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 Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

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

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 (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

, * 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 it is a potential manifestation of many different dis ...

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

Seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

Aphasia Aphasia, also known as dysphasia, is an impairment in a person's ability to comprehend or formulate language because of dysfunction in specific brain regions. The major causes are stroke and head trauma; prevalence is hard to determine, but aph ...

Cause

Mutation in several genes can lead to different types of 2-hydroxyglutaric aciduria. For example, the

D2HGDH D-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''D2HGDH'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of ...

and

L2HGDH L-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''L2HGDH'' gene, also known as C14orf160, on chromosome 14. Function This gene encodes L-2-hydroxyglutarate dehydrogenase, a flavin adenine dinuc ...

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 us ...

- in which these

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

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

mutation 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, ...

s 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 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 ...

gene and

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 gene ...

gene, respectively.

Diagnosis

Classification

2-hydroxyglutaric aciduria is an

organic aciduria Organic acidemia is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present. The branched-chain amino ac ...

, 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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

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

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

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

, tremors, and

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

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 le ...

, muscular choreodystonia,

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

, and psychomotor regression. It is associated with ''

,'' 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 Heredity, familial genetic characteristic. People diagnosed with macrocephaly will receive further medical ...

cardiomyopathy Cardiomyopathy is a group of primary diseases of 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. A ...

, and cortical

blindness Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...

. It is caused by recessive mutations in ''

'' (type I) or by dominant gain-of-function mutations in ''

'' (type II).

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

The combined form is characterized by severe early-onset epileptic

encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

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

'' 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