tremors, and

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

declining into spongiform

leukoencephalopathy Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. It can refer specifically to any of these diseases: *Progressive multifocal leuko ...

, muscular choreodystonia,

mental retardation Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

, and psychomotor regression. It is associated with '' L2HGDH,'' which encodes L-2-hydroxyglutarate dehydrogenase. L-2-hydroxyglutarate is produced by promiscuous action of

malate dehydrogenase Malate dehydrogenase () (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate ...

on 2-oxoglutarate, and L-2-hydroxyglutarate dehydrogenase is an example of a metabolite repair enzyme that oxidizes L-2-hydroxyglutarate back to 2-oxoglutarate.

D-2-hydroxyglutaric aciduria

The D2 form is rare, with symptoms including

macrocephaly Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. ...

, and cortical

blindness Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...

. It is caused by recessive mutations in '' D2HGDH'' (type I) or by dominant gain-of-function mutations in ''

IDH2 Isocitrate dehydrogenase ADP mitochondrial is an enzyme that in humans is encoded by the ''IDH2'' gene. Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to tw ...

'' (type II).

Combined D-2- and L-2-hydroxyglutaric aciduria

The combined form is characterized by severe early-onset epileptic

encephalopathy Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...

and absence of developmental progress. It is caused by recessive mutations in ''

SLC25A1 Tricarboxylate transport protein, mitochondrial, also known as tricarboxylate carrier protein and citrate transport protein (CTP), is a protein that in humans is encoded by the ''SLC25A1'' gene. SLC25A1 belongs to the mitochondrial carrier gen ...

'' encoding the mitochondrial citrate carrier.

Treatment

The treatment of 2-Hydroxyglutaric aciduria is based on seizure control, the prognosis depends on how severe the condition is.

References

External links

{{Medicine Inborn errors of metabolism Autosomal recessive disorders Rare diseases