Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency

Impaired mitochondrial β-oxidation of medium-chain fatty acids caused by biallelic ACADM variants — the founder variant c.985A>G p.(Lys329Glu), tandem mass spectrometry newborn screening, emergency protocols, fasting management and prevention of sudden death

Literature and regulatory information updated: 4 October 2026. Integration of the French National Diagnosis and Care Protocol (PNDS): 2 November 2026.

0. Initial Reference Table

1. Introduction

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited defect of mitochondrial fatty acid oxidation and the clinical prototype of this group of inborn errors of metabolism [6, 18]. Medium-chain acyl-CoA dehydrogenase, abbreviated MCAD, catalyses the first step of each β-oxidation cycle for coenzyme A (CoA) esters of fatty acids with six to twelve carbon atoms [4, 6]. When this enzyme fails, the body loses the ability to use fat as fuel when glycogen stores are depleted, during prolonged fasting and particularly during common infections that reduce intake and increase energy expenditure [2]. The classic clinical consequence is hypoketotic hypoglycaemia with encephalopathy, which may progress within hours to coma and death and, before newborn screening, often presented as unexplained sudden infant death or a Reye-like syndrome [2, 6].

The disease has a relatively recent history, which Nyhan himself describes as an indication of the continuing difficulty in recognising fatty acid oxidation defects [6]. In 1982, Kølvraa, Gregersen and colleagues in Aarhus studied fibroblasts from a patient with C6–C10 dicarboxylic aciduria and proposed a defect in a "general" acyl-CoA dehydrogenase; Nyhan and colleagues regard this work as the starting point of the field of fatty acid oxidation defects as currently understood [17, 23]. Two descriptions established the disorder in 1983: Rhead and colleagues demonstrated impaired [1-¹⁴C]octanoate oxidation and MCAD deficiency in fibroblasts from patients with dicarboxylic aciduria in Science, and Stanley and colleagues in Philadelphia described MCAD deficiency in children with non-ketotic hypoglycaemia and low carnitine concentrations [24, 25]. The term "non-ketotic hypoglycaemia" used in these foundational studies was subsequently replaced by "hypoketotic", because acute decompensation may involve ketone bodies at concentrations below those expected for the degree of fasting [2, 6].

The gene was cloned in 1986 and assigned to chromosome 1, and in 1990 three independent groups (Matsubara and colleagues, Yokota and colleagues, and Kelly and colleagues) identified an A→G transition at cDNA position 985 that replaces lysine with glutamate and accounted for almost all alleles in symptomatic patients of European origin [6, 26–28]. In 1993, Gregersen and colleagues demonstrated 100% association of this variant with a common intragenic haplotype and higher carrier frequencies in the Netherlands, Ireland, England, Belgium and Denmark, documenting a founder effect in north-western Europe [29]. At the same time, evidence accumulated that many cases labelled Reye syndrome were actually inborn errors of metabolism, most commonly MCAD deficiency and ornithine transcarbamylase deficiency, and that siblings of patients who had died with a diagnosis of sudden infant death syndrome had MCAD deficiency retrospectively documented in their newborn screening cards [6, 12].

The introduction of acylcarnitine analysis by tandem mass spectrometry (MS/MS) in the late 1990s enabled population screening, and MCAD deficiency became the central argument for expanding newborn screening programmes [7, 17]. In 2001, Andresen and colleagues showed that the variant spectrum detected by prospective screening differed from that in symptomatic patients, identifying the mild c.199T>C variant; in 2007, Wilcken and colleagues demonstrated in an Australian cohort that screening reduces mortality and severe episodes up to age four [30, 31]. MCAD deficiency is now included in newborn screening panels in virtually all countries with expanded programmes, including Portugal since 2004, the British blood spot panel (expanded in 2015), all United States states, France since 1 December 2020 (recommended by the HAS since June 2011) and, in Brazil, the second phase of the heel-prick screening expansion provided for in Law No. 14.154/2021 [2, 10, 14, 32, 33]. ClinGen classified the gene–disease pair as strongly actionable in paediatric and adult settings [15].

2. Molecular Genetics and Pathophysiology

2.1 Gene, protein and inheritance pattern

ACADM lies at 1p31.1 and encodes a 421-amino-acid precursor whose 25-residue transit peptide is cleaved after import into the mitochondrial matrix; the mature protein is folded with assistance from the chaperonin HSP60 (60 kDa heat shock protein) and assembled into a homotetramer of 42.5 kDa monomers, each containing one FAD molecule [2, 4]. The physiological electron acceptor is electron transfer flavoprotein (ETF), which delivers electrons to the respiratory chain through ETF–ubiquinone oxidoreductase; this dependence explains why metabolites characteristic of MCAD deficiency also occur in multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II) [2, 18]. MCAD belongs to a family of acyl-CoA dehydrogenases with overlapping specificities: short-chain acyl-CoA dehydrogenase (SCAD) acts on C4–C6, medium-chain on C6–C12 and very-long-chain (VLCAD) on C14–C20 [6].

Inheritance is autosomal recessive, and heterozygotes are asymptomatic [2, 18]. A patient's parents are generally obligate carriers; if the variant is found in only one parent, possibilities include a de novo variant, parental mosaicism, a deletion undetected by sequencing that mimics homozygosity, or uniparental isodisomy [2].

2.2 Spectrum of pathogenic variants

The c.985A>G variant causes abnormal folding, destabilisation of the quaternary structure and rapid degradation of the mutant protein, with loss of function [2]. Classical immunochemical studies in homozygous fibroblasts detected no cross-reacting material, and pulse–chase labelling demonstrated enzyme instability [6]. Before screening was introduced, rapid testing for c.985A>G and a 4 bp deletion accounted for more than 93% of alleles in symptomatic patients, and Yokota and colleagues identified five rare variants in 55 patients [6, 17]. ACADM sequence analysis detects approximately 98% of pathogenic variants, and intragenic deletions/duplications are rare (fewer than 10 described) [2]. Current nomenclature numbers the protein from the precursor's first amino acid; historical numbering began with the mature protein, explaining K304E = p.Lys329Glu and Y42H = p.Tyr67His [2]. In ClinVar (accessed 4 October 2026), c.985A>G p.(Lys329Glu) (VCV000003586) and c.199T>C p.(Tyr67His) (VCV000003597) are classified as pathogenic/likely pathogenic, with multiple submitters and no conflicts; classification of c.199T>C does not contradict the observation that homozygotes probably have low risk, because it describes the allele's pathogenicity, particularly in combination with a severe allele, rather than the clinical risk of each genotype [2, 5, 34].

2.3 Fasting physiology and mechanism of decompensation

Fatty acid oxidation is not substantially required while hepatic glycogen remains available, providing approximately 12 hours of glucose in most individuals; hypoglycaemia after a short fast therefore suggests a carbohydrate metabolism defect, whereas hypoglycaemia after prolonged fasting suggests a fatty acid oxidation defect [6]. Frequently fed infants rarely need alternative fuels, but as feeding intervals lengthen, for example when night feeds cease, reliance on lipid oxidation increases proportionally [2]. Medium- and short-chain fatty acids cross the mitochondrial membrane by diffusion, independently of carnitine, and are activated to CoA esters in the matrix; MCAD performs the initial dehydrogenation of medium-chain acyl-CoA, and each turn of the spiral produces acetyl-CoA, FADH₂ and NADH [2].

In MCAD deficiency, long-chain fatty acid β-oxidation proceeds as far as medium-chain lengths and then stops; acetyl-CoA production for hepatic ketogenesis and the tricarboxylic acid cycle decreases, and peripheral dependence on glucose increases [2, 18]. Hypoglycaemia in fatty acid oxidation defects results mainly from increased peripheral glucose consumption, although hepatic glucose production may also decline [18]. Because MCAD acts downstream in the spiral, partial long-chain fatty acid oxidation still generates some ketone bodies, explaining why ketonuria may be present and even recurrent ketotic hypoglycaemic crises have been reported [18, 38]. Hyperammonaemia, generally 1.5 to 2 times the upper limit in older infants, is attributed to reduced synthesis of N-acetylglutamate, the physiological activator of carbamoyl phosphate synthetase 1, because of acetyl-CoA deficiency [2, 18]. Encephalopathy may occur without hypoglycaemia, presumably through accumulation of free fatty acids and their carnitine and CoA esters [18].

Accumulated medium-chain acyl-CoA molecules are diverted into several detoxification pathways: transesterification with carnitine (acylcarnitines, particularly octanoylcarnitine C8, with C6, C10 and C10:1), glycine conjugation (hexanoylglycine, suberylglycine and phenylpropionylglycine), and microsomal and peroxisomal ω-oxidation, producing dicarboxylic acids (adipic C6, suberic C8, sebacic C10 and dodecanedioic C12) and ω-1 hydroxy acids (5-hydroxyhexanoic and 7-hydroxyoctanoic acids) [2, 6, 17]. cis-4-Decenoic acid (C10:1) is a specific marker found in the livers of four infants who died with a diagnosis of sudden death and had MCAD deficiency [6]. Urinary loss of carnitine esters causes secondary free carnitine deficiency; accumulated acylcarnitines also inhibit OCTN2 (organic cation/carnitine transporter 2), lowering the renal reabsorption threshold and worsening depletion [2, 6, 39]. Carnitine depletion in turn provides a second mechanism compromising fatty acid oxidation and may attenuate the acylcarnitine profile [2, 6]. Accumulated metabolites may cause oxidative damage, and mouse models suggest dysfunction of respiratory chain complexes I–III in liver and muscle [2].

2.4 Tissue injury and the basis of arrhythmias

Pathological changes are predominantly hepatic, with microvesicular and macrovesicular steatosis; lipid deposition also occurs in the kidneys and heart [6]. In Iafolla and colleagues' series of 120 patients, cerebral oedema was recorded in 14 of 23 autopsies, and hyperammonaemia may contribute to intracranial hypertension in isolated cases [6]. Ventricular arrhythmias, more typical of long-chain defects, have been documented in neonates with MCAD deficiency even with normal blood glucose and after many hours of intravenous glucose, suggesting a direct arrhythmogenic effect of medium-chain acylcarnitines or other accumulated metabolites [40]. Nyhan and colleagues argue that arrhythmia is a more plausible cause of sudden infant death than hypoglycaemia alone [6].

2.5 Genotype–phenotype correlation

Genotype–phenotype correlation is weak: patients with the same genotype may die or remain asymptomatic depending on exposure to fasting and intercurrent illness [2, 18]. Nevertheless, c.985A>G homozygotes have higher screening C8 values (mean 13.8 µmol/L, range 9–22, versus 2.6 µmol/L, range 1.9–3.2, in compound heterozygotes), higher lifelong plasma C8 concentrations (6.2 ± 5 versus 3.6 ± 1.9 µmol/L), higher transaminases, more hypoglycaemic events on average (1.44 versus 0.49 per patient, not statistically significant), and a greater likelihood of neonatal symptoms [2, 41, 42]. In a cohort of 221 newborns screened in the United States, mean C8 at first screening was 11.2 µmol/L (median 8.6; range 0.36–43.91), and higher values were associated with neonatal symptoms [42]. Residual enzyme activity correlates better with risk: in the Netherlands, classical genotypes had median activity of 0% (0–8%), fatal neonatal presentations had activity below 1%, and activity below 10% was associated with greater hypoglycaemia risk and need for carnitine [43]. Compound heterozygotes carrying c.199T>C and a severe allele have milder biochemical profiles, but two patients in this group had neonatal decompensation with hypoglycaemia before diagnosis, so individuals with a "mild" biochemical phenotype should be considered at risk [2, 34]. In Japan, residual lymphocyte activity ranged from 0–3% in symptomatic patients and approximately 10% to 30% in screen-detected cases, demonstrating a continuous severity spectrum [35].

3. Clinical Spectrum and System-Specific Manifestations

3.1 Classical childhood form

Affected newborns are normal at birth, and historically disease manifested between 2 and 24 months, almost always after prolonged fasting or during a common infection (viral gastroenteritis or upper respiratory tract infection) that reduced appetite and increased energy expenditure through fever [2]. Nyhan and colleagues place the first episode between six months and two years, usually after 12 or more hours of fasting during intercurrent illness, beginning with vomiting, lethargy or a seizure and rapidly progressing to coma [6]. Morris and Spiekerkoetter describe pre-screening presentation between 4 months and 4 years, with acute hypoglycaemic encephalopathy and hepatic dysfunction, noting that 30–50% of affected individuals remained asymptomatic even before screening [18]. In the Netherlands, most of 155 patients presented between 3 months and 5.1 years, and 13% had neonatal symptoms, which were not exclusively associated with breastfeeding [44].

Iafolla and colleagues' series of 120 patients referred to Duke University for diagnosis remains the most informative description of natural history: mean onset age was 12 months (2 days to 6.5 years), 19% (23/120) died before diagnosis, 12 siblings had previously died (11 diagnosed with sudden infant death syndrome and 1 with Reye syndrome), and 95% required emergency care or admission during the first episode [6, 12]. Initial manifestation frequencies are summarised in Table 3.1.

Table 3.1 — Manifestations at clinical presentation (Iafolla and colleagues' series of 120 patients) [6, 12]

3.2 System-specific manifestations

Central nervous system. Encephalopathy (lethargy, irritability, seizures and coma) is the dominant manifestation of a crisis; survivors of uncontrolled decompensation may lose developmental skills and develop aphasia and attention deficit hyperactivity disorder (ADHD), attributed to acute brain injury [2]. During follow-up of 73 patients older than two years, 29% had developmental delay (12 with global disability), seven had behavioural problems, 14% epilepsy and 11% attention deficit [6]. In adults, MCAD deficiency is included in the differential diagnosis of metabolic encephalopathies [45].

Liver. Crises involve hepatomegaly, elevated transaminases, hyperammonaemia and microvesicular steatosis on biopsy, a presentation that frequently led to a diagnosis of Reye syndrome; in one patient, concurrent orotic aciduria even fulfilled published criteria for ornithine transcarbamylase deficiency despite normal hepatic enzyme activity [2, 6]. True liver failure is unusual and jaundice rare [17, 18].

Heart. Cardiomyopathy is not part of the typical phenotype, and the Oxford Desk Reference emphasises that the characteristic severe complication is sudden death from hypoglycaemia rather than cardiomyopathy [18, 46]. However, QTc prolongation, pulseless ventricular tachycardia and torsades de pointes have been described in neonates, as have severe arrhythmias during decompensation in adults [6, 40, 47–49]. Bala and colleagues identified six reports of ventricular tachyarrhythmia, five in neonates [40].

Skeletal muscle. Patients appear completely healthy between crises, although some are hypotonic and avoid exercise [6]. Chronic myopathy was observed in 18% of individuals with multiple decompensation episodes [2, 12]. In the Dutch cohort, after diagnosis, 35% reported fatigue, 31% muscle pain and 39% reduced exercise tolerance, without cardiac dysfunction explaining this in 11 adults studied [44]. Exertional myalgia, progressive proximal weakness and dropped head syndrome have also been described, and rhabdomyolysis occurs mainly in adults [2, 6].

Kidneys. Renal fatty infiltration has been documented at autopsy, but established clinical kidney disease has not been described [2].

Growth and weight. After treatment begins, the need for frequent meals favours overweight, unrelated to the disease itself [2, 44].

Pregnancy. Carnitine deficiency, acute liver failure and HELLP syndrome (haemolysis, elevated liver enzymes and thrombocytopenia) have been described in affected women; maternal MCAD deficiency may also be discovered through low free carnitine in the child's newborn screening [2, 50].

Laboratory warning signs. During crises, alongside hypoketotic hypoglycaemia, uric acid and creatine kinase (CK) concentrations rise markedly: uric acid frequently exceeds 10 mg/dL and may reach 20 mg/dL, and CK may exceed 1000 U/L, reflecting cell destruction; these measurements, usually absent from paediatric emergency panels, should be requested specifically [6, 17]. Plasma free carnitine is typically very low and urinary esterified carnitine very high [6].

3.3 Neonatal presentation

Some newborns present within the first 72 hours, before screening results are available, with hypoglycaemia, arrhythmias or sudden death; exclusively breastfed infants are at greater risk because of low milk volumes during the first few days [18, 51]. In Germany between 2005 and 2018, eight term newborns with uneventful neonatal adaptation died from MCAD deficiency at a median age of 3.5 days (3–6); four of the five cases with feeding information had preceding poor feeding, and glucose was severely low in every case in which it was measured during the crisis [13]. Screening cards had been collected at a median age of 46 hours, but results became available at a median of 5 days [13]. In 2026, two breastfed newborns in the United Kingdom were reported to have presented at 4 and 5 days, before screening results, with severe ketoacidosis (pH 6.9 and 7.1; ketonaemia 6.5 mmol/L in the second), normal lactate and frank or only borderline hypoglycaemia; the authors argue that MCAD deficiency should be included in the differential diagnosis of neonatal ketoacidosis, with or without hypoglycaemia (see section 10.3) [52]. The French PNDS estimates that approximately 5% of patients decompensate before the screening result is known, sometimes fatally, and draws attention to hypoglycaemic episodes in the first days of life in exclusively breastfed infants and to rhythm disturbances as a mode of presentation, particularly in the neonatal period [10, 40]. The same document recommends that the team receiving the screening notification should consider that the newborn may already be in hospital at the time of contact [10].

3.4 Presentation in adolescence and adulthood

Individuals born before screening may remain asymptomatic into adulthood and decompensate after prolonged fasting, surgery, vomiting or excessive alcohol consumption [2, 53]. In Lang's review of 14 cases, mortality was 50% among those presenting acutely and 29% overall; arrhythmias, cardiac arrest and rhabdomyolysis were prominent, and cardiac symptoms resolved with carnitine supplementation in two patients [6, 53]. A 16-year-old girl developed hepatic, renal and cardiac failure after excessive alcohol intake followed by fasting [2]. MCAD deficiency has also been identified in non-diabetic adults investigated for fasting hypoglycaemia [2, 54]. The French PNDS adds pregnancy and undernutrition during physical exertion to the list of adult triggers, describes headache with vomiting, followed by altered consciousness and multi-organ failure (neurological, muscular, hepatic and cardiac) with metabolic acidosis, hyperammonaemia, hyperlactataemia and hypoglycaemia, as the typical presenting picture, and highlights two reasons for diagnostic delay: hypoglycaemia may be absent, and the picture is sometimes attributed to ingestion of toxic substances [10].

3.5 The so-called "mild" or "asymptomatic" form

MS/MS screening identifies individuals with less abnormal acylcarnitine profiles, often compound heterozygous for c.985A>G and another variant or carrying two variants other than c.985A>G [2]. The term "asymptomatic" is imprecise: whether absence of symptoms reflects higher residual activity or simply fasting prevention remains unclear, and individuals with a mild biochemical phenotype have experienced potentially fatal decompensation [2, 34]. All individuals with MCAD deficiency should therefore be considered at risk and remain under follow-up [2].

4. Clinical Recognition and Warning Signs

Recognition of MCAD deficiency rests on two scenarios: a positive newborn screening result and a symptomatic patient without a previous diagnosis, whether because screening was not performed, the result was not yet available, or treatment was not followed [2]. In both, the guiding principle is that hypoglycaemia is a late event: intervention should begin while blood glucose remains normal, and treatment must never be delayed because glucose is not low [16, 18].

Table 4.1 — Warning signs and their interpretation

Early signs of decompensation may be subtle, such as lethargy or "floppiness", and British emergency protocols advise establishing intravenous access whenever there is any doubt [16]. In adults with fatty acid oxidation defects and an inappropriately low ketogenic response, neither blood nor urine ketones are reliable for treatment decisions [55]. A fatty acid oxidation defect may be implicated in approximately 5% of all sudden deaths in the first year of life, according to Boles and colleagues' retrospective analysis of 418 post-mortem livers, which identified two cases of MCAD deficiency [56].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

Diagnosis is established through confirmatory biochemical tests and/or identification of biallelic pathogenic (or likely pathogenic) ACADM variants, or significantly reduced MCAD enzyme activity in blood or cultured fibroblasts [2]. Because of its high sensitivity, molecular testing may obviate enzyme measurement, which is available at only a few academic centres [2]. Identification of two variants of uncertain significance, or one pathogenic variant and one variant of uncertain significance, neither establishes nor excludes the diagnosis; in such cases, the biochemical profile and enzyme activity help resolve classification under the five-class ACMG/AMP system (American College of Medical Genetics and Genomics/Association for Molecular Pathology) [2, 43]. Provocative fasting tests are no longer necessary because biochemical and molecular methods identify asymptomatic individuals [2, 6, 18].

5.2 Newborn screening

Screening quantifies dried blood spot acylcarnitines by MS/MS. The primary marker is octanoylcarnitine (C8), accompanied by smaller elevations of hexanoylcarnitine (C6), decanoylcarnitine (C10) and decenoylcarnitine (C10:1); cut-offs vary between programmes and are combined with secondary markers, particularly C8/C2 (C2, acetylcarnitine) and C8/C10 ratios [2]. The Oxford Desk Reference describes British screening as based on the C8/C10 ratio [14]. Pooled 99th percentiles from North American screen-detected case samples, published in GeneReviews, are C8 2.46 nmol/mL, C6 2.44 nmol/mL, C10 2.38 nmol/mL, C10:1 2.44 nmol/mL, C8/C2 2.43 and C8/C10 2.53 [2]. In normal newborns, C8 is below 0.22 µmol/L, and a value above 0.3 µmol/L has been used as a diagnostic criterion; published patient means were 8.4 µmol/L (3.1–28.3) and 3.0 µmol/L (0.4–21.8) [6].

Table 5.1 — Newborn screening markers and interpretation

Screening performance is high: in the Dutch programme (2007–2015), sensitivity was 99%, specificity approximately 100% and positive predictive value 86%, with prevalence of 1:8,300 [58]. The French PNDS attributes a sensitivity of 97% to C8, citing the North American cohort of 221 newborns reported by Bentler and colleagues [10]. That cohort included only newborns with a positive screen and a confirmed diagnosis and therefore cannot be used to estimate screening sensitivity; the 97% figure corresponds to the proportion of abnormal plasma acylcarnitine profiles in the confirmatory study (161 of the 166 patients in whom it was performed), and all patients had C8 ≥0.36 µmol/L on the first sample, with a median of 8.6 µmol/L [42]. The PNDS summarises the evidence from countries with screening as a reduction to approximately one quarter in the risk of death and decompensation in screened newborns, compared with historical cohorts diagnosed on the basis of symptoms [10]. False positives are uncommon and occur in c.985A>G heterozygotes (in one study, 8 of 17 newborns with C8 between 0.5 and 0.7 µmol/L were carriers) and premature infants; carriers may also have elevated C8 during stress, and the C8/C10 ratio improves specificity [2, 18]. False negatives occur in newborns with low free carnitine, such as children of mothers with undiagnosed MCAD deficiency or carnitine transporter deficiency or with nutritional carnitine deficiency, and in genotypes with higher residual activity, such as c.985A>G/c.600-18G>A [2, 36]. Cases of severe neonatal-onset MCAD deficiency with fatal outcomes and normal acylcarnitine profiles have also been described [2]. Intravenous glucose infusion at the time of sampling may reduce abnormalities, and in a newborn at familial risk receiving intravenous glucose, acylcarnitines should be repeated after 24 hours of full feeding [18, 51]. In Texas, where two screening samples are collected and the population is predominantly Hispanic, all MCAD deficiency cases were identified in the first sample; the second mainly added false positives (partly because of a low C8 cut-off), and combining dried blood spot C8 with plasma C6 and the C8/C10 ratio distinguished patients from carriers and non-carriers [59].

Timing is critical. In Germany, samples were collected between 36 and 72 hours, but results became available at a median of 5 days, after several newborn deaths; the authors recommend sampling at the beginning of the mandated window and additional sampling after outpatient deliveries or early discharge [13]. In the United States, primary care or metabolic centres received the first result at a mean age of 7.45 days [42].

5.3 Management of a positive screening result

Following a positive result, preventive measures should begin immediately (fasting avoidance and an emergency plan with enteral or intravenous glucose if intake is interrupted) while confirmatory investigations proceed [2]. In the British model, the laboratory notifies the clinical liaison service that day; the specialist team contacts the family the same day, checks whether the newborn is well and feeding, provides an emergency letter and the leaflet "MCADD is suspected", and arranges an in-person appointment that day or the next working day for diagnostic sampling, including DNA, dietary review, and provision of the emergency regimen and glucose polymer [60]. If the newborn is ill or feeding poorly, the family is directed immediately to the hospital emergency department and the emergency protocol is implemented [60]. The first follow-up appointment occurs within the next five working days, reviewing C8, urinary organic acids and c.985A>G testing; if diagnosis is inconclusive, expanded molecular testing and quantitative organic acids follow at a second appointment, and, if confirmed, sibling testing is arranged [60].

In the French model, described in the 2021 PNDS, C8 is measured by MS/MS on the same blood spot as the phenylalanine used for phenylketonuria screening, and the C8/C10 ratio is reported to the clinician for guidance only, without yet forming part of the laboratory decision algorithm (a high ratio favours a true positive) [10]. On the day of the result, the regional newborn screening centre notifies the reference clinical team, whose physician telephones the parents that same day, following an organised protocol. The telephone call has four aims: to assess the newborn's condition (urgent admission to the nearest hospital if there is fever, vomiting or lethargy; otherwise, assessment in clinic or admission within the next 24 hours), to inform the parents while limiting the emotional impact and establishing a relationship of trust from the outset, to give initial instructions on fasting prevention and on what to do in at-risk situations, and to indicate the department where the child will be assessed [10]. The first assessment aims to confirm the diagnosis, taking into account false positives (prematurity, enteral or parenteral feeding with MCT, heterozygosity for a severe variant such as c.985A>G) and alternative diagnoses, particularly other β-oxidation defects such as multiple acyl-CoA dehydrogenase deficiency; because plasma C8 falls spontaneously during the first days of life while the C8/C10 ratio remains stable, the ratio is more informative in confirmatory samples [10, 58]. Confirmatory acylcarnitines are taken on a new sample, after a fast of no more than 4 hours and with an MCT-free milk, together with urinary organic acids, with results ideally within 48 working hours of receipt by the laboratory for acylcarnitines and within 72 hours for organic acids [10]. ACADM testing is performed whenever these tests do not exclude the disease, with a result ideally within 3 months; in addition to confirming the diagnosis, it helps to predict the phenotype, because some genotypes carry a risk of decompensation up to five times higher [10, 42]. If genetic testing is inconclusive, a functional study is performed (MCAD enzyme activity or a cellular β-oxidation flux study). The PNDS states that management is the same whether the variant is severe (no residual activity) or moderate and that, once the diagnosis is confirmed, siblings should be tested (Table 5.3) [10].

Table 5.3 — French algorithm after a positive newborn screen (PNDS HAS/Filière G2M, 2021) [10]

5.4 Confirmatory tests

Table 5.2 — Confirmatory investigations in MCAD deficiency

Plasma 3-hydroxybutyrate and free fatty acids sampled during hypoglycaemia document hypoketosis: in oxidation defects, free fatty acids exceed 3-hydroxybutyrate [17, 18]. Saudubray's approach to emergency hypoglycaemia recommends sampling acylcarnitines, glucose, insulin, free fatty acids, ammonia and ketone bodies before correction, because metabolites normalise rapidly with treatment [19]. Phenylpropionate loading has fallen out of use, although it was recently proposed again for variants of uncertain pathogenicity [61]. The French PNDS sets out practical sampling rules: blood should be taken before correction of hypoglycaemia and urine as close as possible to the crisis; outside a crisis, both are collected at the end of a physiological fast appropriate for age, and in the newborn immediately before a feed; a fasting test is contraindicated and is acceptable only as a last resort, in a specialist setting [10]. Capillary glucose should be confirmed on a venous sample and accompanied by measurement of ketone bodies in blood or urine, because it is the discrepancy between the duration of fasting and the scant ketosis that points to a β-oxidation defect; when specialist investigations are collected outside the acute phase, profiles may be subtle or normal and, if clinical suspicion is strong, they should be repeated after a physiological fast [10].

5.5 Post-mortem diagnosis

Following unexpected sudden death, MCAD deficiency can be confirmed by acylcarnitine analysis and molecular testing of the original newborn screening card, which can be stored at 4–8 °C for at least a decade, or of post-mortem blood [2, 62]. Acylcarnitine analysis in post-mortem bile and fatty acid analysis in liver (including C10:1) also permit diagnosis [6, 17]. Terminal or post-mortem samples often show multiple elevated acylcarnitines resembling multiple acyl-CoA dehydrogenase deficiency, requiring molecular confirmation [18]. Mütze and colleagues propose systematic sampling: uncentrifuged EDTA whole blood (3–10 mL) for DNA, serum/plasma (2–10 mL) frozen at −20 °C in aliquots, filter paper blood spots dried at room temperature and stored at 4–8 °C, frozen urine (2–20 mL), a skin biopsy for fibroblast culture within 24 hours after death (do not freeze), and, if possible, cerebrospinal fluid frozen at −80 °C (table available at https://pmc.ncbi.nlm.nih.gov/articles/PMC9110443/table/Tab4/) [13].

5.6 Diagnostic algorithm

The practical algorithm is as follows. With elevated screening C8, fasting prevention and the emergency plan begin immediately; plasma acylcarnitines, urinary organic acids and acylglycines, free and total carnitine, and DNA for ACADM testing are collected; two pathogenic variants confirm diagnosis, and cases with variants of uncertain significance or discordant profiles benefit from lymphocyte or fibroblast enzyme activity measurement [2, 43, 60]. In a symptomatic patient, critical samples are collected before glucose without delaying treatment, including acylcarnitines, urinary organic acids and acylglycines, free fatty acids, 3-hydroxybutyrate, ammonia, uric acid and CK; when presentation does not suggest a specific gene, GeneReviews recommends exome or genome sequencing [2, 17, 19]. Following sudden death, the metabolic autopsy protocol is followed and the screening card retrieved [2, 13]. Figure 2 in Touw and colleagues illustrates the relationship between residual enzyme activity, C8 and C8/C10 at screening (https://pmc.ncbi.nlm.nih.gov/articles/PMC3543239/figure/F2/) [43].

5.7 Genetic testing: coverage, limitations and report content

ACADM sequencing (exons and intron–exon junctions) detects approximately 98% of pathogenic variants but does not reliably identify deletions or duplications of one or more exons, which are rare (fewer than 10 described) and require targeted analysis (MLPA, quantitative PCR or an array), or deep intronic or regulatory variants, which only RNA studies or genome sequencing with splicing analysis can resolve [2, 18]. The c.600-18G>A variant, located outside the canonical junctions, illustrates the problem: it produces partial splicing and a mild phenotype that may escape screening and panels with limited intronic coverage [36]. Assays targeting only c.985A>G, still used first-line at some centres, miss rare alleles, which predominate in Asian populations and in some screened newborns; a single c.985A>G allele in a patient with a typical biochemical profile requires a search for the second allele, and apparent homozygosity unconfirmed in the parents may represent a deletion on the other allele, uniparental isodisomy or a de novo variant [2, 30, 35]. Mosaicism is rare and relevant only to parental counselling [2]. A negative or incomplete molecular result does not exclude the disease in the presence of elevated C8 and C8/C10 or characteristic acylglycines; in such cases, lymphocyte or fibroblast enzyme activity resolves most discrepancies [2, 43]. The French PNDS systematises the indications for in vitro functional studies, which reproduce fasting conditions at the cellular level without exposing the patient to the risk of a fasting test: cells (cultured fibroblasts or lymphocytes) are incubated with a stable-isotope-labelled long-chain fatty acid, and accumulation of labelled intermediate-chain acylcarnitines indicates the block; measurement of a specific enzyme activity is a particular case of this approach [10]. Before genetic testing, they are indicated when the acylcarnitine profile is atypical or when clinical suspicion is strong and specialist biochemistry remains uninformative despite repetition; as a complement to genetic testing, they are indicated when variants of uncertain significance or a single heterozygous variant are identified. The decision should be made jointly by clinicians and the laboratory, and the list of French laboratories performing these studies is maintained by the Filière G2M [10].

The report should specify the gene, transcript and version (NM_000016.6, the MANE Select transcript used by ClinVar; the 2024 GeneReviews cites NM_000016.5, with the same c. numbering for the variants cited), DNA- and protein-level HGVS nomenclature, zygosity and, where two variants exist, phase (cis/trans) confirmed through parental testing, ACMG/AMP classification, and technical limitations (deletion/duplication and intronic coverage) [2, 5, 63]. Historical designations K304E and A985G (mature protein and old cDNA numbering) and Y42H should accompany rather than replace the standardised forms c.985A>G p.(Lys329Glu) and c.199T>C p.(Tyr67His), because much screening literature before 2010 uses only historical numbering [2, 27, 30]. In MCAD deficiency, a specific acylcarnitine profile and enzyme activity may serve as phenotypic and functional evidence within formal ACMG/AMP criteria, but a variant of uncertain significance does not become pathogenic because decompensation is absent under preventive measures or because of partial segregation in a family; additional segregation or functional studies are described as research until formal laboratory reclassification [2, 43, 63].

6. Differential Diagnosis

The differential diagnosis includes all causes of a Reye-like presentation (acute non-inflammatory encephalopathy with hyperammonaemia, hepatic dysfunction and fatty liver infiltration), particularly other β-oxidation and carnitine cycle defects, ketogenesis defects, urea cycle disorders, organic acidurias, respiratory chain defects and inborn errors of carbohydrate metabolism such as hereditary fructose intolerance [2]. Because clinical presentation is non-specific, distinguishing β-oxidation defects requires biochemical and molecular investigation supported by the acylcarnitine pattern, organic acids and organ phenotype (Table 6.1) [2, 18].

Table 6.1 — Differential diagnosis with other mitochondrial fatty acid oxidation defects

Table 6.2 — Other differential diagnoses and causes of misleading results

7. Treatments and Risk Management Strategies

7.1 General principles

There is no curative treatment; therapy consists of avoiding catabolism and is highly effective [2, 15]. Fasting prevention is central, complemented by intensive family education, current written emergency letters and protocols, medical alert identification (bracelet or pendant), home supplies of glucose polymers and advance communication with the local hospital [2, 60]. Care should be coordinated by a specialist inherited metabolic disease centre with a metabolic dietitian, and the nearest paediatrician and hospital should be informed immediately after diagnosis [2, 20]. ClinGen's assessment assigned metabolic management (diet and intercurrent illness protocols) scores of 11 (paediatrics) and 10 (adults), and carnitine supplementation when concentrations are insufficient a score of 8, with a lower evidence level [15].

7.2 Age-specific fasting management

Maximum fasting duration in clinically well individuals derives from fasting test data and consensus. Derks and colleagues compiled 35 tests: up to age one, median safe duration was 12 hours (8–19) and unsafe duration 18 hours (15–20); after the first year, medians were 18 hours (10–24) and 20 hours (13–32), with substantial overlap, and symptoms preceded hypoglycaemia in 6 of 35 tests [65]. Nyhan and colleagues rarely observed hypoglycaemia before 16–18 hours during controlled tests outside crises, and Morris and Spiekerkoetter state that healthy children older than one year tolerate 12–14 hours [6, 18]. These tolerances do not apply during intercurrent illness, particularly with fever [65].

Table 7.1 — Recommended maximum fasting intervals in asymptomatic, clinically well individuals

When overnight coverage is required, a bedtime meal, night feeding or uncooked cornstarch is used: GeneReviews specifies 2 g/kg, while Nyhan and colleagues start at 0.5 g/kg (one tablespoon ≈ 8 g), progressing to 1.0 g/kg, and used 2.0 g/kg in a vulnerable infant [2, 6]. This supplement may be unnecessary in a child without intercurrent illness [2]. The French PNDS accepts uncooked cornstarch from 12 to 24 months of age, to avoid overnight enteral feeding or to extend the daytime fasting interval, provided that digestive tolerance and severity allow, but requires its effect to be assessed in hospital, with measurement of free fatty acids, lactate and acylcarnitines, rather than relying merely on the absence of hypoglycaemia [10]. For β-oxidation defects as a whole, the same document proposes a general table distinguishing recommended and maximum duration (newborn 3 and 4 hours; 1–6 months 4 and 6–8 hours; 6–12 months 4 hours by day and 6–8 hours at night, with a night-time maximum of 10–12 hours; 1–6 years 4 hours by day and 10 hours at night, maximum 12 hours; over 6 years 4 hours by day and 12 hours at night, maximum 14 hours), to be adjusted case by case by the specialist team; the MCAD-specific values appear in the example emergency regimen in the annex and are those reproduced in Table 7.1 [10].

7.3 Maintenance diet

Breast milk or standard infant formulas meet infant requirements, and breastfeeding should continue [2, 18]. Thereafter, a normal healthy diet with no more than 30% of energy from fat is recommended; specific fat restriction is unnecessary, and additional calories should be avoided because of obesity risk [2, 18]. Avoid infant formulas, coconut oil and manufactured foods in which medium-chain triglycerides are the main fat source (small amounts are not contraindicated), ketogenic or high-fat, low-carbohydrate diets, fasting weight-loss diets and skipped meals [2, 18]. MCT and triheptanoin are contraindicated in MCAD deficiency because medium-chain fatty acids cannot be oxidised [16, 18]. Prolonged or intense exercise should be supported with adequate carbohydrate and hydration [2].

The French PNDS frames the same rules as explicit contraindications in MCAD deficiency: all MCT supplements, infant formulas with a high MCT content (in particular preterm formulas, extensively hydrolysed protein formulas and anti-diarrhoeal formulas), coconut and its derivatives (coconut milk, oil and fat, or copra) and triheptanoin [10]. For β-oxidation defects as a whole, the document recommends a normal energy intake for age, with at least 50–55% of energy as carbohydrate, preferably complex, and 20–35% as fat; in MCAD deficiency, quantitative fat restriction is unnecessary, and dietary assessment may be informal [10]. Physical activity should not be started in the fasting state: complex carbohydrates are advised before exercise and sugary foods or drinks during prolonged exertion [10]. In overweight patients, any weight-loss diet or bariatric surgery may be dangerous and should not be decided without prior advice from the specialist centre [10].

7.4 Home emergency regimen (mild illness)

For mild illness (fever below 38.5 °C, tolerated enteral feeding without recurrent vomiting or diarrhoea, and no neurological signs), home treatment may be attempted for up to 12 hours, using oral or tube-fed carbohydrate, reassessment approximately every 2 hours, antipyretics (paracetamol, ibuprofen) and occasionally antiemetics [2]. Parents or the local hospital should contact the metabolic centre if temperature exceeds 38.5 °C, vomiting, diarrhoea or other intercurrent illness symptoms develop, or new neurological signs appear [2]. The British regimen uses glucose polymer solutions at age-dependent concentrations, given every 2 hours, day and night, for a maximum of 24–36 hours, with normal feeding reintroduced as soon as possible (Table 7.2); oral rehydration solutions are unsuitable because of their low carbohydrate content [16].

Table 7.2 — Oral emergency regimen (BIMDG) [16, 55, 66]

The French PNDS proposes an example emergency regimen specific to MCAD deficiency, given every 3 hours, which assigns to each age the maximum fasting duration when well, the carbohydrate concentration and the volumes per feed and per day (Table 7.2b) [10]. At home, during intercurrent illness, the family gives a sugar solution in divided doses every 3 hours (glucose-enriched oral rehydration solution or dextrin-maltose in water) and continues it if it is well tolerated and there is no vomiting; the emergency certificate simplifies the composition to 10% glucose before age 2 and 20% after age 2, with a daily volume covering basal requirements, and stipulates that the hospital protocol should be started if this fails [10]. The emergency regimen should be normocaloric, high in carbohydrate and low in fat and, when the oral route is not possible, may be given by continuous enteral feeding, at a glucose delivery rate sufficient to block lipolysis (at least 10 mg/kg/min in infants and down to 5 mg/kg/min in adolescents and adults) [10].

Table 7.2b — Example emergency regimen for MCAD deficiency (PNDS HAS/Filière G2M, 2021) [10]

7.5 Hospital emergency protocol

Persistent vomiting, insufficient intake, drowsiness, altered consciousness or moderate to severe dehydration requires hospital treatment with intravenous glucose; intravenous access should be established whenever there is doubt [2, 16]. The patient is triaged as a priority, and treatment should begin without waiting for hypoglycaemia [16]. The aim is to provide sufficient glucose to stimulate insulin secretion and suppress lipolysis [18].

Table 7.3 — Hospital emergency protocol (synthesis of sources)

The BIMDG paediatric and adult protocols do not define a maximum volume for glucose and 0.9% NaCl boluses or a maximum infusion rate; the child column applies to the paediatric protocol and the adult column to the adult protocol, and the initial rate of 5 mL/kg/h in children should be replaced by a deficit-plus-maintenance calculation as soon as possible [16, 55].

Nyhan and colleagues warn that starting 5% glucose is insufficient, having observed symptomatic hypoglycaemia under those circumstances [6]. Saudubray's emergency chapter recommends, for fatty acid oxidation defects generally, glucose at 10–12 mg/kg/min (120–150 mL/kg/day of a 12–15% solution), preferably with insulin, an initially fat-free diet, and deferral of any MCT until the precise defect is known, because MCT benefits only long-chain defects [19]. For a newborn with a family history who becomes drowsy or ill, British protocols specify transfer to the neonatal unit, a 2 mL/kg bolus of 10% glucose and 10% glucose infusion at 100 mL/kg/day, increased over three days to 150 mL/kg/day if there is no oral intake [51]. The 2021 American Academy of Pediatrics clinical report reinforces the attending paediatrician's role in applying these principles early during common childhood illnesses [20].

The French PNDS and the Filière G2M emergency certificate for MCAD deficiency, annexed to the PNDS, define a specific protocol (Table 7.3b) [10]. The patient is a priority and should not wait in the waiting room; the infusion is started without waiting for results and without waiting for signs of decompensation. The glucose bolus, given intravenously, intraosseously or, in the absence of venous access, orally or enterally, is repeated every 5 to 10 minutes until blood glucose normalises, and is graded by age in the general PNDS text: 10% glucose 2 mL/kg in newborns and infants; 10% glucose 2–3 mL/kg or 30% glucose 10 mL per 20 kg body weight in children; 30% glucose 10–30 mL in older children and adults; the text does not set a maximum cumulative volume for repeated boluses [10]. Normalisation of blood glucose does not in itself correct the other abnormalities and should be followed by a continuous infusion at a glucose delivery rate above basal requirements, 120–200% of normal intake for age: 10–12 mg/kg/min in newborns and young children, 6–8 mg/kg/min in older children and 3–4 mg/kg/min in adolescents and adults; a more concentrated solution via a central line is useful when heart failure requires fluid restriction [10]. To prevent hyperglycaemia, the rate may be increased over a few hours starting from approximately two thirds of the target, and if hyperglycaemia develops, insulin should be added rather than reducing the glucose delivery rate; normalisation of lactate is a good marker of recovery of energy metabolism [10]. In severe forms, echocardiography and electrocardiography should be performed at the outset, and fat-free enteral feeding (also protein-free if there is significant hyperammonaemia) should replace the infusion as soon as digestive tolerance and haemodynamic status allow [10].

In moderate hyperammonaemia (less than 2–3 times the upper limit), acute and well tolerated, abundant glucose intake and removal of fat are usually sufficient to normalise it [10]. In more severe hyperammonaemia, the PNDS refers to the management of urea cycle disorders: a high-carbohydrate fat-free diet, temporary exclusion of protein for 24–48 hours and ammonia scavengers, such as sodium benzoate (loading dose of 250 mg/kg over 90–120 minutes, maximum 6 g, followed by 250–500 mg/kg/day as a continuous infusion, or 5.5 g/m²/day above 20 kg, maximum 12 g/24 h, according to the table taken from the PNDS for urea cycle disorders) or oral sodium phenylbutyrate at the same doses (maximum 12 g/24 h), with carglumic acid (Carbaglu®; 100 mg/kg as a loading dose and then 100–250 mg/kg/day in 4 oral doses, with no maximum dose defined in the source) as an alternative and extracorporeal clearance reserved for signs of severity or lack of response [10]. The MCAD emergency certificate is more specific: with ammonia above 150 µmol/L in children or 100 µmol/L in adults, the measurement is repeated and, without waiting for the result, continuous intravenous sodium benzoate is started (or oral or by tube if there is no venous access) at 250 mg/kg over 2 hours (maximum 8 g), followed by 250 mg/kg/24 h (maximum 12 g/24 h); each gram of benzoate contains 7 mEq of sodium; the certificate's ceiling for the loading dose (8 g) is higher than that in the general PNDS table (6 g), an internal inconsistency in the document [10]. Hepatocellular failure, when present, is secondary and usually reverses quickly, and may require fresh frozen plasma or albumin, but not liver transplantation [10].

Table 7.3b — Filière G2M emergency certificate “MCAD deficiency” (annex to the 2021 PNDS) [10]

The general PNDS text, written for β-oxidation defects with multi-organ failure, proposes starting insulin at 0.2 IU/kg/h and maintaining blood glucose between 1 and 1.5 g/L, whereas the MCAD certificate starts at 0.01 IU/kg/h, accepts 1–1.8 g/L and sets no maximum insulin dose, instructing that glucose intake be reduced by 20–25% if hyperglycaemia persists at 0.05 IU/kg/h; the difference reflects distinct populations (neonatal multi-organ failure versus the usual decompensation of MCAD deficiency), and the certificate is the disease-specific document [10].

7.6 Pharmacological treatment

Table 7.4 — Drugs used or studied in MCAD deficiency

GeneReviews (September 2024 version) cites NCT06067802 for both glycerol phenylbutyrate and triheptanoin; in ClinicalTrials.gov, accessed 4 October 2026, this identifier corresponds to a phase II triheptanoin study marked "withdrawn" because funding was withdrawn (as was NCT07097311), and the phase II sodium phenylbutyrate study NCT06069375 (≥10 years) is suspended "pending completion of another study"; that study, NCT06773026, has recruited patients aged 4 or older since 30 June 2025 (24 planned), has treatment-related adverse events at 5 weeks as its primary outcome, and anticipates primary completion in January 2027 [2, 71]. Non-drug physiological studies are also registered, including a high-intensity exercise pilot in 8 children and adolescents (NCT06796530, completed March 2026, no published results) and a study of medium-chain fatty acid metabolic effects in adults (NCT06623032, recruiting) [74]. None of these therapies should be offered outside a clinical trial. Carnitine remains controversial: Nyhan and colleagues support supplementation for detoxification and the improved ketogenesis observed in a fasting test, whereas Dutch cohort data show no benefit, and Saudubray considers its value unproven in defects other than carnitine transporter deficiency [6, 18, 39]. In the south-western European series, 82% of patients required carnitine to maintain normal concentrations, for longer in c.985A>G homozygotes (31 versus 18 months), and GeneReviews notes that these patients may require higher doses [2, 57].

7.7 Agents and circumstances to avoid

Avoid hypoglycaemia and prolonged fasting, formulas and foods with MCT as the main fat source, coconut oil, high-fat, low-carbohydrate diets, alcohol (particularly acute intoxication, which frequently triggers decompensation) and acetylsalicylic acid, which increases mitochondrial fatty acid oxidation and long-chain fatty acid flux and inhibits peroxisomal oxidation [2, 53, 75]. The French emergency certificate adds valproic acid to the prohibitions, asks that corticosteroid therapy lasting more than 3 days be carefully considered (without precluding hydrocortisone when needed in resuscitation), recommends all vaccinations, with emphasis on influenza vaccination, contraindicates prolonged fasting without glucose supply by infusion or continuous enteral feeding, recalls the need for vitamins and trace elements during exclusive parenteral nutrition, and asks that, on any admission or emergency attendance, patients bring their usual treatments and the products needed to prepare the emergency regimen [10]. The PNDS also advises against smoking, asks that fever be actively treated and that patients always carry a written emergency protocol with the contact details of the follow-up centre [10].

7.8 Surgery, procedures and special circumstances

The metabolic centre should be notified in advance of any surgery or procedure, including dental procedures, to plan perioperative fluid and nutritional management with surgeons and anaesthetists; any procedure requiring several hours of fasting should be covered with intravenous glucose [2]. Recommendations include flagging the diagnosis in the electronic medical record, providing written school protocols and contacting a specialist centre at the destination before travel [2]. Transition to adult care should be planned and multidisciplinary [2]. Affected women should avoid catabolism during pregnancy and delivery [2].

The French PNDS sets out detailed guidance on general anaesthesia, which it regards as an at-risk situation to be prepared jointly by the anaesthetic team and the specialist centre [10]. Preoperative fasting should be limited and covered by a continuous glucose infusion providing at least basal requirements (6–8 mg/kg/min in children and approximately 2.2 mg/kg/min in adults), or more if fasting is prolonged; because it is preventive, this infusion may be below the rates used during decompensation. In practice, it proposes 10% glucose with electrolytes at 100–150 mL/kg/day from birth to 6 years, 80–120 mL/kg/day in older children and 2.5–4 L/day in adolescents and adults (or 1–1.5 L/day of 30% glucose in adults), replaced by oral intake as soon as possible, and prefers adding insulin to reducing the rate if hyperglycaemia develops [10]. Regarding drugs, propofol, whose excipient is a lipid emulsion, should be avoided or used only as a bolus at induction; etomidate should be avoided (it contains, depending on the formulation, propylene glycol or a lipid emulsion); ketamine at anaesthetic doses should be avoided, because it stimulates the sympathetic nervous system and endogenous catecholamines; halogenated agents, thiopental, midazolam and opioids can be used safely [10]. Depolarising neuromuscular blockers may raise CK and confound monitoring for postoperative decompensation, whereas non-depolarising agents are used with neuromuscular monitoring; no specific complications have been described with opioids, non-steroidal anti-inflammatory drugs, paracetamol or local and regional anaesthesia. Premedication, prevention of hypothermia and multimodal analgesia reduce perioperative stress [10].

In pregnancy, the PNDS recommends prior planning and closer monitoring in the first trimester, when nausea and vomiting increase the risk of decompensation, continuous intravenous glucose during labour with subsequent transition to the oral route, repeated laboratory monitoring in the immediate postpartum period, a period of particular risk (including rhabdomyolysis), and high caloric intake during breastfeeding; these recommendations are formulated for β-oxidation defects as a whole [10]. Children attend their usual school, with an individualised care plan covering the diet and emergency management during school hours, with no mandatory contraindication to school sport [10]. Transition to adult services should be anticipated and prepared early, promoting the adolescent's autonomy; because adult specialists in these diseases are few, patients may need to travel, and the Filière G2M has published its own transition recommendations [10].

7.9 Evidence of strategy effectiveness

In Australia, among 2,495,000 newborns (810,000 screened), three screened patients had a severe episode before age four (including one neonatal death), compared with 23 unscreened patients (including five deaths); the relative risk of an adverse event by age two was 0.26 (95% CI 0.07–0.97) [31]. After diagnosis, death risk is very low at any age with good management, and a Utah series reported no irreversible complications after diagnosis [41, 76]. Among the 97 survivors in Iafolla and colleagues' series, there were no deaths during a mean 2.6-year follow-up after diagnosis [6, 12].

Table 7.5 — Studies supporting principal management decisions

These studies measure different outcomes and should not be directly compared. Screening benefit rests on non-randomised birth cohort comparisons with few events, wide confidence intervals and a conservative estimate that did not reach statistical significance; relative reduction coexists with residual absolute risk concentrated in the first days of life before notification [13, 31]. Fasting limits derive from medians of individual tests with substantial overlap between "safe" and "unsafe" durations and cannot be applied during febrile intercurrent illness [65]. The absence of demonstrated carnitine benefit comes from observational data subject to confounding by indication and does not exclude benefit in subgroups with very low carnitine [39]. Phenylbutyrate trials primarily assess safety rather than prevention of decompensation; the only completed trial (phase I, 4 adults) published no efficacy results, and both triheptanoin studies were withdrawn before enrolling patients because of funding loss [71].

7.10 Regulatory status of drugs used or studied

No drug is specifically authorised for MCAD deficiency in the United States or European Union; management relies on nutritional measures and the emergency protocol, and the drugs discussed are authorised for other indications or remain experimental [2, 69, 77]. The evidence hierarchy should be explicit: management recommendations draw on peer-reviewed cohorts and series and consensus documents (GeneReviews, BIMDG, AAP and French consensus); phenylbutyrate and triheptanoin studies exist only as trial registrations without published results; and no authority has issued an opinion or authorisation decision for this indication [2, 16, 20, 21, 71]. Marketing authorisation alone does not guarantee reimbursement or access in each country.

Table 7.6 — Regulatory status (accessed 4 October 2026)

The distinction between evidence extrapolation and off-label use is particularly clear. Oral levocarnitine is the same drug on both sides of the Atlantic, but chronic use in MCADD falls outside the US label and within European national SmPC indications that include secondary deficiency; prescribing it extrapolates from pathophysiological and observational evidence, whereas "on-label" or "off-label" status depends on the SmPC wording, age and jurisdiction [69, 79]. Phenylbutyrate and triheptanoin, authorised for other diseases, have no MCADD indication in any jurisdiction and should be administered only in clinical trials [71].

7.11 Divergences between the French PNDS and other guidelines

The PNDS of the HAS and the Filière G2M (June 2021), which updates the 2012 French consensus, is the French national guideline for MCAD deficiency; its recommendations broadly coincide with those of GeneReviews, the BIMDG and the American Academy of Pediatrics (fasting prevention, a written emergency regimen, intravenous glucose without waiting for hypoglycaemia, contraindication of MCT and triheptanoin), but diverge on several specific figures (Table 7.7) [2, 10, 16, 20, 21]. For doses, the guideline is the reference and the label serves as a comparison: for oral levocarnitine, the PNDS and GeneReviews agree on the range (20–50 and 25–50 mg/kg/day), both below the doses in the Portuguese and American labels, and the PNDS adds an indication threshold (free carnitine ≤12 µmol/L) that GeneReviews does not set [2, 10, 68, 69]. In France, levocarnitine is marketed as Levocarnil® (solution for injection, 1 g/5 mL; oral solution, 1 g/10 mL; the injectable form can be given orally, bearing in mind that it is twice as concentrated) [10].

Table 7.7 — Divergences between the French PNDS (2021) and the other sources cited

7.12 Therapeutic education

Therapeutic education, in the sense used by the French PNDS, is a multidisciplinary programme, delivered mainly in hospitals by teams specialising in inherited metabolic diseases, with individual and group sessions for the patient and family [10]. It aims to ensure that they understand the disease, the treatments (benefits, risks and adverse effects) and the preventive measures, that they can recognise the first signs of decompensation and initiate the first measures at home in agreement with the specialist, and that they take part in decisions. It begins with the parents and progressively includes the child, with tools adapted to age and level of understanding, seeks to reinforce adherence particularly in adolescence, and covers the lived experience of the disease, personal plans, preparation for pregnancy and psychosocial support [10]. The general practitioner has a defined role: to confirm that the patient and family have understood the disease and its treatment, that the patient always carries the written emergency protocol and that they adhere to treatment and follow-up, to monitor growth, development and vaccination, to manage common illnesses according to the centre's instructions and to contact the centre in case of doubt [10].

8. Reproductive Options and Family Counselling

At conception, a patient's siblings have a 25% probability of being affected, a 50% probability of being asymptomatic carriers and a 25% probability of being neither affected nor carriers [2]. Because genotype–phenotype correlation is unclear and individuals with biallelic variants may remain asymptomatic into adulthood, all apparently healthy siblings, older or younger, should be tested, using targeted molecular testing if the familial variants are known or plasma acylcarnitines and urinary acylglycines if not [2]. A patient's children are obligate heterozygotes but, given the high population carrier frequency, should also be tested, and carrier testing should be discussed with the reproductive partner [2]. Nyhan and colleagues described a family in which the proband's father, homozygous for c.985A>G, had experienced two hypoglycaemic episodes in childhood and subsequently avoided fasting, illustrating pseudodominant transmission in populations with high carrier frequency [6]. Biochemical tests (acylcarnitines, organic acids and acylglycines) do not identify carriers [2]. The French PNDS asks that the diagnosis be disclosed at a dedicated appointment, by a physician with good knowledge of the disease, if possible with both parents and with a psychologist and, where appropriate, a dietitian present, in two stages: first, explanation of the suspected diagnosis and the life-threatening risk; then, once the disease is confirmed, the complications, the follow-up plan and the therapeutic options; this appointment should offer genetic counselling for future pregnancies and family testing, and genetic counselling after molecular confirmation should take place at a separate appointment [10]. For couples at risk, the PNDS accepts prenatal diagnosis and preimplantation genetic testing in selected cases [10].

The ACMG includes MCAD deficiency among conditions for which carrier screening should be offered to all pregnant women and those planning pregnancy, and National Society of Genetic Counselors guidelines favour sequencing over targeted variant testing [2, 81]. Once both familial variants are identified, prenatal diagnosis through chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis are possible; all fatty acid oxidation enzymes are expressed in chorionic villi and amniocytes, also permitting enzyme-based diagnosis [2, 18]. Regardless of the prenatal option, immediate postnatal testing (newborn screening, plasma acylcarnitines and urinary acylglycines) with biochemical genetics consultation is indicated, and genetic risk and reproductive options are ideally discussed before pregnancy [2].

For newborns at familial risk, perinatal protocols recommend informing the responsible paediatrician when the mother is admitted in labour, ensuring feeding at least every 4 hours (3 hours for premature infants) from birth, supplementing breastfeeding with formula during the first 72 hours, and collecting acylcarnitines, urinary organic acids and targeted molecular tests between 24 and 48 hours of life; cord blood is unreliable because of maternal contamination risk [51, 82]. With effective feeding, neonatal decompensation risk after 72 hours is very low, and discharge before results is possible if feeding is assured [51]. Detection of maternal MCAD deficiency through the child's screening requires counselling for the mother, who may be unaware of her condition [50]. Following a child's sudden death, retrieval of the screening card permits retrospective diagnosis and family counselling [2, 6].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Global prevalence and the effect of screening

Among almost 8.2 million newborns screened by MS/MS across several countries, pooled incidence was 1:14,600 (95% CI 1:13,500–1:15,900), two to three times higher than clinically identified incidence in the same populations [7]. Orphanet reports a worldwide point prevalence of 6.85 per 100,000 [1]. Screening identifies more cases than predicted from c.985A>G frequency because MS/MS detects mild biochemical phenotypes and rare genotypes [2, 30]. In Australia, frequency was 5.2 per 100,000 in screened populations versus 2.28 per 100,000 in unscreened populations, with some unscreened cases presumed undiagnosed [31].

Table 9.1 — Birth prevalence by region (newborn screening data)

9.2 Founder effect and carrier frequency

The c.985A>G variant descends from a north-western European founder: Gregersen and colleagues found 100% association with an intragenic haplotype in 17 families, a heterozygote frequency of 1:84 in the White North Carolina population (5 to 10 times higher than in non-White Americans), 1:68 to 1:101 in United Kingdom and Danish newborns, and 1:333 in Italy [29]. Lazarin and colleagues' empirical study, reproduced in the Oxford Desk Reference, placed MCAD deficiency among the ten recessive conditions with the highest carrier frequencies in north-western Europe, at 1:73.5 (95% CI 1:62–1:90) in 12,915 individuals [11, 87]. Before screening, approximately 80% of symptomatic patients were c.985A>G homozygotes; in screened populations, homozygotes constitute 47–80% of cases [7, 30].

9.3 Portugal and the Portuguese Roma population

Portugal has one of the highest recorded MCAD deficiency prevalences (1:8,380), explained by more than 90% of Portuguese patients belonging to the Roma community, which has a high degree of consanguinity [9]. Expanded MS/MS newborn screening was introduced in 2004 at the national laboratory of the Instituto Nacional de Saúde Doutor Ricardo Jorge, with 99.8% national coverage, including Madeira and the Azores; 316,243 newborns were screened in the first four years, with diagnostic sensitivity of 100% for the screened disease groups [32]. In the south-western European multicentre series (Portugal and Spain), 75% of 45 patients were c.985A>G homozygotes, free carnitine at diagnosis was lower in homozygotes, 82% required carnitine during a mean 43-month follow-up, and both deaths and all three recorded metabolic crises occurred in homozygotes [57]. These data suggest that most Portuguese cases have the genotype associated with the highest C8 values and greatest neonatal symptom risk [2, 57].

9.4 Other populations with founder variants or distinct spectra

Japan's first patient was identified only in 2000; in a series of 18 symptomatic children and 50 newborns with elevated C8, the most prevalent variant was c.449_452delCTGA, followed by c.50G>A, c.1085G>A, c.157C>T and c.843A>T, together accounting for approximately 60% of alleles, without c.985A>G [35]. The same deletion predominates in Taiwan and Korea [2]. Pennsylvania Mennonite communities have the founder variant c.287-30A>G, and c.199T>C is common in Europeans and Lancaster County Amish [2]. Californian data show that deficiency may be as prevalent in Native Americans as in northern Europe [2, 8].

9.5 Regional data gaps

Indexed literature yielded no MCAD-specific population birth prevalence data from newborn screening for Brazil, most Latin American countries or sub-Saharan Africa; these gaps are reported rather than filled by extrapolation. For the Indian subcontinent, only the genetic estimate in Table 9.1 is available, and a series of 21 patients at an Indian centre reported overall mortality of 19%, with a distinct variant spectrum [86]. In Brazil, c.985A>G genotyping in 1722 individuals found 0.41% heterozygotes (allele frequency 0.0020) and no homozygotes, an estimate of this variant's carrier frequency in a laboratory sample rather than disease prevalence [88]; in selective screening of 7268 patients with suspected inborn errors, assessed through acylcarnitines at Hospital de Clínicas de Porto Alegre between 2008 and 2016, multiple acyl-CoA dehydrogenase deficiency was the most common oxidation defect and MCAD deficiency unusually rare, describing a referral series rather than population frequency [89]. In north-eastern Mexico, the state screening programme published only the combined fatty acid oxidation defect frequency (1:10,693), without specifying MCAD deficiency [84]. In Brazil, Law No. 14.154 of 26 May 2021 provides for phased expansion of heel-prick screening in the Sistema Único de Saúde, including fatty acid β-oxidation disorders in phase 2, but published prevalence data from implementation were not identified [33]. Published estimates of c.985A>G frequency in the general Portuguese Roma population were also not found, only the proportion of patients from this community [9].

9.6 Special populations

Exclusively breastfed newborns in the first 72 hours, outpatient deliveries and early discharges constitute the highest-risk groups before screening results [13, 18]. Adults born before screening implementation, particularly in countries that introduced it late, remain at risk of a fatal first manifestation, with alcohol and surgery as triggers [53]. Pregnant women with MCAD deficiency and women whose condition is revealed by their child's screening require specific surveillance [2, 50].

9.7 Reference networks and patient organisations

In the European Union, MCAD deficiency falls within the European Reference Network for inherited metabolic disorders (MetabERN), in the carbohydrate, fatty acid oxidation and ketone body disorders subgroup (C-FAO), comprising healthcare providers designated by participating Member States [22]. Patient and family organisations offering specific information include the FOD Family Support Group in the United States and Metabolic Support UK in the United Kingdom; in Brazil, Instituto Vidas Raras supports patients with rare diseases generally [90–92]. Personalised emergency letters can be generated in several languages at www.emergencyprotocol.net [93]. At a 2023 international meeting of families, adult patients and professionals, participants agreed on the value of emergency letters but differed about provision of sick-day protocols and home glucose meters, demonstrating variation in practice between centres [94].

In France, the organisation of care is based on the Filière de santé G2M (inherited metabolic diseases), based at the Hôpital Necker-Enfants Malades (AP-HP, Paris), which maintains the up-to-date list of reference and competence centres, the emergency certificates for MCAD deficiency and for long-chain defects, an “MCAD toolkit” (list of foods and formulas containing MCT and a post-screening algorithm) and the list of laboratories performing functional studies [10]. Follow-up is organised by a reference or competence centre, in liaison with the general practitioner and the hospital in the area of residence, and patients are exempt from co-payment, with 100% coverage of disease-related healthcare costs, under the ALD 17 long-term condition scheme; the Caisse d'allocations familiales (CAF) and the Maison départementale des personnes handicapées (MDPH) may grant additional support, with guidance from a social worker [10]. There is no patient association in France specific to β-oxidation defects; the PNDS directs families to the No Myolyse association (https://www.nomyolyse.com) and to the Alliance Maladies Rares (https://www.alliance-maladies-rares.org) [10]. French newborn screening for MCAD deficiency began on 1 December 2020, and the HAS assessment of 3 February 2020 recommended extending it to LCHAD deficiency and primary carnitine deficiency [10].

10. Illustrative Clinical Case

10.1 Published case 1 — neonatal presentation with ventricular tachycardia (Bala and colleagues, 2016)

A newborn girl presented on the second day of life with poor feeding and lethargy. She was hypotonic, with glucose of 1.8 mmol/L and ammonia of 182 µmol/L. Despite correction of these abnormalities and continuous glucose infusion at 4.5–6.2 mg/kg/min, she developed generalised tonic–clonic seizures on the third day and two episodes of pulseless ventricular tachycardia, from which she was resuscitated; she died on the fifth day following a third episode [40]. MCAD deficiency was diagnosed, and the authors' literature review identified this as the sixth report of ventricular tachyarrhythmia in the disease, five in neonates, including three with normal glucose at arrhythmia onset despite many hours of intravenous glucose [40].

This case illustrates three clinical points. First, the vulnerability window in the first 72 hours precedes screening results, and poor feeding with lethargy in a term newborn should prompt suspicion of an inborn fatty acid oxidation defect [13, 18]. Second, the glucose rate used (4.5–6.2 mg/kg/min) was below that recommended to suppress lipolysis in a suspected fatty acid oxidation defect (10–12 mg/kg/min) [2, 19]. Third, arrhythmias may result from direct metabolite toxicity and occur with normal glucose, supporting continuous cardiac monitoring of a decompensating newborn [40].

10.2 Published case 2 — adult presentation with coma and severe arrhythmias (Feillet and colleagues, 2003)

A 33-year-old man attended the emergency department with headache and vomiting. Shortly after admission, he became drowsy and agitated, developed ventricular tachycardia and deteriorated neurologically to a Glasgow Coma Scale score of 6. Tests showed respiratory alkalosis, lactate of 8 mmol/L, ammonia of 390 µmol/L and glucose of 2.4 mmol/L. Supraventricular tachycardia, ventricular tachycardia and ventricular fibrillation with cardiac arrest followed, with successful resuscitation; brain computed tomography showed cerebral oedema, and he developed renal failure and rhabdomyolysis in intensive care [49]. Metabolic abnormalities normalised within 48 hours with intravenous glucose. Urinary organic acids and plasma acylcarnitines were consistent with MCAD deficiency, and molecular testing revealed c.985A>G homozygosity [49].

The case demonstrates that homozygosity for the founder variant may remain silent for three decades and first manifest as a life-threatening illness, and that, in adults, hyperammonaemia, hypoglycaemia and ventricular arrhythmia without a structural cardiac cause should prompt acylcarnitine and organic acid sampling [49, 53]. After an adult diagnosis, sibling and child testing is essential because genotype–phenotype correlation is absent and population carrier frequency is high [2].

10.3 Published case 3 — severe neonatal ketoacidosis before screening results (Kamarus Jaman and colleagues, 2026)

An exclusively breastfed term newborn was brought to the emergency department on day four for poor feeding and discharged with breastfeeding support; on day five, he was lethargic, with glucose of 1.7 mmol/L, poor perfusion, pH 6.9, base excess −31 mmol/L, lactate 1.3 mmol/L and ammonia 140 µmol/L [52]. He was intubated and developed refractory ventricular tachycardia with deteriorating left ventricular function in paediatric intensive care, requiring extracorporeal membrane oxygenation for 3 days [52]. Organic aciduria or a ketolysis defect was initially suspected; urinary organic acids showed massive ketonuria with dicarboxylic aciduria, suberylglycine and traces of hexanoylglycine, and dried blood spot acylcarnitines showed C8 of 8.4 µmol/L and C8/C10 of 6.2; newborn screening, collected on day five as standard in the United Kingdom, was also positive, and molecular testing showed c.985A>G homozygosity [52]. Cardiac function normalised and no further decompensation occurred, but the child developed a tic disorder, seizures controlled with levetiracetam and autism spectrum disorder, attending mainstream education at age 15 [52]. A second newborn, compound heterozygous for c.985A>G/c.1055A>G p.(Tyr352Cys), presented on day four with ketonaemia of 6.5 mmol/L, pH 7.1 and glucose of 2.6 mmol/L, and recovered without apparent deficits [52]. Biochemical data for both patients appear in Table 1 of the original article (https://pmc.ncbi.nlm.nih.gov/articles/PMC13456951/), which has no figures.

The case shows that ketones, even at markedly elevated levels, do not exclude neonatal MCAD deficiency, and that ketoacidosis with normal lactate and moderate hyperammonaemia in a breastfed newborn should prompt immediate acylcarnitine testing without waiting for screening [18, 52]. The authors emphasise that this is a report of two patients from one centre and that the presentation is unusual; it does not change the classical definition of hypoketotic hypoglycaemia, but extends the differential diagnosis [52].

10.4 Teaching commentary on the current post-screening pathway

In a screening system, the expected pathway for a c.985A>G homozygous newborn comprises notification of elevated C8 and C8/C10, same-day family contact, an in-person appointment with provision of an emergency regimen and emergency letter, confirmation through plasma acylcarnitines, organic acids and molecular testing, and follow-up with age-specific fasting prevention and early intervention during each intercurrent illness [2, 60]. Australian and German experience shows that deaths along this pathway are almost entirely confined to the first days of life before notification [13, 31].

11. Prognosis and Long-Term Follow-up

11.1 Prognosis

Before screening, 18% to 25% of individuals died during their first crisis; in the Netherlands, acute presentation before diagnosis had 22% mortality (25/114), and 21% (19/89) of survivors had disabilities [2, 12, 44]. Wilcken's review found a death risk of approximately 4% in the first 72 hours, with additional case fatality of 5–7% in the first six years and very low risk thereafter in undiagnosed patients; following encephalopathy, approximately 7% of survivors have neuropsychological deficits [18, 76]. Mortality in adults presenting acutely reaches 50% [53].

With screening, neonatal mortality fell to 0.6–2.4%: in Germany, 0.6% overall (6 of 968 cases) and approximately 1.3% in c.985A>G homozygotes, compared with 2.4% in the screened Australian cohort and 7.5% in the unscreened cohort (Mütze and colleagues' Table 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC9110443/table/Tab3/) [13]. In the Netherlands, 13 of 189 identified newborns had neonatal symptoms and three died [58]. Following diagnosis and with good management, the risk of death is very low at any age, and development is usually normal in prospectively treated patients, with no cognitive differences detected between screened and surviving unscreened patients in Australian neuropsychological assessment [2, 31, 76]. Fatigue, myalgia, exercise intolerance and overweight are the most frequent chronic complaints [44]. The French PNDS considers that, once the diagnosis has been made and treatment maintained, the prognosis of MCAD deficiency is excellent and without specific long-term complications, and places mortality of the undiagnosed presenting episode between approximately 10% and 25%, with neurological sequelae in 5–20% of survivors; none of these estimates derives from a French cohort of its own, being syntheses of the Dutch, North American and German cohorts [10, 44]. The same document acknowledges that there are few studies of quality of life in β-oxidation defects and that follow-up frequency is an expert recommendation, to be adapted case by case [10].

11.2 Follow-up

Table 11.1 — Follow-up plan

12. Summary and Final Considerations

MCAD deficiency is the most common mitochondrial fatty acid oxidation defect, caused by biallelic ACADM variants, with the founder variant c.985A>G p.(Lys329Glu) predominating in populations of northern European origin and, in Portugal, in the Roma population, accounting for one of the highest reported prevalences [2, 9]. Its pathophysiology reflects inability to use medium-chain fatty acids when glycogen is depleted, resulting in hypoketotic hypoglycaemia, accumulation of medium-chain acylcarnitines and dicarboxylic acids, secondary carnitine deficiency and risk of encephalopathy, arrhythmia and sudden death, even with normal blood glucose [18, 40].

MS/MS newborn screening, based on C8 and C8/C10 and C8/C2 ratios, has sensitivity and specificity approaching 100% and has demonstrably reduced mortality and severe episodes; residual risk is concentrated in the first 72 hours before results are notified, supporting early sampling, rapid communication, attention to feeding in breastfed newborns and metabolic autopsy protocols after unexpected neonatal death [13, 31, 58]. Treatment relies on straightforward measures (age-specific fasting limits, a normal diet without MCT as the principal fat source, avoidance of excessive alcohol and acetylsalicylic acid) and a written emergency protocol, with early oral glucose and intravenous 10% glucose without waiting for hypoglycaemia [2, 16]. Carnitine supplementation remains controversial and phenylbutyrate therapies are under investigation [39, 71]. The absence of genotype–phenotype correlation requires all affected individuals, including those with mild biochemical phenotypes and undiagnosed adults identified through family studies, to be treated as at risk throughout life [2, 53].

13. References

1. Orphanet. Medium chain acyl-CoA dehydrogenase deficiency (ORPHA:42) [Internet]. Paris: INSERM; 2026 [accessed 2026 Oct 3]. Available at: https://www.orpha.net/en/disease/detail/42. Epidemiological data: Orphadata, en_product9_prev.xml (https://www.orphadata.com) and ICD mapping via https://api.orphacode.org.
2. Chang IJ, Lam C, Vockley J. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2000 Apr 20 [updated 2024 Sep 26]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1424/. PMID: 20301597.
3. Online Mendelian Inheritance in Man (OMIM). #201450 Acyl-CoA dehydrogenase, medium-chain, deficiency of (ACADMD); *607008 Acyl-CoA dehydrogenase, medium-chain (ACADM) [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 3]. Available at: https://omim.org/entry/201450.
4. National Center for Biotechnology Information. Gene ID: 34, ACADM acyl-CoA dehydrogenase medium chain [Homo sapiens]; and UniProt Consortium. UniProtKB P11310 (ACADM_HUMAN) [Internet]. [accessed 2026 Oct 3]. Available at: https://www.ncbi.nlm.nih.gov/gene/34 and https://www.uniprot.org/uniprotkb/P11310.
5. National Center for Biotechnology Information. ClinVar [Internet]. Bethesda (MD): National Library of Medicine. NM_000016.6(ACADM):c.985A>G (p.Lys329Glu), VCV000003586; NM_000016.6(ACADM):c.199T>C (p.Tyr67His), VCV000003597; NM_000016.6 as the MANE Select transcript (NCBI Gene ID 34, annotation RS_2025_08) [accessed 2026 Oct 4]. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/3586/.
6. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Chapter 39, Medium-chain acyl CoA dehydrogenase deficiency; p. 296–303.
7. Rhead WJ. Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):370-7. doi:10.1007/s10545-006-0292-1. PMID: 16763904.
8. Feuchtbaum L, Carter J, Dowray S, Currier RJ, Lorey F. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet Med. 2012 Nov;14(11):937-45. doi:10.1038/gim.2012.76. PMID: 22766612.
9. Rocha H, Castiñeiras D, Delgado C, Egea J, Yahyaoui R, González Y, et al. Birth Prevalence of Fatty Acid β-Oxidation Disorders in Iberia. JIMD Rep. 2014;16:89-94. doi:10.1007/8904_2014_324. PMID: 25012579.
10. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Déficit en MCAD (acyl-CoA déshydrogénase des acides gras à chaîne moyenne) et autres déficits de la β-oxydation mitochondriale des acides gras. Saint-Denis La Plaine: HAS; 2021 Oct 14 [text dated June 2021; Filière de santé maladies rares G2M, coordinated by F. Labarthe, CHU de Tours]. Available at: https://www.has-sante.fr/jcms/p_3289772
11. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Appendix, Table A8 (Top ten most common carrier frequencies by population); p. 811–812.
12. Iafolla AK, Thompson RJ Jr, Roe CR. Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children. J Pediatr. 1994 Mar;124(3):409-15. doi:10.1016/s0022-3476(94)70363-9. PMID: 8120710.
13. Mütze U, Nennstiel U, Odenwald B, Haase C, Ceglarek U, Janzen N, et al. Sudden neonatal death in individuals with medium-chain acyl-coenzyme A dehydrogenase deficiency: limit of newborn screening. Eur J Pediatr. 2022 Jun;181(6):2415-2422. doi:10.1007/s00431-022-04421-y. PMID: 35294644.
14. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Neonatal (newborn) screening; p. 762.
15. ClinGen Actionability Working Group. Gene-condition actionability report AC1016: ACADM — Medium-chain acyl coenzyme A dehydrogenase deficiency (paediatric context, v1.0.3, and adult context, v1.0.0; assertion: Strong Actionability; released 2023 Oct 16) [Internet]. Available at: https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC1016 and https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC1016.
16. British Inherited Metabolic Disease Group (BIMDG). Medium chain acyl CoA dehydrogenase deficiency (MCADD) – acute illness/decompensation: emergency protocol, v5 [Internet]. BIMDG; 2008 [revised July 2021]. Available at: https://bimdg.org.uk/wp-content/uploads/2024/11/ER-MCADD-v5_232766_05042017.pdf.
17. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Chapter 34, Introduction to disorders of fatty acid oxidation; p. 265–270.
18. Morris AAM, Spiekerkoetter U. Disorders of Mitochondrial Fatty Acid Oxidation & Riboflavin Metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 12, section 12.1; p. 287–301. doi:10.1007/978-3-662-63123-2_12.
19. Schiff M, Mochel F, Dionisi-Vici C. Emergency Treatments. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 4; p. 167–176. doi:10.1007/978-3-662-63123-2_4.
20. McGregor TL, Berry SA, Dipple KM, Hamid R, COUNCIL ON GENETICS. Management Principles for Acute Illness in Patients With Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. Pediatrics. 2021 Jan;147(1):e2020040303. doi:10.1542/peds.2020-040303. PMID: 33372121.
21. Feillet F, Ogier H, Cheillan D, Aquaviva C, Labarthe F, Baruteau J, et al. [Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management]. Arch Pediatr. French. 2012 Feb;19(2):184-93. doi:10.1016/j.arcped.2011.10.025. PMID: 22244319.
22. MetabERN — European Reference Network for Hereditary Metabolic Disorders. Subnetwork C-FAO (carbohydrate, fatty acid oxidation and ketone bodies disorders) [Internet]. [accessed 2026 Oct 4]. Available at: https://metab.ern-net.eu/.
23. Kølvraa S, Gregersen N, Christensen E, Hobolth N. In vitro fibroblast studies in a patient with C6-C10-dicarboxylic aciduria: evidence for a defect in general acyl-CoA dehydrogenase. Clin Chim Acta. 1982 Nov 24;126(1):53-67. doi:10.1016/0009-8981(82)90361-8. PMID: 7172449.
24. Rhead WJ, Amendt BA, Fritchman KS, Felts SJ. Dicarboxylic aciduria: deficient [1-14C]octanoate oxidation and medium-chain acyl-CoA dehydrogenase in fibroblasts. Science. 1983 Jul 1;221(4605):73-5. doi:10.1126/science.6857268. PMID: 6857268.
25. Stanley CA, Hale DE, Coates PM, Hall CL, Corkey BE, Yang W, et al. Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. Pediatr Res. 1983 Nov;17(11):877-84. doi:10.1203/00006450-198311000-00008. PMID: 6646897.
26. Matsubara Y, Narisawa K, Miyabayashi S, Tada K, Coates PM, Bachmann C, et al. Identification of a common mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency. Biochem Biophys Res Commun. 1990 Aug 31;171(1):498-505. doi:10.1016/0006-291x(90)91421-n. PMID: 2393404.
27. Yokota I, Indo Y, Coates PM, Tanaka K. Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency. An A to G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation. J Clin Invest. 1990 Sep;86(3):1000-3. doi:10.1172/JCI114761. PMID: 2394825.
28. Kelly DP, Whelan AJ, Ogden ML, Alpers R, Zhang ZF, Bellus G, et al. Molecular characterization of inherited medium-chain acyl-CoA dehydrogenase deficiency. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9236-40. doi:10.1073/pnas.87.23.9236. PMID: 2251268.
29. Gregersen N, Winter V, Curtis D, Deufel T, Mack M, Hendrickx J, et al. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe. Hum Hered. 1993 Nov-Dec;43(6):342-50. doi:10.1159/000154157. PMID: 7904584.
30. Andresen BS, Dobrowolski SF, O'Reilly L, Muenzer J, McCandless SE, Frazier DM, et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001 Jun;68(6):1408-18. doi:10.1086/320602. PMID: 11349232.
31. Wilcken B, Haas M, Joy P, Wiley V, Chaplin M, Black C, et al. Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet. 2007 Jan 6;369(9555):37-42. doi:10.1016/S0140-6736(07)60029-4. PMID: 17208640.
32. Vilarinho L, Rocha H, Sousa C, Marcão A, Fonseca H, Bogas M, et al. Four years of expanded newborn screening in Portugal with tandem mass spectrometry. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S133-8. doi:10.1007/s10545-010-9048-z. PMID: 20177789.
33. Brasil. Lei n.º 14.154, de 26 de maio de 2021. Altera a Lei n.º 8.069/1990 (Estatuto da Criança e do Adolescente) para aperfeiçoar o Programa Nacional de Triagem Neonatal. Diário Oficial da União. 2021 May 27. Available at: https://www.planalto.gov.br/ccivil_03/_ato2019-2022/2021/lei/l14154.htm.
34. Gramer G, Haege G, Fang-Hoffmann J, Hoffmann GF, Bartram CR, Hinderhofer K, et al. Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening. JIMD Rep. 2015;23:101-12. doi:10.1007/8904_2015_439. PMID: 25940036.
35. Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, et al. Screening of MCAD deficiency in Japan: 16years' experience of enzymatic and genetic evaluation. Mol Genet Metab. 2016 Dec;119(4):322-328. doi:10.1016/j.ymgme.2016.10.007. PMID: 27856190.
36. Grünert SC, Wehrle A, Villavicencio-Lorini P, Lausch E, Vetter B, Schwab KO, et al. Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening. BMC Med Genet. 2015 Jul 30;16:56. doi:10.1186/s12881-015-0199-5. PMID: 26223887.
37. Lovera C, Porta F, Caciotti A, Catarzi S, Cassanello M, Caruso U, et al. Sudden unexpected infant death (SUDI) in a newborn due to medium chain acyl CoA dehydrogenase (MCAD) deficiency with an unusual severe genotype. Ital J Pediatr. 2012 Oct 24;38:59. doi:10.1186/1824-7288-38-59. PMID: 23095120.
38. Saudubray JM, García-Cazorla Á. Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, sections 1.4.1 and 1.4.13; p. 3–123. doi:10.1007/978-3-662-63123-2_1.
39. Jager EA, Schaafsma M, van der Klauw MM, Heiner-Fokkema MR, Derks TGJ. Plasma carnitine concentrations in Medium-chain acyl-CoA dehydrogenase deficiency: lessons from an observational cohort study. J Inherit Metab Dis. 2022 Nov;45(6):1118-1129. doi:10.1002/jimd.12537. PMID: 35778950.
40. Bala P, Ferdinandusse S, Olpin SE, Chetcuti P, Morris AA. Recurrent Ventricular Tachycardia in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. JIMD Rep. 2016;27:11-5. doi:10.1007/8904_2015_463. PMID: 26404458.
41. Anderson DR, Viau K, Botto LD, Pasquali M, Longo N. Clinical and biochemical outcomes of patients with medium-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2020 Jan;129(1):13-19. doi:10.1016/j.ymgme.2019.11.006. PMID: 31836396.
42. Bentler K, Zhai S, Elsbecker SA, Arnold GL, Burton BK, Vockley J, et al. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative. Mol Genet Metab. 2016 Sep;119(1-2):75-82. doi:10.1016/j.ymgme.2016.07.002. PMID: 27477829.
43. Touw CM, Smit GP, de Vries M, de Klerk JB, Bosch AM, Visser G, et al. Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: data from a cohort study. Orphanet J Rare Dis. 2012 May 25;7:30. doi:10.1186/1750-1172-7-30. PMID: 22630369.
44. Derks TG, Reijngoud DJ, Waterham HR, Gerver WJ, van den Berg MP, Sauer PJ, et al. The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome. J Pediatr. 2006 May;148(5):665-670. doi:10.1016/j.jpeds.2005.12.028. PMID: 16737882.
45. Mochel F, Sedel F. Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 2, section 2.3.1, Table 2.3; p. 125–145. doi:10.1007/978-3-662-63123-2_2.
46. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Cardiomyopathy in children under 10 years; p. 84–86.
47. Wiles JR, Leslie N, Knilans TK, Akinbi H. Prolonged QTc interval in association with medium-chain acyl-coenzyme A dehydrogenase deficiency. Pediatrics. 2014 Jun;133(6):e1781-6. doi:10.1542/peds.2013-1105. PMID: 24799540.
48. Yusuf K, Jirapradittha J, Amin HJ, Yu W, Hasan SU. Neonatal ventricular tachyarrhythmias in medium chain acyl-CoA dehydrogenase deficiency. Neonatology. 2010;98(3):260-4. doi:10.1159/000295713. PMID: 20414003.
49. Feillet F, Steinmann G, Vianey-Saban C, de Chillou C, Sadoul N, Lefebvre E, et al. Adult presentation of MCAD deficiency revealed by coma and severe arrythmias. Intensive Care Med. 2003 Sep;29(9):1594-7. doi:10.1007/s00134-003-1871-3. PMID: 12897989.
50. Leydiker KB, Neidich JA, Lorey F, Barr EM, Puckett RL, Lobo RM, et al. Maternal medium-chain acyl-CoA dehydrogenase deficiency identified by newborn screening. Mol Genet Metab. 2011 May;103(1):92-5. doi:10.1016/j.ymgme.2011.01.011. PMID: 21354840.
51. British Inherited Metabolic Disease Group (BIMDG). MCAD deficiency: management of newborn babies with a family history [Internet]. BIMDG; 2015 [revised May 2023]. Available at: https://bimdg.org.uk/wp-content/uploads/2024/11/MCADD_Dietary_BIMDG_babies_2015v0_7_742847_13052015.pdf.
52. Kamarus Jaman N, Bernhardt I, Ward S, Hassall F, Nurse J, Lemonde H, et al. Medium Chain Acyl-CoA Dehydrogenase Deficiency; an Unexpected Cause of Neonatal Ketoacidosis. JIMD Rep. 2026;67(5):e70118. doi:10.1002/jmd2.70118. PMID: 42578122. PMCID: PMC13456951.
53. Lang TF. Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD). J Inherit Metab Dis. 2009 Dec;32(6):675-683. doi:10.1007/s10545-009-1202-0. PMID: 19821147.
54. Douillard C, Mention K, Dobbelaere D, Wemeau JL, Saudubray JM, Vantyghem MC. Hypoglycaemia related to inherited metabolic diseases in adults. Orphanet J Rare Dis. 2012 May 15;7:26. doi:10.1186/1750-1172-7-26. PMID: 22587661.
55. British Inherited Metabolic Disease Group (BIMDG). Adult emergency management: medium chain fat oxidation disorders (MCAD deficiency, HMG-CoA synthase deficiency, CPT1 deficiency). Revision 2018 [Internet]. Available at: https://bimdg.org.uk/wp-content/uploads/2024/11/ADULT_MCAD-rev_2015_566641_09012016.pdf.
56. Boles RG, Buck EA, Blitzer MG, Platt MS, Cowan TM, Martin SK, et al. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr. 1998 Jun;132(6):924-33. doi:10.1016/s0022-3476(98)70385-3. PMID: 9627580.
57. Couce ML, Sánchez-Pintos P, Diogo L, Leão-Teles E, Martins E, Santos H, et al. Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency. Orphanet J Rare Dis. 2013 Jul 10;8:102. doi:10.1186/1750-1172-8-102. PMID: 23842438.
58. Jager EA, Kuijpers MM, Bosch AM, Mulder MF, Gozalbo ER, Visser G, et al. A nationwide retrospective observational study of population newborn screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the Netherlands. J Inherit Metab Dis. 2019 Sep;42(5):890-897. doi:10.1002/jimd.12102. PMID: 31012112.
59. Snyder MT, Divin K, Liu N, Sun Q, Wang Y, Luo X, et al. Effective algorithm to differentiate NBS MCADD cases from carriers and non-carriers and an assessment of the utility of the second newborn screen for MCADD. Mol Genet Metab. 2025;145(4):109183. doi:10.1016/j.ymgme.2025.109183. PMID: 40660651.
60. British Inherited Metabolic Disease Group (BIMDG), NHS Newborn Blood Spot Screening Programme. MCADD clinical management guidelines (presumptive positive MCADD) [Internet]. 2017. Available at: https://bimdg.org.uk/wp-content/uploads/2024/10/MCADD_clinical_management_guidelines_2017_294592_14092017.pdf.
61. Touati G, Mochel F, Artuch R. Diagnostic Procedures. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 3, section 3.2; p. 147–166. doi:10.1007/978-3-662-63123-2_3.
62. Kaku N, Ihara K, Hirata Y, Yamada K, Lee S, Kanemasa H, et al. Diagnostic potential of stored dried blood spots for inborn errors of metabolism: a metabolic autopsy of medium-chain acyl-CoA dehydrogenase deficiency. J Clin Pathol. 2018 Oct;71(10):885-889. doi:10.1136/jclinpath-2017-204962. PMID: 29720407.
63. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. doi:10.1038/gim.2015.30. PMID: 25741868.
64. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Chapter 1, Introduction to the organic acidemias; p. 6.
65. Derks TG, van Spronsen FJ, Rake JP, van der Hilst CS, Span MM, Smit GP. Safe and unsafe duration of fasting for children with MCAD deficiency. Eur J Pediatr. 2007 Jan;166(1):5-11. doi:10.1007/s00431-006-0186-0. PMID: 16788829.
66. British Inherited Metabolic Disease Group (BIMDG). MCADD emergency regimen recipes – age up to 1 year (10% CHO solution) [Internet]. 2014. Available at: https://bimdg.org.uk/wp-content/uploads/2024/11/05112024_202248_MCADDRecipe_1Year_2014_421566_12052015.pdf.
67. Weiss KJ, Berger U, Haider M, Wagner M, Märtner EMC, Regenauer-Vandewiele S, et al. Free carnitine concentrations and biochemical parameters in medium-chain acyl-CoA dehydrogenase deficiency: Genotype-phenotype correlation. Clin Genet. 2023 Jun;103(6):644-654. doi:10.1111/cge.14316. PMID: 36840705.
68. Laboratório Medinfar — Produtos Farmacêuticos, S.A. Disocor 1000 mg/10 ml solução oral (levocarnitina): resumo das características do medicamento (approved by INFARMED on 29 Dec 2023) [Internet]. Lisbon: INFARMED, I.P. — Infomed. Available at: https://extranet.infarmed.pt/INFOMED-fo/ (accessed 26 Oct 2026).
69. Leadiant Biosciences, Inc. CARNITOR® (levocarnitine) tablets, oral solution and injection: prescribing information [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2023–2024 [accessed 2026 Oct 3]. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b2cbc620-59fd-47b6-9e4b-7e3e31533a1c (oral solution) and https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cf801cc4-775e-433d-9d32-e5d9a98981d3 (injection).
70. Kormanik K, Kang H, Cuebas D, Vockley J, Mohsen AW. Evidence for involvement of medium chain acyl-CoA dehydrogenase in the metabolism of phenylbutyrate. Mol Genet Metab. 2012 Dec;107(4):684-9. doi:10.1016/j.ymgme.2012.10.009. PMID: 23141465.
71. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine. NCT01881984 (Ravicti in patients with MCADD c.985A>G; phase I, completed); NCT06069375 and NCT06773026 (sodium phenylbutyrate ACER-001; phase II, suspended and recruiting); NCT06067802 and NCT07097311 (triheptanoin; phase II, withdrawn) [accessed 2026 Oct 3]. Available at: https://clinicaltrials.gov/study/NCT06773026.
72. Horizon Therapeutics USA, Inc. RAVICTI® (glycerol phenylbutyrate) oral liquid: prescribing information [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2025 [accessed 2026 Oct 3]. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=900e7dc0-9afe-4f50-80de-90567bb78519.
73. European Medicines Agency. Ravicti (glycerol phenylbutyrate): EPAR – medicine overview [Internet]. Amsterdam: EMA; [accessed 2026 Oct 3]. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/ravicti.
74. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine. NCT06796530 (Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Exercise; University Hospital, Ghent; completed) and NCT06623032 (Metabolic Effects of Medium-Chain Fatty Acids in Patients With MCADD; University of Copenhagen; recruiting) [accessed 2026 Oct 4]. Available at: https://clinicaltrials.gov/study/NCT06796530.
75. Uppala R, Dudiak B, Beck ME, Bharathi SS, Zhang Y, Stolz DB, et al. Aspirin increases mitochondrial fatty acid oxidation. Biochem Biophys Res Commun. 2017 Jan 8;482(2):346-351. doi:10.1016/j.bbrc.2016.11.066. PMID: 27856258.
76. Wilcken B. Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis. 2010 Oct;33(5):501-6. doi:10.1007/s10545-009-9001-1. PMID: 20049534.
77. European Medicines Agency. Medicines data (human medicines file: Ravicti, Ammonaps, Pheburane; no centralised authorisation for levocarnitine or triheptanoin) [Internet]. Amsterdam: EMA; updated 2026 [accessed 2026 Oct 4]. Available at: https://www.ema.europa.eu/en/documents/report/medicines-output-medicines_json-report_en.json.
78. U.S. Food and Drug Administration. Drugs@FDA: NDA 018948, 019257 and 020182 (Carnitor, levocarnitine); NDA 203284 (Ravicti, glycerol phenylbutyrate); NDA 020572 (Buphenyl, sodium phenylbutyrate); NDA 214860 (Olpruva, sodium phenylbutyrate); NDA 213687 (Dojolvi, triheptanoin) [Internet]. Silver Spring (MD): FDA; [accessed 2026 Oct 4]. Available at: https://api.fda.gov/drug/drugsfda.json.
79. Agencia Española de Medicamentos y Productos Sanitarios. CIMA: Carnicor 200 mg/mL solución inyectable (registration no. 55334) and Carnicor 100 mg/mL solución oral (registration no. 55500), summary of product characteristics, section 4.1 [Internet]. Madrid: AEMPS; [accessed 2026 Oct 4]. Available at: https://cima.aemps.es/cima/publico/detalle.html?nregistro=55334.
80. Acer Therapeutics Inc. OLPRUVA (sodium phenylbutyrate) for oral suspension: prescribing information [Internet]. DailyMed; 2024 Dec 20 [accessed 2026 Oct 4]. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=89abc31c-43e8-4809-9eb7-172cb31a86f1.
81. Gregg AR, Aarabi M, Klugman S, Leach NT, Bashford MT, Goldwaser T, et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021 Oct;23(10):1793-1806. doi:10.1038/s41436-021-01203-z. PMID: 34285390.
82. van Rijt WJ, Jager EA, van Spronsen FJ, de Koning T, Heiner-Fokkema MR, Derks TG. Neonates at risk of medium-chain acyl-CoA dehydrogenase deficiency: a perinatal protocol for use before population neonatal screening test results become available. Genet Med. 2016 Dec;18(12):1322-1323. doi:10.1038/gim.2016.149. PMID: 27657689.
83. Ruoppolo M, Cereda C, Giovanniello T, Malvagia S, Boenzi S, Teofoli F, et al. Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) Newborn Screening in Italy: Five Years' Experience from a Nationwide Program. Int J Neonatal Screen. 2025 Sep 26;11(4):86. doi:10.3390/ijns11040086. PMID: 41133698.
84. Torres-Sepúlveda MDR, Martínez de Villarreal LE, Villarreal-Pérez JZ, Ruiz Herrera MDC, Arredondo Vázquez PDC, Treviño-Morales AK. Outcome of Expanded Newborn Screening Among 194 000 Neonates at Northeast México. Glob Pediatr Health. 2024;11:2333794X241280830. doi:10.1177/2333794X241280830. PMID: 39315058.
85. Hu H, Ma Q, Huang Y, Song W, Xu H, Zhu P, et al. Prevalence and Mutation Analysis of Medium-Chain Acyl-CoA Dehydrogenase Deficiency Detected by Newborn Screening in Hefei, China. Int J Neonatal Screen. 2025;11(3):83. doi:10.3390/ijns11030083. PMID: 41002789.
86. Akella RRD, Kadali S, Naushad SM. Medium-chain acyl-CoA dehydrogenase deficiency: A ten-year single-center case series from India. Clin Chim Acta. 2026;594:121348. doi:10.1016/j.cca.2026.121348. PMID: 42749071.
87. Lazarin GA, Haque IS, Nazareth S, Iori K, Patterson AS, Jacobson JL, et al. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med. 2013 Mar;15(3):178-86. doi:10.1038/gim.2012.114. PMID: 22975760.
88. Ferreira AC, Orlandi MP, Oliveira VC, Malta FS, Caxito FA, Gomes KB, et al. A985G mutation incidence in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in Brazil. Genet Mol Res. 2009;8(2):487-93. doi:10.4238/vol8-2gmr579. PMID: 19551636.
89. Vargas CR, Ribas GS, da Silva JM, Sitta A, Deon M, de Moura Coelho D, et al. Selective Screening of Fatty Acids Oxidation Defects and Organic Acidemias by Liquid Chromatography/tandem Mass Spectrometry Acylcarnitine Analysis in Brazilian Patients. Arch Med Res. 2018;49(3):205-12. doi:10.1016/j.arcmed.2018.08.004. PMID: 30119976.
90. FOD Family Support Group. Fatty Acid Oxidation Disorders [Internet]. [accessed 2026 Oct 4]. Available at: https://www.fodsupport.org/.
91. Metabolic Support UK [Internet]. [accessed 2026 Oct 4]. Available at: https://www.metabolicsupportuk.org/.
92. Instituto Vidas Raras [Internet]. [accessed 2026 Oct 4]. Available at: https://www.vidasraras.org.br/.
93. Metabolic Emergency Protocol — Metabolic Emergency Letter [Internet]. [accessed 2026 Oct 4]. Available at: https://www.emergencyprotocol.net/.
94. Singh RH, Gurung SR, Kenneson A, Andersson HC. 2023 MCADD patient and family education summit with providers: meeting highlights, congruences and contradictions. Orphanet J Rare Dis. 2026;21(1):141. doi:10.1186/s13023-025-04117-0. PMID: 41957765.