3-hydroxy-3-methylglutaric aciduria (HMG)

HMGCL is a gene that codes for an enzyme (protein) that is involved in two processes. The first process is to break down leucine, which is a building block (amino acid) found in protein. The second process is to create ketones from fat. Ketones are a form of energy that the body uses during stress, illness or periods of fasting and are created from the breakdown of fat stores. The body uses ketones for energy for the brain and other tissues when our blood sugar is low or not abundant.

Mutations or pathogenic gene variants in the HMGCL gene impact the structure or function of the HMG CoA lyase enzyme that the gene encodes. Mutations or pathogenic gene variants in the HMGCL gene are like spelling mistakes in the instruction code for the gene. These spelling mistakes lead to an enzyme that does not work properly within each cell. When an enzyme does not work efficiently or correctly, it can lead to the build-up of certain substances in the cells that can have a toxic effect. The HMG CoA lyase enzyme plays a role in breaking down leucine. When leucine is unable to be broken down efficiently, it can have a toxic effect on the cell and lead to the symptoms of 3-Hydroxy-3-methylglutaric aciduria. Additionally, the enzyme (HMG CoA lyase) assists in creating an energy source from fats during stress, illness or fasting. When this enzyme does not work properly, the body is also unable to create ketones as an energy source during stress, illness, and/or fasting.

Most likely, if a family member has not shown symptoms of 3-Hydroxy-3-methylglutaric aciduria, then they do not have 3-Hydroxy-3-methylglutaric aciduria. Family members of an individual diagnosed with 3-Hydroxy-3-methylglutaric aciduria may a carrier. This means that they do not have the medical concerns associated with this condition, but have a chance of having children with 3-Hydroxy-3-methylglutaric aciduria. The risk to have a child with 3-Hydroxy-3-methylglutaric aciduria are dependent on if their partner(s) were also a carrier of the syndrome.

If the parents of an affected child have any siblings that are interested in having children, they may want to be tested to see if they are carriers. If they find that they are carriers, their partner may also want to be tested to determine their risk of having a child with 3-Hydroxy-3-methylglutaric aciduria.

The usual abbreviation is HMG.

3-hydroxy-3-methylgutaric aciduria or HMG lyase deficiency is a metabolic disorder that causes the body to not be able to break down a protein building block (amino acid) that is referred to as leucine. This syndrome also affects the body from making “ketones” which the body uses for energy during fasting, illness or physiological stress.

Low blood sugar is something that all patients with 3-hydroxy-3-methylglutaric aciduria should monitor, even if their syndrome is controlled by diet. If this syndrome goes undiagnosed, babies with 3-hydroxy-3-methylglutaric aciduria will most likely pass away or have permanent brain damage.

The gene that is involved in 3-Hydroxy-3-methylglutaric aciduria is HMGCL.

To have inherited a “variant” in a gene means to have inherited a changed copy of the gene from either mom or dad. Variants are further classified according to whether or not they can cause or are associated with HMG lyase deficiency. A pathogenic variant is also known as a mutation. This is a change that can cause HMG lyase deficiency when inherited with a second pathogenic variant or change.

A variant of unknown significance may also be identified in the HMGCL gene. Variants of unknown significance are changes in the gene that have not been reported before in associated with HMG lyase deficiency, nor has that change been seen in the general population. Therefore, there is simply not enough information to know if that particular change is associated with HMG lyase deficiency. As more individuals are identified to have HMG lyase deficiency, variants of unknown significance are reinterpreted and reclassified. If your child is identified to have a variant of unknown significance in the HMGCL gene, additional family member testing may be considered to further classify and interpret what that particular change may mean. A benign variant is a change in the gene that has been reported before in the general population and is not associated with disease.

A geneticist that specializes in inborn errors of metabolism or metabolic conditions, as well as a dietitian will be involved in your child’s care. Additionally, depending on the symptoms your child may experience, you may also need to see a feeding specialist, neurologist, gastroenterologist, cardiologist, ophthalmologist, audiologist, and/or developmental specialist.

A Genetics specialist as well as a nutritionist or dietitian would be helpful for patients with 3-Hydroxy-3-Methylglutaric Aciduria to see regularly.

3-hydroxy-3-methylglutaric aciduria will generally appear within the first year of life. Presenting symptoms include vomiting, diarrhea, dehydration, extreme tiredness, and weak muscle tone. If this syndrome goes undiagnosed, when the infant is having one of these episodes their blood sugar may become dangerously low and the acidity of their blood will become increased (metabolic acidosis). If this syndrome is not diagnosed the patient may start having breathing problems, convulsions, coma, and ultimately death.

Because 3-Hydroxy-3-methylglutaric aciduria is so rare, it is difficult to answer this question. It appears that different families may demonstrate similar features and some children even within the same family may be more susceptible to metabolic decompensation with fasting or illness compared to others within the same family that have 3-Hydroxy-3-methylglutaric aciduria.

Changes reported within this gene do lead to this syndrome. Incomplete penetrance has not been reported.

Yes, 3-Hydroxy-3-methylglutaric aciduria is included on newborn screening.

For a positive diagnosis of 3-Hydroxy-3-methylglutaric aciduria (HMG), blood and urine from the patient needs to be tested for organic acid and amino acid levels. Genetic testing may then be completed to further confirm the diagnosis.

No clinical trials are currently available in the United States for 3-Hydroxy-3-methylglutaric aciduria.

The current treatment for 3-Hydroxy-3-methylglutaric aciduria is a strict diet. There are specific formulas for infants that are made specifically for this condition. These formulas may also be utilized through an individual’s lifetime to ensure adequate and appropriate nutrition. The specialized formulas and medical foods are low in leucine, the protein building block that individuals with HMG CoA lyase deficiency are unable to break down appropriately. Furthermore, dietary modifications may include avoiding foods with high leucine levels. A dietitian will work with you closely to ensure that your child’s diet is optimized for adequate nutrition and providing enough calories to promote growth and development.

Because of the risk of low blood sugar, parents are advised to avoid prolonged fasting. The number of hours or duration of fasting will be determined by your metabolic specialist based on your child’s medical concerns, growth and development, and age. A doctor may also advise that a patient take L-carnitine. This is a substance that the body naturally makes. It is an over-the-counter supplement that can assist the body in utilizing alternative energy pathways.

Two pathogenic variants or mutations in the HMGCL gene result in 3-Hydroxy-3-methylglutaric aciduria. If there are two pathogenic changes within this gene, the patient will have this syndrome.

Doctors should be aware that their patient’s blood sugar needs to be monitored regularly, and that they should be seeing a dietitian regularly in coordination with a metabolic specialist to ensure adequate nutrition for growth and development. A low protein diet is one of the maintstays of treatment for HMG CoA Lyase deficiency and therefore, children or individuals should not be encouraged to consume additional protein for nutrition.

Additionally, your primary care physician should be aware of the recommendation to avoid fasting. This is particularly important should your child become sick and unable to eat or has persistent vomiting. These symptoms, if prolonged, can lead to a metabolic crises. Therefore, if a child is fasting or sick, you should reach out to your primary care physician to notify them and discuss alternative ways to provide nutrition. This may ultimately result in a child requiring a hospital admission for IV nutrition and fluids to prevent further complications and metabolic crisis.

Lastly, some medical procedures such as dental work, diagnostic tests such as an MRI or any procedures that may require anesthesia may require a child or individual to fast for a prolonged period of time beforehand. Fasting is contraindicated for children with HMG CoA lyase deficiency and can also result in metabolic crises and decompensation. Therefore, any recommendations for fasting should be reviewed with your physician carefully. IV fluids or nutrition may need to be provided during a period of fasting.

3-Hydroxy-3-methylglutaric aciduria is inherited in an autosomal recessive pattern. Each individual inherits one copy of every gene from their mother and one copy from their father. Autosomal recessive conditions are those in which both copies of a gene have a pathogenic variant or mutation. It is likely that one pathogenic variant came from the mother and the other pathogenic variant came from the father. Parents themselves are considered unaffected carriers. This means that they have one working copy of the HMGCL gene and one non-working copy of the HMGCL gene. Their one working copy of the HMGCL gene creates enough of the HMG CoA lyase enzyme for the parent to not have any symptoms.

Therefore, there is a 25% risk or 1 in 4 risk for both parents to pass on their non-working copies of the HMGCL gene. This risk exists for each pregnancy. There is a 50% or a 1 in 2 chance that only one parent would pass on a non-working copy of the HMGCL gene. These pregnancies or children would be unaffected carriers like their parents. Lastly, there is a 25% or 1 in 4 chance that both parents would pass on their working copies of the HMGCL gene and a child would not be a carrier or affected with HMG lyase deficiency.

To start or locate a support group in your area, try contacting the Organic Acidemia Association.

If the newborn screen comes back positive for 3-Hydroxy-3-methylglutaric aciduria, follow up testing would need to be completed for a positive diagnosis of 3-Hydroxy-3-methylglutaric aciduria. This involves testing the blood and urine of the patient to look for organic acid and amino acid levels. There is a specific pattern of these that would indicate a positive diagnosis of 3-Hydroxy-3-methylglutaric aciduria.

New clinical trials are being initiated every day. [link url="Clinicaltrials.gov” target=”_blank”>Clinicaltrials.gov is a great resource to learn about clinical trials that are active across the United States. You can search for 3-Hydroxy-3-methylglutaric aciduria or any of the other abbreviations for this condition to locate any available clinical trials.

Your child will be referred to a hospital or medical center with a metabolic disease specialty clinic when they are diagnosed or suspected to have 3-Hydroxy-3-methylglutaric aciduria on their newborn screen test. Additionally, you can locate other metabolism specialty clinics through one of the following organizations: The Organic Acidemia Association (a ThinkGenetic Advocacy Partner), The North American Metabolic Academy (NAMA) or the Society for Inherited Metabolic Disorders.

If you are interested in carrier testing or a family member would like to be tested for HMG CoA lyase deficiency, you can also try reaching out to a local genetic counselor through [link url="NSGC.org” target=”_blank”>The National Society for Genetic Counselors or reaching out to a geneticist in your area through [link url="ACMG.net” target=”_blank”>The American College of Medical Genetics

Funding options and initiatives can be discussed with a metabolic specialist who is completing research on HMG CoA Lyase deficiency. Some available organizations dedicated to the understanding, research and management of metabolic conditions include: The Organic Acidemia Association, The North American Metabolic Academy (NAMA) or the Society for Inherited Metabolic Disorders.

Because different tissues will have different levels of organic and amino acids, it is important to test both urine and blood for a positive diagnosis of 3-Hydroxy-3-methylglutaric aciduria. Amnio acid and urine organic acid levels are not measured adequately in saliva tissue. Genetic testing is usually completed on a blood sample, however, DNA can also be isolated for testing from a saliva sample or skin biopsy.

Yes. Infants and children diagnosed with HMG lyase deficiency need to avoid fasting. Fasting will lead to the symptoms of HMG lyase deficiency. Therefore, infants and children will need to eat frequently to prevent metabolic crisis from occurring. Infants may need to eat more frequently than young children with the diagnosis. A metabolic specialist will be able to tell you how long a child is able to fast. Fasting may also occur when children are sick or prior to a planned medical procedure. Therefore, special precautions and IV nutrition may be needed when a child is sick or requires prolonged fasting.

Additionally, infants and children will have a strict diet that is low in leucine-rich foods. Therefore, the diet may be rich in carbohydrates. It is recommended that foods that are high in leucine be limited or avoided. Foods that are high in leucine include milk and dairy products, meat and poultry, fish, eggs, dried beans, nuts, peanut butter, butters, margarine and oils.

With appropriate dietary modifications and avoidance of fasting, children with HMG lyase deficiency can eliminate or reduce the medical complications associated with their condition.

There are several different names for 3-Hydroxy-3-methylglutaric aciduria including:

There are several organizations that support and promote the education, management, diagnosis and treatment of metabolic conditions including: The Organic Acidemia Association, The North American Metabolic Academy (NAMA), Save Babies Through Screening or the Society for Inherited Metabolic Disorders.

Some families have also connected with one another through facebook or other social media websites.

3-hydroxy-3-methylglutaric aciduria is a rare disorder, but all cases that have been reported in the medical literature are diagnosed within the first year of life. Each variant within the gene may cause slightly different features, but more information is needed to further assess the subtle variations that may exist.

Organic acidurias generally look similar when they are first presenting during the newborn period. If a child starts exhibiting some of these symptoms, it is important to test the blood and urine for amino acids and organic acids to make the proper diagnosis.

Reye syndrome has been a misdiagnosis in the past.