What Are the Symptoms of HMG-CoA Lyase Deficiency?
HMG-CoA lyase deficiency is a rare inherited disorder. It's "autosomal recessive," meaning a child gets a faulty gene from both parents. The core problem is a shortage of the HMG-CoA lyase enzyme, which works in our cells' powerhouses (mitochondria). This enzyme has two crucial jobs: making ketones (an emergency fuel for the brain, especially during fasting) and breaking down leucine (a part of protein from food). When this enzyme doesn't work correctly, the body can't make enough ketones and harmful substances from leucine build up, leading to various symptoms.
The deficiency primarily causes symptoms due to:
- Inability to make ketones: Ketones are vital brain fuel when blood sugar is low. Without them, low blood sugar (hypoglycemia) becomes very dangerous, especially for the brain, leading to symptoms like severe tiredness or seizures. This is called hypoketotic hypoglycemia.
- Leucine breakdown problems: The body can't properly process leucine, an amino acid from protein. This causes harmful substances to build up, contributing to symptoms like vomiting and poor feeding.
- Early onset of symptoms: Symptoms often appear in early infancy, usually as sudden episodes called metabolic crises. These crises are typically triggered by fasting (like during illness or skipping meals) or infections.
- Risk of long-term problems: Repeated crises can cause lasting symptoms such as developmental delays, learning difficulties, and damage to organs like the liver or brain if not managed carefully.
Early Warning Signs of a Metabolic Crisis
A metabolic crisis is a medical emergency in HMG-CoA lyase deficiency. These episodes can develop quickly, often when the body is stressed by illness, fasting, or even just sleeping longer than usual. During a crisis, individuals experience a dangerous drop in blood sugar without the body making ketones for energy. Prompt medical attention is crucial.
Vigilance for these indicators can help in seeking timely intervention:
- Changes in behavior or alertness: An infant or child might become unusually irritable, fussy, or much sleepier than normal. They may seem less responsive or show a noticeable drop in activity.
- Feeding problems or vomiting: Infants may suddenly refuse to feed. Older children might complain of nausea or start vomiting. This worsens the energy crisis and can lead to dehydration.
- Physical signs of distress: The child may look pale, have cool or clammy skin, or breathe rapidly or shallowly. Infants might have a weak cry or appear floppy (a symptom known as hypotonia).
- Severe neurological signs: If not treated quickly, symptoms can worsen to include seizures, loss of consciousness, or coma. These indicate a severe lack of energy supply to the brain.
Neurological Symptoms
The brain needs a constant supply of energy from glucose or ketones. In HMG-CoA lyase deficiency, especially during metabolic crises, this energy supply fails. This can cause a range of neurological symptoms, both immediately during a crisis and as long-term consequences.
Neurological symptoms can include:
- Sudden brain dysfunction (acute encephalopathy) and seizures: During a crisis, lack of energy and buildup of toxins can cause confusion, extreme lethargy, coma, or seizures. These seizures are often widespread, showing the brain is in distress from the metabolic imbalance.
- Developmental delays and learning difficulties: Repeated or severe crises, particularly if they occur early in life, can lead to delays in reaching milestones like walking, talking, or developing cognitive skills. The extent of intellectual disability can vary.
- Changes seen on brain scans: Magnetic Resonance Imaging (MRI) scans may show abnormalities, such as changes in the brain's white matter (its "wiring"). These can indicate areas of swelling or damage, especially after a crisis, and may sometimes lead to permanent structural changes.
- Low muscle tone (hypotonia): Babies and children may seem "floppy" or have weak muscles. This common neurological sign can delay motor skills such as head control, sitting unsupported, crawling, and walking.
Physical Symptoms and Key Laboratory Clues
Certain physical symptoms often prompt doctors to investigate HMG-CoA lyase deficiency, especially during illness. Laboratory tests then help confirm the diagnosis by revealing characteristic biochemical changes that explain these symptoms.
Key physical symptoms and the lab findings that often accompany them include:
- Severe tiredness, poor feeding, and irritability: These common symptoms, especially in infants, signal a dangerous lack of energy in the brain. Lab tests often show very low blood sugar without ketones (hypoketotic hypoglycemia), confirming the body's inability to produce alternative fuel.
- Rapid breathing and vomiting: These can be signs of metabolic acidosis, where the blood becomes too acidic due to the buildup of harmful organic acids. The body may try to compensate with rapid, deep breathing (Kussmaul respirations). Vomiting is also common and can worsen dehydration.
- Decreased alertness, continued vomiting, or worsening brain function: These symptoms may be linked to high ammonia levels in the blood (hyperammonemia). Ammonia is toxic to the brain and can significantly contribute to or worsen encephalopathy.
- Enlarged liver (hepatomegaly) or signs of liver stress: Some individuals may have an enlarged liver, which can sometimes be tender. Lab tests might show elevated liver enzymes (like ALT and AST), indicating liver strain or injury from metabolic disturbances.
- Confirmation through specific markers: While not symptoms themselves, definitive diagnosis relies on specialized tests. Urine tests often show high levels of specific organic acids (like 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, and 3-hydroxyisovaleric acid). Blood tests (acylcarnitine profile) may show elevated 3-hydroxyisovalerylcarnitine (C5-OH). These markers accumulate because the HMG-CoA lyase enzyme is not working properly.
Symptom Triggers and Other Notable Manifestations
Beyond the typical crisis symptoms, certain factors can trigger severe episodes. It's also important to be aware of other ways HMG-CoA lyase deficiency can manifest, including complications that present with their own distinct symptoms.
Factors that can trigger symptoms and other notable signs include:
- Common triggers for symptom onset or worsening: Symptoms can be provoked by periods without food (fasting), common illnesses (like colds, flu, or infections causing vomiting/diarrhea), or intense physical activity. In older individuals, alcohol consumption is a significant risk as it impairs glucose production. Even vaccinations or significant dietary changes can sometimes be triggers if not managed carefully.
-
Symptoms from organ complications:
- Severe abdominal pain, nausea, and vomiting can indicate pancreatitis (inflammation of the pancreas).
- Symptoms like shortness of breath, fatigue, swelling in the legs, or difficulty exercising can arise from dilated cardiomyopathy (a weakened and enlarged heart muscle).
- Severe liver problems, sometimes resembling Reye's syndrome, can cause jaundice (yellowing of skin and eyes) and worsening brain function (encephalopathy). It's important to monitor ammonia levels closely during crises, as brain effects may not always align with liver enzyme levels.
- Severe neurological symptoms during or after a crisis: Beyond initial seizures, a crisis can cause increased pressure inside the skull (intracranial hypertension) due to brain swelling. This may lead to symptoms like severe headache, persistent vomiting, and vision changes. Rarely, blood vessels in the brain can constrict (cerebral vasospasm), reducing blood flow and potentially worsening brain injury even after the initial metabolic issues are corrected.
-
Other important symptoms:
- Infants may show "failure to thrive," meaning poor weight gain and growth. This can be due to chronic metabolic stress, feeding difficulties, or frequent illness.
- An unusual odor in the urine, sometimes described as "cat-like" or "sweaty feet," may occasionally be noticeable, particularly when metabolism is disturbed.
- Low body temperature (hypothermia) can occur during severe metabolic crises, especially in young infants, signaling a profound lack of energy in the body.
