3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency

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This disorder is caused by changes in the HMGCL gene. This gene is responsible for providing instructions for an enzyme called hydroxymethyl-3-methylglutaryl-coenzyme A lyase (often shortened to HMG-CoA lyase). The enzyme is needed by the body to break down fats and proteins from the diet.

Amino acids are the building blocks of protein. Our body uses different enzymes, controlled by genes to break down protein from the food we eat into smaller amino acids so the body can use them as required. Any excess amino acids are broken down further into smaller substances like organic acids and ammonia which are removed from the body via the liver. The HMG-CoA lyase enzyme plays a particular role in breaking down an amino acid called leucine.

This disorder also means that the body cannot produce ketones. Ketones are a chemical that is produced by the liver when it breaks down fats for the body to use for energy. The body uses ketones as a source of energy mainly during long periods without food, during intense or prolonged exercise, or when there is a low amount of carbohydrates in the diet.

In most countries, this is an extremely rare disorder. There is a higher incidence in Saudi Arabia, Spain and Portugal where the prevalence is thought to be around 1 in every 125,000 births.

Signs and symptoms often appear within the first year of life. In half of cases, this is in the newborn period shortly after birth.

This disorder causes episodes of symptoms including:

• Vomiting
• Diarrhoea
• Dehydration
• Extreme tiredness/fatigue (lethargy)
• Low/weak muscle tone (hypotonia)

During these episodes the blood sugar can drop to dangerously low levels (hypoglycaemia) and harmful substances can build up in the blood causing high acidity (metabolic acidosis).

These episodes are often called a metabolic crisis and require immediate medical care. Without such, symptoms can progress to seizures, breathing problems, and coma, quickly becoming life-threatening.

The episodes usually start as a result of the following:

• An infection or illness
• Long periods without food
• Prolonged or strenuous exercise
• Other factors which cause stress on the body

Due to the rarity and similarities of this condition with other disorders such as Reyes syndrome this condition can easily be misdiagnosed for another condition.

In most cases, there are no symptoms between episodes with most children being described as healthy. Following the episodes, some may have an aversion to food, feel fatigued, have behavioural changes and/or muscle weakness.

Long-term neurological complications from the episodes are seen in 50% of individuals. This includes difficulties carrying out mental or physical activities and a delay in reaching developmental milestones including speech delays. Other long-term symptoms may include epilepsy, an enlarged head circumference, or conditions affecting different organs of the body such as the heart, liver, and pancreas.

This condition can be diagnosed through identification of symptoms and analysis of specialised blood and urine tests. Enzyme or genetic analysis can confirm the disorder.

Management of this disorder is life-long and focuses on diet and the avoidance of circumstances which may trigger an episode to occur.

Dietary management includes a specialised diet that is low in protein/leucine and restricted in fat intake. Regular feeding is required and a leucine-free amino acid supplement will be given. In many cases L-carnitine supplements will also be prescribed. Dietary management will be overseen by a specialist dietitian who will ensure that you understand the diet and will be able to advise on recipes and any dietary changes and changes to feeding times that are needed to support growth or which may change with age. Alcohol should be avoided.

An emergency-regimen will also provide clear instructions on what to do during periods of illness and when to seek urgent medical care. During any acute metabolic crisis individuals will be treated in hospital with a glucose drip (intravenous) and supportive treatment.

With early diagnosis and good management, prognosis is generally good

This disorder can only be passed on to a child if both parents have a copy of the faulty gene. This is called autosomal recessive inheritance. A person who has a copy of the faulty gene is known as a carrier.

If both parents are carriers, their child has a one in four (25%) chance of inheriting the disorder, and a one in two chance (50%) of being a carrier. This is the same for each child the parents have.

If the child only inherits one copy of the faulty gene, they will be a carrier but will not have the disorder. In some rare cases, carriers have had mild symptoms of the disorder for which they carry the faulty gene.

Once you are diagnosed, you can speak to a genetic counsellor. They can explain the inheritance pattern in more depth and also tell you about genetic testing for the rest of your family.

References are available on request. Please contact us by phoning 0845 241 2173 or emailing contact@metabolicsupportuk.org [Resource Library No: HAP025].