Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)

2025.10.16

やさしいまとめ

This article provides a clear, evidence-based overview of Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD), a genetic disorder that disrupts energy production from fats. It explains the role of the ACADM gene, how the condition presents in infants and children, how newborn screening enables early diagnosis, and the steps needed for effective management. The content is designed for families seeking reliable information and healthcare professionals looking for a scientifically accurate yet accessible reference.

Introduction

ACADM

Medium-Chain Acyl-CoA Dehydrogenase Deficiency, commonly referred to as MCADD, is a rare inherited metabolic disorder that interferes with the body’s ability to break down certain fats and convert them into energy. This process becomes especially critical during fasting, illness, or periods of increased energy demand, such as fever or infection.

Infants and young children are particularly vulnerable because their energy reserves are limited and their metabolic rate is high. During these times, their bodies depend heavily on fat metabolism to maintain stable blood glucose levels. When this pathway fails, the risk of dangerously low blood sugar, known as hypoglycemia, rises significantly. If left unmanaged, this can lead to seizures, coma, or even sudden death.

This guide explains the genetic basis, symptoms, diagnostic process, and treatment options for MCADD in clear but scientifically accurate language, allowing both families and healthcare professionals to better understand the condition.

Genetic Cause and Mechanism

The ACADM Gene

MCADD is caused by mutations in the ACADM gene, which is located at position p31.1 on chromosome 1. The ACADM gene encodes the Medium-Chain Acyl-CoA Dehydrogenase (MCAD) enzyme. This enzyme plays an essential role in the first step of mitochondrial beta-oxidation, the process by which fatty acids are broken down to release energy.

When functioning correctly, the enzyme targets medium-chain fatty acids, typically those with 6 to 12 carbon atoms, and begins breaking them down into smaller components such as acetyl-CoA. These products are then used to generate ketone bodies or directly enter energy pathways to keep cells functioning. A deficiency of the enzyme disrupts this process. As a result, energy production is impaired, and intermediate by-products accumulate in the bloodstream and tissues. This buildup is toxic and, combined with the lack of sufficient energy, underpins many of the acute symptoms seen in MCADD.

Inheritance Pattern

The condition follows an autosomal recessive pattern of inheritance. This means a child must inherit one copy of the faulty gene from each parent to develop MCADD. Parents who each carry one defective copy are typically asymptomatic but have a one-in-four chance with each pregnancy of passing the disorder to their child. This genetic mechanism explains why MCADD may appear unexpectedly in families with no prior history of metabolic disorders.

Alternate Names for MCADD

MCADD may be referred to in medical records or literature by other terms, such as MCAD deficiency, ACADM deficiency, Medium-Chain Fatty Acid Oxidation Disorder, or, in cases where it leads to secondary issues with carnitine metabolism, Secondary Carnitine Deficiency. All these terms refer to the same underlying disruption of medium-chain fatty acid oxidation and are grouped under mitochondrial fatty acid oxidation disorders.

Understanding the Disorder

In a healthy metabolism, when carbohydrate stores run low during fasting or illness, the body mobilizes fat stores to produce ketone bodies and acetyl-CoA. These molecules provide an alternative and steady energy supply for organs, particularly the brain and muscles. In MCADD, because the MCAD enzyme is absent or insufficient, this process fails. The body cannot produce enough ketones, leading to what is known as hypoketotic hypoglycemia. At the same time, harmful intermediate metabolites build up in the blood and tissues.

With early diagnosis and careful management, however, individuals with MCADD can live full and healthy lives. Consistent attention to preventive measures, such as avoiding prolonged fasting and having an emergency plan during illness, is the key to preventing metabolic crises.

Epidemiology

Although MCADD is considered rare, it is one of the more common disorders in the category of fatty acid oxidation defects. Its prevalence varies geographically. Globally, approximately one in 18,000 individuals is affected. In the United States, the frequency ranges between one in 13,000 and one in 24,000, with some regional variation depending on population genetics and the reach of newborn screening programs. Northern European countries, including Denmark and the Netherlands, report higher incidence rates, while in Asian populations, including Japan, the condition is far less common, with estimates ranging from one in 50,000 to one in 100,000 individuals.

The expansion of newborn screening programs worldwide has greatly increased early detection, often identifying infants with MCADD before any symptoms develop. This early detection has significantly improved clinical outcomes and survival rates.

Etiology and Pathophysiology

The primary cause of MCADD is a mutation in the ACADM gene that reduces or eliminates the activity of the MCAD enzyme. Without this enzyme, the body cannot complete the breakdown of medium-chain fatty acids during fasting or metabolic stress.

When the pathway fails, medium-chain fatty acids accumulate in the form of medium-chain acylcarnitines and dicarboxylic acids. These compounds contribute to liver dysfunction and metabolic imbalances, particularly low blood glucose levels. This explains why metabolic crises typically occur during illness, prolonged fasting, or situations where the body is relying heavily on fat for energy.

Symptoms

Early and Acute Presentation

Newborns with MCADD typically appear healthy for the first few days or weeks of life. Symptoms often emerge during the first significant period of fasting, infection, or other metabolic stress. The most common and dangerous early sign is hypoketotic hypoglycemia, where blood sugar drops to dangerously low levels without a corresponding increase in ketone bodies. Other symptoms often include vomiting, lethargy, and, in more severe situations, seizures or coma. Liver dysfunction, sometimes visible as an enlarged liver, and elevated levels of ammonia in the blood are frequently observed.

In some cases, the first presentation may be sudden and severe, leading to unexpected infant death. Research indicates that undiagnosed MCADD may account for a proportion of sudden infant death syndrome (SIDS) cases.

Long-Term Effects

Children who experience repeated metabolic crises or prolonged hypoglycemia without timely treatment may develop longer-term complications. These can include developmental delays, difficulties with attention and focus that resemble Attention Deficit Hyperactivity Disorder (ADHD), persistent fatigue during physical exertion, and, less commonly, muscle weakness.

Testing and Diagnosis

Role of Newborn Screening

Many countries have integrated MCADD into their newborn screening panels. This involves testing a small blood sample within days after birth. Elevated levels of a specific compound called C8 acylcarnitine strongly suggest MCADD. Other markers, including altered levels of C6 and C10 acylcarnitines and elevated C8-to-C2 ratios, can provide additional diagnostic clues.

Confirmatory Diagnostic Methods

To confirm the diagnosis, blood tests measuring a spectrum of acylcarnitines are performed, alongside urine tests that detect organic acids such as hexanoylglutamine. Carnitine levels are also assessed, as they are frequently reduced in individuals with MCADD. Genetic testing provides definitive confirmation by identifying mutations in the ACADM gene, with the most common being the c.985A>G (p.Lys329Glu) mutation. In certain cases, functional enzyme activity assays in white blood cells or cultured skin cells are used. Enzyme activity below 25% of normal values confirms the diagnosis.

Treatment and Management

Managing Acute Episodes

During an acute metabolic crisis, immediate hospital care is critical. Intravenous glucose is administered at a rate of approximately 10 to 12 milligrams per kilogram per minute to quickly restore and maintain normal blood sugar levels. Concurrently, any underlying triggers, such as infections or other metabolic stressors, are treated. Continuous monitoring and correction of electrolyte imbalances, acid-base disturbances, and elevated ammonia levels are also essential components of care.

Preventive Daily Management

Avoiding prolonged fasting is the cornerstone of MCADD management. For infants, this means feeding every two to three hours, including overnight. Older children should not fast for more than twelve hours, and in some cases, a bedtime snack or uncooked cornstarch supplement is recommended to provide a slow release of glucose overnight. Maintaining adequate overall caloric intake and ensuring that no more than 30% of daily calories come from fat helps to stabilize metabolism and reduce risk.

Some individuals may also require supplementation with L-carnitine, typically in the range of 50 to 100 milligrams per kilogram per day, to help eliminate toxic metabolic by-products and support energy metabolism.

Monitoring and Emergency Planning

Regular follow-up with a pediatric metabolic specialist is essential. In early childhood, visits are typically scheduled every two to three months, shifting to every six months once the child is stable. These visits often include growth assessments, developmental evaluations, and biochemical monitoring, including carnitine levels.

An emergency care plan is also critical. Families are advised to carry an emergency card or written action plan that can be presented to healthcare providers during illnesses or metabolic stress. Rapid access to medical care during fever, vomiting, or reduced food intake is essential to prevent complications.

Prognosis

When MCADD is identified through newborn screening and managed appropriately, the long-term prognosis is excellent. Children and adults with well-controlled MCADD can lead normal, active lives. However, failure to diagnose or manage the condition can lead to severe outcomes. Historically, before widespread screening, 20% to 25% of affected children died during their first metabolic crisis, and survivors often experienced lasting neurological damage.

Today, with proactive care, these outcomes are largely preventable. Nevertheless, lifelong vigilance is required, particularly during times of stress or illness, to maintain metabolic stability and prevent potentially life-threatening complications.

References

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