What Is HMG Aciduria?
3-hydroxy-3-methylglutaric (HMG) aciduria is an inherited metabolic disorder with some significant neurological manifestations. The condition occurs due to the deficiency of 3-methylglutaconyl-CoA hydratase. It begins in infancy to early childhood. Usually, children affected with this condition show delayed development of mental and motor skills (specific movements in the body muscles, such as running or walking), that is, psychomotor delay (slowing down of physical movements and thoughts), speech delay, dystonia (involuntary muscle cramping), and weakness and spasms in the arms and legs called spastic quadriparesis. The affected individuals can also experience optic atrophy (damage to the optic nerve). It is defined as the breakdown of nerve cells that are useful in carrying visual information from the eyes to the brain.
Some patients may show signs and symptoms of this condition during adulthood, like in their twenties or thirties. These individuals experience damage to the brain tissue called white matter. This condition is called leukoencephalopathy. This damage may lead to certain progressive issues with speech (dysarthria), difficulty in coordinating movements, called ataxia, stiffness (spasticity), optic atrophy, and a decrease in the intellectual functioning of the brain called dementia.
All people affected with 3-methylglutaconyl-CoA hydratase deficiency show an accumulation of large amounts of a substance known as 3-methylglutaconic acid in their body fluids. This causes elevated levels of acid in their blood, termed metabolic acidosis, and causes aciduria. Aciduria is a clinical condition in which the patient excretes large amounts of acid in the urine. 3-methylglutaconyl-CoA hydratase deficiency is a group of metabolic disorders that can be diagnosed by increased levels of 3-methylglutaconic acid in the urine (3-methylglutaconic aciduria).
People with 3-methylglutaconyl-CoA hydratase deficiency also have high urine levels of another acid called 3-methyl glutaric acid. This condition is a rare disorder, with only 20 cases reported in the scientific literature. The various other names of this condition are: 3-methylglutaconic aciduria, type I, 3-MG-CoA-hydratase deficiency, AUH defect, MGA, type I, MGA1, MGCA1, and Primary 3-methylglutaconic aciduria.
How Is HMG Aciduria Caused?
The genetic cause is the most common etiology. Mutations occurring in the AUH gene lead to a deficiency of 3-methylglutaconyl-CoA hydratase. The gene's function is to provide instructions for producing 3-methylglutaconyl-CoA hydratase. This enzyme helps in breaking down the amino acid called leucine, which is a protein-building block. Amino acids help in providing energy for cells.
Later, this amino acid is broken down in mitochondria (the powerhouse of the cell), which converts energy from food into a form that can be used by the cells. The mutations in the AUH gene disrupt this enzyme activity. This condition is inherited in individuals in an autosomal recessive pattern. This indicates that both copies of the gene in each cell will undergo mutations. The parents are carrying one copy of the mutated gene, leading to an individual with an autosomal recessive condition. But the parents do not show any signs and symptoms of the condition.
How Is HMG Aciduria Inherited?
HMG aciduria is inherited in individuals in an autosomal recessive pattern. This indicates that both copies of the gene in each cell will undergo mutations. The parents carry one copy of the mutated gene, leading to an individual with an autosomal recessive condition. However, the parents do not show any signs or symptoms of the condition.
What Are The Signs And Symptoms?
The signs vary in different children or individuals. Each child with 3-hydroxy-3-methyl glutaric aciduria (HMG) shows slightly different signs and symptoms. The most affected children begin to show signs of HMG between 3 months and two years of age. Also, in a few cases, the infants or babies show signs and symptoms of the condition immediately a few days after birth.
The various signs of HMG have been mentioned below:
-
Tiredness or fatigue.
-
Poor appetite.
-
Irritability.
-
Sleeping more often or for a long duration.
-
Hypotonia: This means that the muscle tone is weak.
-
Changes in the behavior.
-
Vomiting.
-
Diarrhea or loose motions.
-
Hypoglycemia: Decreased levels of blood sugar.
Most of these signs and symptoms can be observed when the baby eats foods the body cannot break down.
How Can HMG Aciduria Be Diagnosed?
When you visit the physician, you will be asked questions about yourself, the child, and whoever is affected. The questions will include personal history, family history, medical history, and the signs and symptoms you face. Following this, your doctor will perform certain tests to check for deficiency of 3-methylglutaconyl-CoA hydratase. This can be done by assessing the presence of an increase in levels of 3-methylglutaconic acid in urine.
If the screening of newborn babies shows 3-hydroxy-3-methyl glutaric aciduria (HMG) as out of the normal range, additional testing will be required to confirm the diagnosis. The presence of this value does not indicate the confirmation of this condition. However, follow-up testing should be done as soon as possible in such babies as the harmful effects of untreated HMG can be observed within a few days after birth. Follow-up testing includes checking the urine sample of the baby and blood samples for the presence of any harmful levels of acids and toxins.
Certain acids and toxins can build up in the body when a child suffers from an organic acid condition. Hence, it is important to study the amounts of these substances in the baby's body to confirm the diagnosis. Increased levels of C5-OH acylcarnitines in the blood or the presence of organic acids in the urine suggest HMG. Sometimes, testing a very small skin sample can also be included in the follow-up testing to help diagnose.
How Can HMG Aciduria Be Treated?
There are various treatment options suggested in the literature to manage these conditions. The following supplements can be provided to the patient:
Niacin, Coenzyme Q10, L-carnitine and acetyl-L-carnitine, Nicotinamide, Biotin, Riboflavin, and vitamin E.
How Is The Prognosis?
If the baby is provided with early and careful treatment, the child will probably lead a healthy life and experience normal growth and development. There are chances that children diagnosed with 3-hydroxy-3-methyl glutaric aciduria (HMG) and undergoing treatment may have a decrease in blood sugar levels and various other signs and symptoms of HMG. Hence, early screening and treatment are essential. Those babies who do not receive appropriate treatment early may die or develop permanent damage to the brain.
Conclusion
3-methylglutaconyl-CoA hydratase deficiency is an inherited neurological disorder that can lead to HMG aciduria. Early diagnosis and prompt treatment are essential for a better prognosis. You can consult a specialist online to know more about this condition.
