Continuing Education Activity

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder characterized by mitochondrial fatty acid β-oxidation impairment, leading to severe metabolic consequences. The inability to provide energy to tissues during glycogen depletion results in hypoketotic hypoglycemia, the hallmark presentation in young children. Additionally, MCADD may contribute to sudden infant death syndrome cases. While most individuals are asymptomatic at birth, the risk of morbidity and mortality is high during the initial episode. Newborn screening has significantly improved outcomes by preventing severe metabolic crises. However, there is currently no definitive treatment for MCADD, and management primarily involves dietary adjustments and emergency protocols during acute illness or stress.

Clinicians must be proficient in identifying and managing MCADD to improve patient outcomes. Early diagnosis is critical, as it can dramatically improve prognosis and reduce medical care costs. Newborn screening via tandem mass spectrometry measures medium-chain acylcarnitines, aiding in early detection. Several tests can be used for diagnostic confirmation. Clinical management requires dietary adjustments and emergency response protocols during acute illness or stress. This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, managing MCADD, and fostering effective interprofessional teamwork to improve outcomes.

Objectives:

• Identify the clinical phenotypes associated with common genetic variants of the acyl-CoA dehydrogenase medium-chain (ACADM) gene.

• Implement a diagnostic algorithm for individuals who test positive for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency via newborn screening.

• Create an emergency response protocol for the management of individuals with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency during times of catabolic stress. 

• Collaborate with an interprofessional team of healthcare professionals to provide long-term care for individuals with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

Introduction

Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism that result in deficient energy production during fasting and catabolic stress. Fatty acid oxidation occurs in the mitochondria and involves multiple enzymes to oxidize fatty acid chains. FAODs are categorized by the length of the fatty acid chain affected by each disorder. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a prevalent FAOD that affects fatty acid chains of C6 to C12 length.[1] Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes the mitochondria's first step of medium-chain fatty acid oxidation.[2] MCADD is an autosomal recessive disorder caused by mutations in the acyl-CoA dehydrogenase medium chain (ACADM) gene.[2][3]

The inability to provide energy to tissues when glycogen stores are depleted secondary to MCADD results in a wide array of symptoms. Hypoketotic hypoglycemia with vomiting, progressing to seizures, and coma are typical presentations of this disease. MCADD is also thought to be responsible for a small portion of sudden infant death syndrome (SIDS) cases. This disease may become evident in early childhood, typically within the first 24 months of life, or remain asymptomatic until adulthood.[2][3]

While newborn screening (NBS) has helped in the early identification of asymptomatic individuals, current literature lacks a concise and contemporary review of MCADD and its management. Nevertheless, clinicians must be proficient in the identification and management of this disease because early diagnosis can dramatically improve the prognosis for individuals with MCADD. Therefore, to achieve this goal, clinicians should obtain the most up-to-date knowledge regarding the disease's pathogenesis, diagnostic tools, and treatment options. 

Etiology

Mutations in the ACADM gene on chromosome 1p31 are responsible for this disorder. These mutations result in misfolding of the translated protein, leading to decreased or absent function of the MCAD enzyme.[1] The ACADM gene spans 44 kb of DNA and has 12 introns. Current data reports >400 different ACADM gene variations, of which 68 different variations have been classified as pathogenic, 82 variations as likely pathogenic, and around 165 variations grouped as "uncertain." Around 69% of these disease-causing variations are missense mutations.[4]

The most prevalent mutation is c.985A>G, resulting in lysine at position 304 being exchanged for glutamate. Misfolding of the protein subsequently occurs, leading to a complete loss of function.[1] This mutation is the most common mutation in symptomatic patients, seen in up to 80% of the individuals as a homozygous mutation. It may also occur in heterozygosity with other variants, resulting in a milder form of the disease.[5] Another missense mutation is c.199 T>C, associated with less severe symptoms and lower levels of plasma octanoyl-carnitines. Some patients with this mutation may have no clinical signs or symptoms.[1] Furthermore, c.1085G>A, c.50G>A, c.157C>T, and c.843A>T are all missense mutations that are seen in patients of Japanese descent and together account for 60% of the pathogenic variants seen in this population.[1] In patients of Chinese descent, c.727C >T is a missense mutation that has been reported, but the frequency of this variant in the Chinese population is unknown.[1] Recent epidemiologic studies utilizing NBS in China reported that the most common pathogenic variant for MCADD in the Chinese population is c.449_452delCTGA, which occurs with a frequency of 27.7% in patients with this disease.[6] This deletion mutation has also been reported in the Japanese population.[1]

Epidemiology

The combined incidence of all FAODs ranges between 0.9 to 15.2 per 100,000 individuals. The reported incidence of FAODs in European countries and the United States ranges from 6.0 to 16.4 per 100,000 individuals, primarily attributed to the high incidence of MCADD in these countries.[7]

The estimated prevalence of MCADD is 1 in 50,000 live births globally.[1] The prevalence of MCADD in North America and northern Europe is between 1 in every 5,000 individuals and 1 out of every 20,000 individuals.[8][9][10] One study showed a prevalence ranging from 1 in every 10,000 to 1 out of every 27,000 persons in the countries around France.[11] Another study found that the carrier frequency in the general population may be as high as 1 out of every 70 individuals.[12] Males and females are equally affected.[13]

Among Asian populations, the incidence of MCADD is relatively low. The estimated incidence of this disease in Japan is 1 in 100,000 patients, and in China, around 1 out of 80,332 to 1 out of every 282,591 patients. In other countries, epidemiologic data is limited to symptomatic cases. For example, in Saudi Arabia, MCADD is reported to have a prevalence of 1 out of every 18,000, accounting only for patients with symptoms who subsequently underwent diagnostic testing.[14]

NBS has led to an apparent increase in the incidence of this disease due to the detection of milder cases.[7] A large-scale prospective study of MCADD detected via NBS from the United Kingdom, where the cohort consisted of multiple different ethnicities, reported an incidence of approximately 1 in 10,000 babies. Among the individuals diagnosed with MCADD in this study, the majority were Caucasians. Those diagnosed with "uncertain phenotype" were primarily of Asian heritage.[9] This highlights the need for diagnostic protocols to account for the ethnic diversity of this disease to ensure those detected via NBS truly have clinically significant phenotypes.

Pathophysiology

Medium-chain acyl-CoA dehydrogenase (MCAD) is a mitochondrial flavoenzyme involved in mitochondrial fatty acid β-oxidation. MCAD catalyzes the first step in this process, which involves α and β-dehydrogenation of acyl-CoAs of medium chain lengths. It favors C6- to C12-CoA substrates and has maximum catalytic activity for C8-CoA.[4] The ACADM gene encodes MCAD. The translated polypeptide chain is imported into the mitochondria, where it undergoes mature functional protein formation via cleavage of the N-terminal signal peptide. Subsequent protein folding into mature monomers of 396 residues occurs.[4] A normal MCAD protein is a tetramer of 4 identical subunits.[5] Pathogenic mutations disrupt this process, resulting in truncated proteins, altered splice sites, or misfolded MCAD proteins, rendering the enzyme inefficient or completely dysfunctional.[4]

Amino acid substitutions that do not significantly impact the structure of the MCAD protein still have a significant effect on enzyme activity. This manifests as low affinity for the C8-CoA substrate or as defective interaction with the electron-transferring flavoprotein of the mitochondrial matrix. The latter impairs electron transfer from MCAD to electron-transferring flavoprotein, disrupting electron flow and preventing the reoxidation of FADH2 to FAD.[4] 

Medium-Chain Acyl-CoA Dehydrogenase Deficiency Pathophysiology and Biomarker Formation

MCAD dysfunction disrupts the dehydrogenation step of β-oxidation within the mitochondria. This results in decreased production of acetyl-CoA, which is required for ketogenesis. Lack of acetyl-CoA prevents the production of ketone bodies during ketogenesis, which is essential for energy production during prolonged fasting or catabolic stress. The body attempts to compensate by maximizing gluconeogenesis; however, when glycogen stores are depleted, rapid progression to hypoketotic hypoglycemia occurs.[1]

MCAD dysfunction also results in the accumulation of medium-length fatty acyl-CoAs in the mitochondrial matrix. They, in turn, bind to mitochondrial carnitine, resulting in the formation of acylcarnitines. These formed medium-length acylcarnitines, C6 to C12, are then eliminated from the mitochondrial matrix and released into circulation. These acylcarnitines are used as a serum biomarker to detect MCAD dysfunction, forming the basis of NBS and confirmatory diagnostic tests.[14] The accumulated medium-length acyl-CoAs can also be converted to acylglycines by conjugation with glycine. Acylglycines, including hexonylglycine (C6) and suberylglycine (C8), are subsequently excreted in the urine. These urinary organic acids can be measured and are used as diagnostic biomarkers for MCADD.[15] MCAD deficiency results in ineffective mitochondrial oxidative phosphorylation. Impaired mitochondrial oxygen consumption reduces skeletal muscle function, which manifests as weakness. In addition, the accumulation of medium-chain fatty acids and their derivatives results in neurologic dysfunction, which is seen as encephalopathy in these patients.[1]

Causes of Phenotypic Variation

MCADD is considered a "conformational disorder;" however, clinical manifestations of the disease span a broad spectrum of severity, even for those patients with the same genotype. The pathogenic phenotype of the disease appears dependent on additional extrinsic and intrinsic factors that are not clearly understood.[4] One extrinsic factor to consider is riboflavin. As a flavoenzyme, MCADD depends on adequate riboflavin derivatives for its function. A clinical trial testing MCAD activity in the lymphocytes of patients with MCADD reported increased enzyme activity after riboflavin supplementation. However, the genetic profile of the test individuals was not reported in this study.[16] A second study examined lipid and protein oxidative damage in patients with MCADD who were supplemented with carnitine or carnitine and riboflavin. They were compared to individuals who did not receive any supplementation and healthy controls. The study reported increased protein oxidative damage and altered antioxidant defense in unsupplemented and carnitine-supplemented patients.[16] 

These studies suggest that riboflavin supplementation has some role in stabilizing MCAD, likely via increased availability of the riboflavin derivative, flavin adenine dinucleotide. Biochemical studies demonstrate that most MCAD variants have an impaired capacity to retain flavin adenine dinucleotide during their synthesis. Some variants, however, can be "structurally rescued" by riboflavin cofactor supplementation, which explains the heterogeneity of the MCADD phenotype in patients with the same genotype. Some authors postulate that riboflavin supplementation will provide structural stability in most MCAD variants.[4] However, these studies were small, contained a heterogeneous group of genetic variants, and did not report long-term outcomes for patients supplemented with riboflavin. More extensive clinical studies examining the efficacy of riboflavin supplementation in patients with MCADD are still needed. Another factor affecting the phenotype of patients with MCADD is temperature. In biochemical studies, the MCAD tetramer formed in patients with c.985A>G mutation has demonstrated thermosensitivity. Thus, febrile episodes are thought to affect this protein's stability and function further in patients carrying the c.985A>G mutation.[5]

History and Physical

Clinical Features

Individuals with MCADD are typically asymptomatic at birth. The vast majority of individuals with this disease are diagnosed via expanded NBS that has been adopted in many countries around the world.[9] Individuals with severe clinical phenotypes typically present in the first 24 months of life. The onset of symptoms coincides with an intercurrent illness or an episode of prolonged fasting, as may be seen when there is a reduction in overnight feedings.[1] The classic presentation occurs in early childhood during an acute illness, particularly gastroenteritis.[17] Severe hypoglycemia is a characteristic feature of this disease. Other presenting symptoms include vomiting, hypoglycemia-associated seizures, lethargy, and coma.[1] The frequency and severity of symptomatic episodes correlate poorly with the patient's genotypes. Patients with a biochemically "milder" phenotype (eg,  those carrying the c.199T>C mutation) may present with neonatal decompensation and hypoglycemia. Therefore, a clinically asymptomatic phenotype cannot be reliably predicted from a "milder" biochemical phenotype.[18]

Acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver may be seen in patients with hepatomegaly and acute liver failure.[19] These symptoms may be confused with Reye syndrome, which is characterized by acute noninflammatory encephalopathy and fatty degenerative liver failure, often following a viral illness.[1][2] Symptomatic patients with MCADD can also develop muscular hypotonia.[2] The most significant physical examination finding is hepatomegaly, which is considered a sign of severe, life-threatening illness.[1]

Some infants may present with ventricular tachyarrhythmias induced by the accumulation of medium-chain acylcarnitines. Supraventricular arrhythmias have also been reported.[1] Sudden unexpected death in infancy is also associated with MCADD. By some accounts, MCADD accounts for up to 1% of all sudden unexpected deaths in infancy.[20] Autopsy evaluation in patients with MCADD-related sudden death reveals cerebral edema and fatty infiltration of the liver, heart, and kidneys.[1] NBS for FAODs did not become widespread until the early 2000s, and some countries still have not incorporated FAOD testing in their NBS protocols. In addition, the rarity of this disease and the possibility of errant testing make it difficult to diagnose this condition reliably, and some unfortunate individuals may not receive treatment despite the onset of symptoms in infancy. Over time, with recurrent hypoglycemia and metabolic crises, these patients can develop epileptic encephalopathies and cognitive delay.[21] Clinicians evaluating adult patients with epilepsy, especially those with refractory epileptic encephalopathies, should consider MCADD as a cause.

Due to the heterogeneous group of mutations that result in this disease, some patients only have a modest reduction in MCAD activity and may not present until adulthood.[1] Adult presentation is usually accompanied by severe catabolic stress and may prove fatal.[21] Adults who present with symptomatic MCADD often report ingestion of alcohol and subsequent vomiting. Adults are also more likely to present with cardiac symptoms than younger patients. This is likely because undiagnosed adults sustain prolonged uptake of accumulated medium-chain fatty acids into their myocytes throughout childhood and adolescence.[1]

Evaluation

Early diagnosis improves clinical outcomes for these patients. Approximately 20% to 25% of the patients who are not diagnosed via NBS experience death or disability.[10] Additionally, early diagnosis of MCADD has been shown to reduce nearly half of the medical care costs for this disease.[22]

Medium-Chain Acyl-CoA Dehydrogenase Deficiency Newborn Screening

The majority of the MCADD cases today are identified through NBS. NBS for MCADD utilizes tandem mass spectrometry and measures medium-length acylcarnitines, particularly octanoyl-carnitine (C8) and decanoyl-carnitine (C10), on dried blood spot cards. A C8 level above 0.40 μmol/L is considered abnormal and requires further testing.[1] Octanoyl-carnitine levels on NBS may be affected by the time lapse between sample collection and testing. To mitigate the risk of false positive results, triplicate testing on dried blood spots is conducted by most NBS protocols.[1] The average triplicate C8 value ≥0.50 µmol/L establishes a "presumed positive" diagnosis.[9] 

However, NBS using this method can also result in false negative results, especially in individuals not homozygous for the c.985A>G mutation. Even heterozygous individuals with one c.985A>G copy may go undetected via NBS.[5] Higher cutoff values increase the risk of missed diagnoses. A study examining ACADM gene sequencing in infants with abnormal NBS C8 values who were later determined not to have MCADD, utilizing a C8 cutoff value of 0.7 μmol/L, identified heterozygous carriers of the c.985A>G mutation in those patients.[23] 

Abnormal C8 values in premature and low-birth-weight infants do not correlate with MCADD.[23] A 2016 National Institutes of Health study from the United States of America noted that in infants with MCADD, low birth weight was associated with lower C8 values. Despite having neonatal triggers, they indicated that these neonates had no symptoms or abnormal bloodwork. In this cohort, 7 out of 13 patients were homozygous for the c.985A>G mutation. In this multicenter retrospective study, they could not elucidate a clear cause for this trend. The authors posited that these neonates were under intensive medical care from birth, which may have prevented any metabolic decompensation associated with their MCADD.[24]

Medium-Chain Acyl-CoA Dehydrogenase Deficiency Confirmatory Testing

Confirmatory testing involves urinary organic acid levels, repeating the acylcarnitine profile on plasma, MCAD enzyme activity levels, and genotype analysis via chromosomal testing. 

Elevated acylcarnitine concentrations of C6, C8, C10, and C10:1, as well as elevated C8/C2, C8/C6, C8/C10, C8/C12, and C8/C16 ratios, are typically seen. Urinary testing will show elevated levels of hexanoylglycine, isohexanoylglycine, suberylglycine, and phenylpropionylglycine. Molecular testing is used to identify variants in the ACADM gene, but the clinical significance of a single or novel variant may be difficult to predict. Enzyme activity testing is the most efficient and meaningful confirmatory test, directly assessing MCAD activity. Residual enzyme function measured in this manner correlates with the expected phenotype of the affected individual.[2]

According to the American College of Medical Genetics and Genomics and the National Coordinating Center for the Regional Genetics Networks diagnostic algorithm for the diagnosis of MCADD, a positive NBS test should be followed by second-tier testing that includes a plasma acylcarnitine profile and a urinary organic acid profile. Test results that are consistent with MCADD confirm the diagnosis. Additional molecular testing for genotype analysis may be considered but is not required for the diagnosis. A second-tier testing result inconsistent with MCADD is considered a false positive, and no further testing is required.[ACMG]

Serum acylcarnitine profile

The cutoff values for C8 differ between various NBS programs around the world. They are often combined with elevated secondary biomarkers, including C0, C2, C10:1, and the C8/C2 and C8/C10 ratios to improve the positive predictive value of NBS.[25] Liquid chromatography-tandem mass spectrometry on whole blood samples is used to repeat the acylcarnitine profile and is considered the standard method for diagnosing MCADD.[1] This method is preferred because mass spectrometry cannot differentiate branched-chain C8 acylcarnitines from octanoyl-carnitines. The presence of branched-chain C8 acylcarnitines can give a false positive result. Chromography can distinguish octanoyl-carnitine from branched-chain C8 acylcarnitines and correct these false positive MCADD results.[26]

The serum acylcarnitine profiles vary significantly based on the underlying genotype of the affected individual. Compound heterozygotes carrying c.199T>C with c.985A>G or another mutation have the lowest levels of acylcarnitine markers compared to other genotypes. Individuals homozygous for the c.985A>G mutations were historically considered to have the highest serum acylcarnitine levels; however, recent studies report no difference in the biochemical profile of individuals homozygous for the c.985A>G mutation in comparison to those who are heterozygous for this mutation with an alternate second variant, other than c.199T>C. Similarly, other known pathogenic homozygous mutations, eg, c.799G>A, have similar biochemical profiles to homozygous individuals for the c.985A>G mutation.[18] According to recent data, the C8/C10 ratio is the best biochemical marker to differentiate between patients homozygous for c.985A>G and compound heterozygous for c.199T>C and c.985A>G or another mutation.[18]

Initial C6 and C8 values correlate well with residual enzyme function, with the highest C6 and C8 values seen in patients with the lowest enzyme residual activity (ie, (0% to 10%). The C8/C2 and C8/C10 ratios are considered most reliable in differentiating true MCADD from normal controls, often exhibiting values that are 10-fold higher in MCADD.[2] Patients with residual MCAD activity >10% have variable acylcarnitine ratios. Although the differences in laboratory methods and cutoff values may explain this variability to some extent, enzyme activity testing is necessary to discriminate severe MCADD from mild cases, healthy carriers, and healthy individuals.[2]

Urinary organic acid levels

Urine acylglycine assays demonstrate elevated n-hexanoylglycine, 3-phenylpropionylglycine, octanoylglycine, and suberylglycine levels in patients with MCADD. These assays also utilize liquid chromatography-tandem mass spectrometry. Hexanoylglycine is the most significant diagnostic marker for MCADD in this assay.[1] Urinary acylglycine levels may be normal in asymptomatic patients. In addition, there are case reports of urinary acylglycine levels normalizing quickly after dextrose-containing intravenous solutions are administered.[15]

Medium-chain acyl-CoA dehydrogenase enzyme activity testing

Measuring MCAD enzyme activity improves the diagnostic yield in patients with MCADD, especially for those who have variants of unknown significance or only 1 pathogenic variant on molecular testing.[25] MCAD enzyme activity is determined by measuring octanoyl-CoA or phenylpropionyl-CoA oxidation rate in lymphocytes. A definitive diagnosis can be made for patients with an enzyme activity ranging between 10% to 35%.[1]

MCAD enzyme activity can be predicted with some reliability for known genotypes.[1][2] Patients who are homozygous for the c.985A>G mutation consistently have MCAD activity below 2.5%. Patients who are heterozygous for this mutation usually have an MCAD activity between 5.7% and 13.9%.[1] According to one study, the c.985G>A mutation, when present in homozygosity, was associated with a residual activity of around 0.52%. Patients who had this mutation in compound heterozygosity with the c.799A>G mutation were shown to have residual enzyme activity of approximately 3.67%. In comparison, those who were homozygous for the c.799A>G mutation had MCAD enzyme activity of around 6%. Heterozygosity of c.985G>A with the c.199T>C variant exhibited residual activity of around 18.89%. Patients with residual MCAD enzyme activities between 25% and 36% were either homozygous or compound heterozygous for other variants in the ACADM gene.[2]

Molecular testing for genotypic mutations

Molecular genetic testing, utilizing whole DNA or exosome sequencing to detect mutations in the ACADM gene, is highly sensitive for detecting mutant variants. However, the clinical significance of this diagnostic tool for MCADD is unclear. To date, molecular testing has identified more than fifty genetic variants of uncertain significance in the ACADM gene.[14]

Treatment / Management

MCADD has no definitive treatment; management primarily involves acute and long-term dietary interventions to prevent prolonged fasting and ensure adequate nutritional intake to meet metabolic demands during stress.[1]

Acute Management

In symptomatic patients, reversal of catabolism and treatment of hypoglycemia are the mainstay of therapy. Simple carbohydrate administration in patients who tolerate sufficient oral intake is preferred.[1] 

Some specialists recommend a home glucose monitoring plan during acute illness or when hypoglycemic symptoms are suspected. However, subsequent management should be conducted in consultation with a metabolic specialist. Teaching caregivers about glucose requirements during acute illness and suspected decompensation is imperative. Commercially available oral rehydration solutions for diarrhea and vomiting do not contain enough glucose to meet the metabolic demands of patients with MCADD.[17] When administering glucose at home under these scenarios to children who no longer consume infant formula or breastmilk, concentrated glucose solutions (eg, juices or sports drinks) are preferred.[17]

Some experts recommend oral carbohydrate administration only if the patient's serum glucose is at or above normal. Intravenous glucose administration is recommended if there is any evidence of hypoglycemia, even if the child can tolerate oral intake on initial evaluation.[17] In patients who are unable to intake sufficient amounts of carbohydrates orally, 2 mL/kg of 25% dextrose solution should be administered intravenously. Subsequently, 10% dextrose should be given at 1.5 times the maintenance rate to attain a glucose level of ≥5 mmol/L (90 mg/dL).[1] Alternatively, a bolus of 0.25 mg/kg of dextrose solution (up to 25 g) can be given to restore euglycemia. Once euglycemia is established, a maintenance infusion with 10% dextrose containing one-quarter-normal saline should be continuously administered to infants younger than 12 months of age. Older children should receive 10% dextrose solution in half-normal saline for maintenance fluids. The rate of fluids should be 1.5 times the calculated maintenance fluid rate based on weight or body surface area to ensure glucose infusion of 10 mg/kg/min; higher rates may be needed based on the patient's glucose requirements.[17]

Dextrose solutions containing 5% dextrose are not recommended. However, when 10% dextrose is not readily available, 5% dextrose solution in half-normal saline infused at 2 times the calculated maintenance fluid rate can be used as a bridge in the interim. Every effort should be made to ensure that 10% dextrose solution is administered immediately.[17] Emergency care clinicians must note that patients with MCADD require immediate medical attention at the time of arrival, even if the symptoms are mild. Delayed triage can result in life-threatening complications for these patients.[17] Metabolic acidosis is frequently present as well. Rapid correction via bicarbonate infusions is also warranted.[17] Aside from MCADD-specific management, patients who are acutely ill also need thorough evaluation for the precipitating illness. Common triggers include gastroenteritis, otitis media, and pharyngitis. In adolescents and adults, testing for alcohol intoxication is required. Prompt recognition and treatment of the precipitating illness are recommended to ensure quick recovery.[17] 

Long-Term Management

The main goal of long-term management is to prevent prolonged fasting. The maximum fasting times vary by age. However, there is no consensus regarding the maximum fasting time for a given age. According to a recent review, the maximum recommended fasting period is 3 hours for neonates and infants, 4 hours for toddlers, and 5 hours for preschool children. School-age children can have a 6- to 7-hour fasting period, while adolescents and adults can extend it up to 8 hours.[27] Nutrition guidelines by the Genetic Metabolic Dietitians International recommend a maximum fasting time of 4 hours for infants younger than 4 months, with an additional hour every month after that (up to 12 hours) for infants between 5 and 12 months of age.[GMDI] One reason for this discrepancy in recommendations is that patients with MCADD have varying degrees of residual MCAD function. An individualized fasting schedule is likely a better option, especially for patients with known "severe" mutations. An individualized fasting schedule can be formulated by checking serum glucose levels after the longest fasting time of the day. This can help determine tolerance to nighttime fasting in older infants, especially when fasting periods are being adjusted.[GMDI]

Dietary restrictions include avoidance of foods and infant formulas that contain medium-chain fatty acids.[1] Some patients require bedtime doses of raw cornstarch to ensure slow glucose release overnight.[17] Patients should consume meals with a high complex carbohydrate content and follow a low-fat diet. Meals containing medium-chain triglycerides should be avoided.[28] Some patients report chronic muscle weakness and fatigue, which is usually unrelated to any cardiac dysfunction. Physical therapy in consultation with a metabolic physician is recommended to manage these symptoms.[1]

L-carnitine supplementation of 50 to 100 mg/kg/day has historically been prescribed to patients with MCADD. This is theorized to treat secondary carnitine deficiency due to acylcarnitine accumulation. However, the benefit of this supplementation is not consistently seen in clinical trials.[1] A retrospective study evaluating the effect of secondary carnitine deficiency in patients with MCADD concluded that this deficiency is not associated with more frequent or prolonged acute visits to the hospital or clinic. They recommended carnitine supplementation only for patients with severe MCADD who have fasting intolerance and muscle weakness despite MCADD-specific dietary changes.[28]

The Genetic Metabolic Dietitians International guideline for chronic management of patients with MCADD recommends the following interventions:

• A concentrated glucose source for emergency use should be available at all times. Liquid glucose gel formulations sold in single-use tubes containing 24 g of glucose are ideal. 
• The maximum fasting time for infants younger than 4 months is 4 hours. An additional hour can be added per month for infants between 5 and 12 months of age.
• Children older than 12 months should follow age-appropriate meal and snack schedules.
• Skipping meals should be avoided for all individuals with MCADD, regardless of their age.
• Intense or prolonged exercise requires pretreatment with adequate carbohydrate intake and hydration.
• Regular infant formula and breast milk can be continued in infants with MCADD. Careful monitoring for adequate nutritional intake is required for exclusively breastfed infants. 
• Infant formulas that contain medium-chain triglycerides and breast milk enhancers are contraindicated in patients with MCADD.
• Older children and adults should follow age-appropriate heart-healthy diets. Meal planning should limit daily caloric intake from fats to approximately 30%. Over-restriction of dietary fats is not recommended.
• Fruits, vegetables, and complex carbohydrates should be utilized to meet nutritional requirements.
• Anthropomorphic evaluations should ensure that the children follow a normal growth curve. Overfeeding and excess weight gain should be avoided.[GMDI]

Future Treatment Options

Nitrogen scavengers, eg, glycerol phenylbutyrate, are currently being studied as an adjunct therapy for patients with MCADD. Thus far, the studies have been restricted due to their sample size, limiting the extrapolation of results. Gene therapy using recombinant adenovirus vectors has shown promising results in animal models of MCADD, but human trials are still lacking.[1] Proteomics testing a kinetic model of a human liver with FAOD showed decreased pathway flux and low levels of free-mitochondrial CoA in symptomatic cases of MCADD. They predict that therapies that increase short-chain acyl-CoA dehydrogenase levels in patients with MCADD will increase pathway flux and free-mitochondrial CoA levels, which in their kinetic model correlates with a clinically asymptomatic state.[29] 

Emergency Protocol Letter and Medical Alert Tag

All patients with MCADD should receive an emergency protocol letter from their metabolic specialist. This letter or a digital copy should always be kept with the patient or caregivers. In this letter, the metabolic physician should outline pertinent findings of this disorder and give detailed management instructions for the emergency response team. The letter should also contain contact information for the patient's metabolic specialist. A medical alert tag or bracelet should be considered in school-age children and adults, which should identify patients with MCADD and the risk for hypoglycemia. This will help the emergency response team provide dextrose without delay and help improve clinical outcomes for these patients.[17][GMDI]

Differential Diagnosis

MCADD symptoms overlap with multiple inborn errors of metabolism. The diseases that must be considered in the differential diagnosis of MCADD are listed below:

• Short-chain acyl-CoA dehydrogenase deficiency
• Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and trifunctional protein deficiency
• Very-long-chain acyl-CoA dehydrogenase deficiency
• Multiple acyl-CoA dehydrogenase deficiency
• 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency
• Ornithine transcarbamylase (OTC) deficiency
• Reye syndrome:
  • Often presents with the same symptoms as MCADD
  • Differentiated by the typical presentation in older children with known aspirin ingestion
  • Has higher transaminase levels and distinct histology changes [30][1][30]

Prognosis

The prognosis for patients with MCADD is excellent if diagnosed early and provided appropriate management during acute illnesses. Early diagnosis via NBS and subsequent management by metabolic specialty centers has reduced the morbidity and mortality associated with this disease to nearly zero.[31] Undiagnosed children have a mortality rate as high as 25% after the first symptomatic episode.[1] Many of the surviving individuals subsequently develop severe neurocognitive impairment after the initial presentation.[5]

According to a recent study, the prevalence of acute symptomatic MCADD episodes was reduced from 0% to 13% from a pre-NBS rate of 66% to 95%. In the same study, the mortality associated with the initial episode was reduced to 3% to 4% from a pre-NBS rate of 14% to 21%.[27]  In addition, this study reported a decrease in the prevalence and severity of cognitive impairment in patients with MCADD from 67% to 11% after the institution of expanded NBS in their cohort. The authors note that the higher prevalence of cognitive impairment in their study, both before and after NBS, when compared to other studies, is likely due to their inclusion of borderline and mild cognitive impairment. When restricting cognitive impairment to moderate and severe intellectual disability, they report results similar to previous studies, with a 13% prevalence before and 0% after NBS.[27] 

Complications

Neurocognitive impairment is the most feared complication of this disease. Neurologic sequelae with loss of developmental milestones, including aphasia and attention deficit disorder, have been reported in these patients.[1] Clinical studies demonstrate a strong correlation between intellectual disability and the number and severity of symptomatic episodes of MCADD.[27] Preventive strategies during acute illness and avoidance of prolonged fasting are essential in decreasing the incidence of this complication. With early diagnosis and effective management, the prevalence of neurocognitive impairment in patients with MCADD reduces dramatically.[27] 

Weight gain and obesity are other potential complications of MCADD. They occur due to overzealous carbohydrate administration by caregivers who fear hypoglycemia in these patients. Obesity and its associated complications, such as glucose intolerance, are a significant concern for individuals living with MCADD. Current literature includes many reports of diabetes mellitus type 2 in patients following an MCADD-specific diet.[1] Caregiver and eventually patient education, preferably by a metabolic dietician, regarding appropriate caloric intake is required to minimize the risk of obesity in these individuals.[GMDI] Of note, the risk of obesity and weight gain is higher in individuals who are on L-carnitine supplementation.[1] Another potential complication of MCADD is chronic renal failure. In patients with MCADD, chronic renal failure develops due to fatty infiltration of the kidney with subsequent tubulointerstitial fibrosis. Regular screening for renal function and evaluation by a clinician is recommended for these patients.[1]

Deterrence and Patient Education

MCADD requires patients to live a lifestyle different from their peers. The daily burden of a strict diet regime and the need for constant surveillance causes significant stress for the family. One study reported that nearly 75% of parents caring for a child with a metabolic disorder felt a substantial burden in their daily lives.[32] Even without a confirmed diagnosis, parents and caregivers suffer significant anxiety surrounding MCADD. When NBS results are confirmed as falsely positive, caregivers continue to experience some level of anxiety, which manifests as higher healthcare use in the first year of life.[33] Patients with MCADD experience higher emergency department visits and inpatient hospitalizations from the age of 6 to 12 months.[13] A recent national study from Canada reported that children diagnosed with MCAD deficiency use healthcare services at a significantly higher rate throughout early childhood, extending to 4 years of age, as compared to a population-based cohort of children with negative newborn screening results for MCADD.[13]

Therefore, caregiver support and education are an essential part of MCADD treatment. Reassuring parents in times of "health" and educating them about the potential signs of metabolic decompensation must occur with every clinical encounter. Metabolic dieticians and nurses play an essential role in accomplishing this goal by providing extended sessions that supplement information provided by the metabolic physicians. Well-informed caregivers experience less anxiety about the care of their child and are more likely to ensure timely medical evaluation for children when a potential decompensation occurs. In-depth and ongoing conversations with metabolic specialists and nurses help parents understand the day-to-day dietary management of this disease and emergency response strategy during an acute illness. This is especially true in the first year of life when parents report significant physical and mental burdens.[34]

Parents raising children with MCADD also report increased anxiety as the child grows. This is particularly true regarding transition points between fasting intervals and changes in food intake. Overcompensation due to fear of hypoglycemia often occurs. Another study reported that the day-to-day dietary management regimes followed by caregivers of children with MCADD were more stringent than those advised in the guidelines, highlighting the prevalence of the "risk-averse approach" in these parents.[34] Caregiver support, frequent reiteration about the plan of care, and open discussion regarding their fears must be provided to ensure optimal treatment strategies are followed and the impact of this diagnosis is minimized on the life of the child.

Enhancing Healthcare Team Outcomes

MCADD is a rare autosomal recessive FAOD that can result in devastating consequences for the affected individual if left untreated. With early intervention, the clinical outcomes are remarkably improved. The first step in enhancing clinical outcomes for this disease is to implement expanded NBS programs worldwide. Once a diagnosis is made, the care of the affected individual and clinical support for the caregivers must be provided by an interprofessional team of pediatricians, metabolic specialists, dieticians, and nurses. 

In the absence of definitive enzyme replacement or gene therapy, the management of this disease revolves around dietary changes and emergency response protocols during an acute illness. This requires caregiver education and support on an ongoing basis for the first few years of life. Metabolic dieticians are an integral part of the interprofessional team managing these patients. They can help parents understand the infants' feeding times and diet compositions to ensure prolonged fasting is avoided. As the child grows, dieticians and nurses play a crucial role in ensuring parents avoid the "risk-averse" approach and do not implement overly stringent diet regimens for the child. The metabolic specialist and pediatric clinicians must also ensure that the adolescent child with MCADD understands the dietary requirements of their disease and the risk of non-compliance. Additional parent/child counseling may be required if the psychological burden of the disease begins to impact their life. Specialist metabolic nurses and counselors play a vital role in providing ongoing emotional care support to help meet these families' emotional and psychosocial needs.

A recent study from the United Kingdom reported that long-term therapeutic relationships with an interprofessional team of clinicians, nurses, and dieticians are of indispensable value to individuals living with MCADD and their caregivers. A collaborative approach to managing this disease utilizing an interprofessional team can improve clinical outcomes for MCADD and minimize its impact on their lives.