3-methylcrotonyl-CoA carboxylase deficiency (3-MCC deficiency) is an inherited metabolic condition caused by a deficient enzyme. This deficiency disrupts the body’s ability to process leucine, an amino acid that is a building block for protein. As a result, byproducts from leucine can accumulate in the body, potentially leading to health issues. The disorder is included in many newborn screening programs, allowing for early identification and management before symptoms appear.
Genetic Inheritance of 3-MCC Deficiency
3-MCC deficiency follows an autosomal recessive inheritance pattern, meaning a child must inherit a non-working gene from both parents to have the condition. The parents, who each carry one functional and one non-working copy, are considered carriers and do not show symptoms.
The genes responsible for this condition are the MCCC1 and MCCC2 genes. These genes provide the instructions for creating the 3-methylcrotonyl-CoA carboxylase enzyme. A mutation in either of these genes can reduce or eliminate the enzyme’s activity, which disrupts the normal processing of leucine.
When both parents are carriers, there is a specific probability with each pregnancy. There is a 25% chance the child will inherit two non-working gene copies and have 3-MCC deficiency. There is a 50% chance the child will become a carrier like the parents, and a 25% chance the child will inherit two functional copies of the gene.
Diagnosis Through Screening and Symptoms
Most individuals with 3-MCC deficiency are identified shortly after birth through routine newborn screening. This process involves analyzing a small blood sample from a heel prick for elevated levels of C5-OH acylcarnitine, an indicator of the disorder.
An initial positive screen is not a definitive diagnosis and requires follow-up confirmatory testing. These subsequent tests provide a more detailed view of the body’s metabolic byproducts and may include a urine organic acid analysis, a plasma acylcarnitine analysis, and genetic testing to identify specific gene mutations.
If the condition is not detected at birth, symptoms can develop, often triggered by periods of fasting or illness. During these episodes, known as metabolic crises, the body breaks down its own proteins for energy. The signs of a crisis can include poor feeding, vomiting, extreme tiredness, and low muscle tone (hypotonia), which can progress to seizures or a coma if untreated.
A positive newborn screen can also occur if the mother has an undiagnosed, asymptomatic case of 3-MCC deficiency, as metabolic byproducts can cross the placenta. In these situations, testing the mother is necessary to confirm her status and clarify the baby’s screening result.
Treatment and Management Strategies
For many children identified with 3-MCC deficiency through newborn screening, no specific treatment may be necessary. When treatment is indicated, it is tailored to the individual and focuses on preventing the buildup of harmful substances. A primary management strategy involves dietary adjustments to control leucine intake, which usually means a moderate restriction of high-protein foods.
Supplementation can also be part of the management plan. A physician may recommend L-carnitine, a compound that helps the body remove toxic byproducts from unprocessed leucine. Glycine is another supplement sometimes used to aid in detoxification. The need for these supplements is determined by a metabolic specialist based on the individual’s health.
A key part of managing 3-MCC deficiency is an emergency protocol, or “sick day plan.” Illnesses or fasting can be dangerous because they cause the body to break down its own protein, which can trigger a metabolic crisis. Developed with a healthcare team, this plan gives families clear instructions on how to respond when a child is sick, including providing extra fluids and knowing when to seek immediate medical attention.
Prognosis and Lifelong Health
For most individuals diagnosed with 3-MCC deficiency through newborn screening, the long-term outlook is excellent. With early identification and management, most children grow and develop normally. The goal of screening is to begin management before symptoms occur, which helps prevent developmental delays or other health issues.
The prognosis can differ for individuals diagnosed later in life after symptoms have appeared. In these cases, metabolic crises may have caused brain damage, leading to developmental or learning challenges. However, even for those who show symptoms, prompt and consistent treatment can lead to good health outcomes and typical development.
Continuous care is important for managing 3-MCC deficiency. Regular follow-up appointments with a specialized metabolic team are recommended for long-term well-being. This team, which often includes a metabolic geneticist and a dietitian, monitors health, tracks growth and development, and makes necessary adjustments to the management plan over time.