Long-Chain Fatty Acid Beta-Oxidation and Carnitine Cycle Disorders

VLCAD deficiency (ACADVL), LCHAD and mitochondrial trifunctional protein deficiency (HADHA/HADHB), and primary carnitine deficiency (SLC22A5)

Literature and regulatory information updated: 4 October 2026.

0. Initial Reference Table

This article groups four entities that share the same pathophysiological logic (inability to oxidise long-chain fatty acids during fasting or exertion), the same screening tool (acylcarnitine profiling by tandem mass spectrometry) and most emergency measures. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency serves as a comparison wherever useful; carnitine palmitoyltransferase 1A and 2 (CPT1A, CPT2) and carnitine–acylcarnitine translocase (CACT) deficiencies appear here in the differential diagnosis, with a dedicated table in section 6.

Table sources: Orphanet and Orphadata [1]; OMIM [2]; GeneReviews [3–5]; Lindner et al. [6]; Lefèvre et al. [7]; Rasmussen et al. [8]; ClinGen [9]; HAS PNDS [10]; MetabERN [11].

1. Introduction

Fat is the body's main energy reserve. The myocardium preferentially uses fatty acids rather than glucose, skeletal muscle depends on them during sustained exercise, and most tissues obtain energy from mitochondrial beta-oxidation during prolonged fasting, sparing glucose for the brain; in addition to oxidising fatty acids, the liver converts acetyl-CoA into ketone bodies, allowing the brain to use energy derived from fat indirectly [12]. Inherited defects of this pathway have three characteristic presentations—acute hypoketotic hypoglycaemia with encephalopathy and hepatic dysfunction (“Reye-like syndrome”), cardiomyopathy (usually hypertrophic) with arrhythmias or conduction disturbances, and myopathy, presenting either as chronic weakness or acute rhabdomyolysis—which may coexist in the same patient depending on residual enzyme activity, age and exposure to stressors [12]. Long-chain defects and primary carnitine deficiency encompass all three presentations, whereas the predominant risk in MCAD deficiency is sudden hypoglycaemic death without cardiomyopathy [13].

The history of these disorders begins with carnitine. Carnitine deficiency was first described in 1973 [14], and in 1975 Karpati and colleagues described systemic carnitine deficiency syndrome, including its clinical, morphological and biochemical features [15]. In 1982, Waber, Valle and colleagues reported treatable familial cardiomyopathy due to carnitine deficiency, subsequently recognised as a transport defect [16]. In 1988, Treem, Stanley and colleagues demonstrated a defect of carnitine transport in the kidney, muscle and fibroblasts of a three-month-old girl with hypoglycaemic coma after prolonged overnight fasting [17, 18]; that same year, Lindstedt and colleagues documented the defect in the fibroblast membrane [18]. In 1999, Nezu and colleagues identified mutations in the sodium-dependent carnitine transporter gene OCTN2 (SLC22A5) as the cause of primary systemic carnitine deficiency [19].

The history of the long-chain defects is more recent. The field as we know it today dates from the discovery of MCAD deficiency in 1982 [20]. Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency was first reported in 1983 in a boy with repeated episodes of hypoketotic hypoglycaemia from nine months of age, hypotonia and cardiomyopathy, who progressed to massive hepatic necrosis and died at 19 months, with plasma accumulation of long-chain acylcarnitines and 3-hydroxydicarboxylic aciduria [21]. In 1989 Wanders and colleagues linked LCHAD deficiency to sudden infant death [22]. In 1992 the enzyme was recognised as a component of a trifunctional protein bound to the inner mitochondrial membrane, purified that year [21], and Wanders and colleagues described human deficiency of all three activities of the trifunctional protein as a new beta-oxidation disorder [23]. In 1996 IJlst and colleagues characterised the common G1528C variant (historical designation, = NM_000182.5:c.1528G>C p.(Glu510Gln)) and mapped the α-subunit gene to chromosome 2 [24]. In 1999 Ibdah and colleagues showed that a fetal fatty acid oxidation defect causes liver disease in heterozygous pregnant women, linking acute fatty liver of pregnancy and HELLP syndrome to LCHAD deficiency in the fetus [25].

Very-long-chain acyl-CoA dehydrogenase (VLCAD) was characterised in 1992 by Izai and colleagues as an inner mitochondrial membrane enzyme catalysing dehydrogenation of acyl-CoA esters containing 14 to 20 carbons [26]. Three independent reports of patients with VLCAD deficiency appeared in 1993, including those by Bertrand and colleagues in fibroblasts [27] and Aoyama and colleagues [28]; patients initially described as having long-chain acyl-CoA dehydrogenase (LCAD) deficiency were retrospectively found to have VLCAD deficiency [26]. In 1999, Andresen and colleagues established a clear genotype–phenotype correlation in this disorder, unlike MCAD deficiency [29].

The application of tandem mass spectrometry to expanded newborn screening from the late 1990s opened the whole population to the prevention of death and disability [20], but also brought the identification of numerous asymptomatic children, carriers and mothers with undiagnosed primary carnitine deficiency [6, 7]. The 2009 consensus recommendations [30, 31], the 2020 nutrition guideline for VLCAD deficiency [32] and the first international guideline for long-chain fatty acid oxidation disorders, published in September 2026 by a group of 34 experts using adapted GRADE methodology and Delphi consensus [33], form the basis of the recommendations in this article, together with the GeneReviews chapters [3–5]. The authors of the editorial commentary on the guideline stress that most recommendations rest on low-quality evidence and that controlled trials are lacking for most therapeutic decisions [11]. In France, the national diagnosis and care protocol (PNDS) of the Haute Autorité de Santé, drafted by the G2M health network and published in October 2021, covers all mitochondrial beta-oxidation and carnitine cycle defects, including the four entities in this article, and serves as the reference for the care protocol under long-term condition no. 17 (ALD 17) [10]; its recommendations, which predate the 2026 international guideline, are based on expert opinion, and the divergences between the two documents are gathered in section 7.16.

2. Molecular Genetics and Pathophysiology

2.1 The pathway: from carnitine transport to the beta-oxidation spiral

Fatty acids released by lipolysis enter cells and are activated to acyl-CoA. Long-chain fatty acids cannot cross the inner mitochondrial membrane as CoA esters: CPT1 on the outer membrane esterifies them to carnitine, CACT transports the acylcarnitine, and CPT2 in the matrix regenerates acyl-CoA and releases carnitine [18, 20]. Carnitine uptake by muscle, cardiac and renal cells requires the specific high-affinity transporter OCTN2, encoded by SLC22A5 [5, 18]. In the matrix, each turn of the beta-oxidation spiral shortens the chain by two carbons, releasing acetyl-CoA, NADH and FADH2. The first step is catalysed by acyl-CoA dehydrogenases with overlapping substrate specificities—SCAD (C4–C6), MCAD (C6–C10), LCAD (C10–C14) and VLCAD (C14–C20)—all dependent on flavin adenine dinucleotide and linked to the respiratory chain by electron transfer flavoprotein (ETF) and ETF dehydrogenase [3]. The next three steps for long chains (hydration, NAD-dependent dehydrogenation and thiolysis) are catalysed by mitochondrial trifunctional protein [4]. The resulting shorter chains are processed by matrix enzymes; in the liver, acetyl-CoA supports ketogenesis through HMG-CoA synthase and lyase [18].

When beta-oxidation is blocked, acyl-CoAs accumulate upstream of the defect, undergo transesterification to acylcarnitines (the basis of screening) and microsomal omega-oxidation, producing dicarboxylic acids; for medium-chain acids, which have low affinity for the microsomal system, dicarboxylic acids arise mainly from peroxisomal beta-oxidation of longer compounds [20].

The French PNDS classifies fatty acids by chain length into long (14 to 18 carbons), medium (more than 6 and fewer than 14) and short (6 or fewer), and notes that the diet supplies mainly long-chain fatty acids (the only medium-chain sources are coconut and MCT-enriched products, including some infant formulas) and that lipolysis supplies exclusively long-chain fatty acids; medium- and short-chain fatty acids cross membranes without a transporter. It distinguishes the primary defects of long-chain (CPT1, CACT, CPT2, VLCAD, LCHAD/TFP), medium-chain (MCAD) and short-chain (SCAD, SCHAD) oxidation from two separate entities: PCD, which causes a secondary defect of long-chain oxidation through lack of carnitine, and multiple acyl-CoA dehydrogenase deficiency, which impairs beta-oxidation of all chain lengths [10].

2.2 Shared metabolic consequences

Fasting hypoglycaemia is the classical disturbance, chiefly resulting from increased peripheral glucose consumption, although hepatic production may also be reduced; it is hypoketotic because ketone levels are lower than expected for the degree of hypoglycaemia or free fatty acid concentration [12]. A high free fatty acid/3-hydroxybutyrate ratio during illness is the biochemical signature of hypoketosis [20]. Hyperammonaemia in some severe defects, with normal or low glutamine, is attributed to reduced acetyl-CoA production and therefore reduced N-acetylglutamate, the physiological activator of carbamoyl phosphate synthetase 1; hyperuricaemia is common during crises; hyperlactataemia particularly characterises LCHAD and TFP deficiencies, owing to inhibition of steps in pyruvate metabolism by accumulated metabolites [12]. Accumulated long-chain acylcarnitines may cause arrhythmias and interfere with surfactant metabolism; in LCHAD and TFP deficiencies, long-chain 3-hydroxyacylcarnitine concentrations correlate with retinopathy severity and may contribute to retinopathy and peripheral neuropathy [12]. Insufficient energy supply causes compensatory changes with hypertrophy; profound energy deficiency may activate proapoptotic pathways, leading to cell death and replacement fibrosis [34]. Physiologically, fatty acid oxidation supplies up to 70% of ATP for cardiac contraction, and these defects account for approximately 25% of paediatric hypertrophic and dilated cardiomyopathies [34]. The editorial accompanying the 2026 guideline summarises recent research: pathophysiology extends beyond energy deficiency and metabolite toxicity to secondary alterations in the tricarboxylic acid cycle and respiratory chain, cardiolipin synthesis, peroxisome proliferator-activated receptor (PPAR) signalling and atypical inflammatory responses [11].

2.3 VLCAD deficiency (ACADVL)

VLCAD is loosely bound to the inner mitochondrial membrane and uses ETF as its electron acceptor. Its size, structure and location distinguish it from other acyl-CoA dehydrogenases: it is a 154 kDa dimer composed of 70 kDa subunits, does not react with anti-LCAD antibodies, has maximal activity with palmitoyl-CoA (C16) and has tenfold greater activity than LCAD [26]. Anti-VLCAD immunoreactivity is reduced by 66–75% in patient fibroblasts [26]. ACADVL comprises 20 exons at 17p13.1, and more than 150 pathogenic variants have been described across all exons [26]. Acyl-CoA dehydrogenase 9 (ACAD9), a VLCAD homologue and complex I assembly factor, produces the C14:1 acylcarnitine that accumulates in VLCAD deficiency [12]. The mechanism is loss of function, and ClinGen has published ACADVL expert panel specifications for applying ACMG/AMP variant interpretation rules (version 2.1.0) [3].

The genotype–phenotype correlation is robust. In the study by Andresen and colleagues, with 58 variants in 55 unrelated patients, the severe early-onset phenotype was associated with variants lacking residual activity and the mild phenotypes with variants compatible with residual activity [29]; about 81% of truncating variants are associated with the severe form [3]. The homozygous missense variant NM_000018.4:c.709T>C p.(Cys237Arg), with low oxidation flux, may be associated with cardiac disease, whereas the variant NM_000018.4:c.848T>C p.(Val283Ala), in the homozygous or compound heterozygous state, is typically associated with non-cardiac phenotypes and accounts for about 10–29% of pathogenic alleles [3]. In the North American series of 693 screen-positive newborns sequenced by Sanger, 94 pathogenic variants (40 novel) and 134 variants of uncertain significance were identified; the most frequent finding was carrier status (57% with a single pathogenic variant or variant of uncertain significance), and at least one p.Val283Ala allele was present in about 10% of positive cases, with a mild phenotype and good response to standard treatment, although hypoglycaemia may occur [35]. The p.Val283Ala variant is the most frequent in European patients and has been found only in mild or asymptomatic patients [12]. A variant NM_000018.4:c.1748C>G p.(Ser583Trp) showed that association of the mature protein with the inner membrane is required for activity, even though import is normal [26]. In a study of 37 patients, only one variant was found in seven despite sequencing of all exons, and the high frequency of cardiomyopathy in this group argues against inferring heterozygosity from a single variant [26].

2.4 LCHAD and trifunctional protein deficiencies (HADHA, HADHB)

Trifunctional protein is an octamer of four α subunits (encoded by HADHA) and four β subunits (encoded by HADHB), with both genes at 2p23.3. The α subunit has 2-enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase activities; the β subunit has long-chain 3-ketoacyl-CoA thiolase (LCKAT) activity [4, 21]. LCHAD has optimal activity with C12–C16 substrates, maximal activity with C16 and no activity with C4, and uses NAD as its hydrogen acceptor [21]. The α subunit also participates in cardiolipin remodelling, and trifunctional protein physically interacts with respiratory chain complex I, potentially explaining similarities to respiratory chain disorders (hyperlactataemia, cardiomyopathy, polyneuropathy, retinopathy) [4]. Hyperlactataemia may also result from inhibition of the pyruvate dehydrogenase complex by long-chain acyl-CoAs, changes in the NADH/NAD ratio or altered oxidative phosphorylation [21].

Isolated LCHAD deficiency, almost always due to specific HADHA variants, is distinguished from generalised TFP deficiency, due to variants in either subunit [12, 21]. The variant NM_000182.5:c.1528G>C p.(Glu510Gln), also designated E474Q in the historical numbering of the mature protein, lies in the coding region of the dehydrogenase, abolishes LCHAD activity and is present on about 87% of chromosomes from patients with LCHAD deficiency [21, 24]; in the largest cohort, 84 of 98 alleles carried this variant [4]. Homozygosity for c.1528G>C defines LCHAD deficiency; compound heterozygotes with another HADHA variant may have TFP deficiency, so in the absence of homozygosity the enzyme assay is needed to distinguish the two entities [4]. In HADHB, missense variants are associated with milder phenotypes than termination or frameshift variants; residue p.Arg28 (historical numbering of the mature protein, = p.Arg61 in NP_000174.1) appears critical, and variants altering it produce severe forms when combined with a severe variant on the other allele [4, 36]. About half of patients with HADHA variants have a severe or lethal phenotype, whereas 70% of patients with HADHB variants have a milder phenotype [4]. In the French cohort of 52 patients with TFP deficiency, most variants generated premature termination codons with nonsense-mediated messenger RNA decay, suggesting that both normal subunits are needed to stabilise the protein [21, 37]. Lethal disease due to uniparental disomy of chromosome 2 with homozygosity for a HADHA variant has been described, as has isolated LCKAT deficiency due to HADHB variants (published as c.185G>A p.(Arg62His) and c.1292T>C p.(Phe431Ser), historical numbering offset by one codon; = NM_000183.3:c.182G>A p.(Arg61His) and NM_000183.3:c.1289T>C p.(Phe430Ser)) in a newborn who died at six weeks [21]. In the 2026 guideline, HADHB variants located in the outer loops of the protein, with less impact on stability, are associated with mild disease, and severity correlates with reduction in thiolase antigen [33].

The pathophysiology of maternal liver disease remains unclear. One hypothesis attributes acute fatty liver and HELLP syndrome to transfer into the maternal circulation of long-chain 3-hydroxyacyl derivatives produced by the affected fetus and placenta; another proposes a role for relative hepatic insufficiency in the heterozygous mother [4, 33].

2.5 Primary carnitine deficiency (SLC22A5)

SLC22A5 comprises 10 exons spanning 26 kb at 5q31.1 and encodes OCTN2, a high-affinity 557-amino-acid transporter in the sodium-dependent organic cation transporter family [18]. OCTN2 is expressed in the kidney, heart, muscle and other tissues; deficiency causes urinary carnitine loss through impaired tubular reabsorption, low plasma concentrations and intracellular depletion, with secondary fatty acid oxidation impairment, hypoglycaemia from glucose consumption without replenishment, and fat accumulation in the liver, muscle and heart [5, 34]. Fractional free carnitine excretion approaches 100% of the filtered load and exceeds it after treatment withdrawal; in a patient with nearly absent plasma carnitine, an oral dose of 100 mg/kg raised plasma carnitine to only 21 µmol/L, with urinary excretion of 2911 µmol/g creatinine [18]. Muscle carnitine ranges from 0.05% to 17% of the normal mean, and hepatic carnitine is approximately 5%; treatment normalises hepatic carnitine, but muscle levels rise only to 22–80 nmol/g (normal 2500–3500), indicating that the defect affects muscle and kidney but not the liver, where uptake has different kinetic properties [18]. The jvs (juvenile visceral steatosis) mouse model reproduces steatosis, hypoglycaemia and hyperammonaemia, the latter due to reduced expression of urea cycle enzyme genes and corrected by carnitine [18].

No genotype–phenotype correlation has been established: nonsense and frameshift variants are more frequent in symptomatic patients and missense variants in asymptomatic ones, but severity depends mainly on the chance occurrence of intercurrent illness and fasting [5, 18]. Most families have private variants; some recurrent variants illustrate founder effects — an 11 bp deletion in Switzerland and northern Italy, NM_003060.4:c.505C>T p.(Arg169Trp) in Italy, NM_003060.4:c.760C>T p.(Arg254*) in Lebanon, and NM_003060.4:c.1400C>G p.(Ser467Cys) and the published protein designations p.(Trp132*), p.(Trp283Cys) and p.(Met179Leu) (NP_003051.1) in Japan [18]. The founder variant NM_003060.4:c.95A>G p.(Asn32Ser) explains the prevalence in the Faroe Islands [5, 8]. The 5′ untranslated region variant NM_003060.4:c.-149G>A creates an out-of-frame upstream initiation codon, reduces translation and transporter activity and was found in 57 of 236 individuals with an incomplete genetic diagnosis (allele frequency of 24.2% in the Dutch cohort), so sequencing should include the 5′ UTR [5, 38]. Heterozygotes may have reduced transport and plasma carnitine and benign cardiac hypertrophy; in a Japanese study, heterozygosity was associated with benign late-onset cardiac hypertrophy with an odds ratio of 15.1 [34, 39].

Carnitine deficiency may also be secondary: in beta-oxidation defects and organic acidaemias, acylcarnitines are preferentially excreted and competitively inhibit the transporter, and some patients initially classified as having primary deficiency actually had MCAD deficiency [12, 18]. No primary defect of carnitine biosynthesis from protein-bound lysine has been described [18].

2.6 Comparative overview

Sources: [3–5, 12, 33].

3. Clinical Spectrum and Manifestations by System

3.1 Overview of the group

In the Paris series of 107 patients with fatty acid oxidation defects assembled by Saudubray and colleagues in 1999, only 57 were alive at reporting; including 47 siblings who died in infancy or childhood, there were 97 deaths, 30% in the first week and 69% before one year of age [20]. Seventy-three per cent had hepatic presentations (hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome, microvesicular steatosis), 51% cardiac presentations (cardiomyopathy and arrhythmias), and 51% muscle involvement (myalgia, myopathy, rhabdomyolysis with myoglobinuria); true hepatic failure, present in 11%, occurred only in CACT and multiple acyl-CoA dehydrogenase deficiencies [20]. These figures reflect the era before screening and explain the priority given to fasting prevention. Today, increasing numbers of screen-detected individuals remain asymptomatic because their defects are mild or they have not encountered the necessary stressor [12].

Table sources: [3–5, 13, 18, 21, 26, 34]. LCHAD and TFP percentages represent frequencies before newborn screening [4].

3.2 VLCAD deficiency

VLCAD deficiency has three overlapping phenotypes whose distinction is useful because they correlate with residual enzyme activity [26, 29]. The severe early-onset cardiac and multiorgan form presents in the first months with hypertrophic or dilated cardiomyopathy, pericardial effusion and arrhythmias, hypotonia, hepatomegaly and intermittent hypoglycaemia [3]. Neonatal presentations include lethargy, tachypnoea, seizures and hypoglycaemia, sometimes metabolic acidosis or arrhythmia, followed by decompensation and evidence of hypertrophic heart disease [26]. In a series of 54 patients, approximately half presented severely in the first three days, with cardiomyopathy in 92%, hepatomegaly in 80% and early death in 80%; approximately 50% of patients died within two months of initial symptoms [26]. In six of 11 families, there were eight cases of sudden infant death or unexplained death [26]. Ventricular tachycardia, ventricular fibrillation and atrioventricular block have been described, and cardiac dysfunction may be reversible with early intensive care and dietary modification [3].

The hepatic or hypoglycaemic form develops in early childhood, usually during the first intercurrent illness, with hypoketotic hypoglycaemia and hepatomegaly resembling MCAD deficiency, but without cardiomyopathy; many patients or siblings were diagnosed with Reye syndrome, and ammonia, uric acid and creatine kinase (CK) rise during crises [3, 26]. A two-year-old patient with hypoglycaemia (1.7 mmol/L), encephalopathy and marked ketosis—which initially led to exclusion of the diagnosis—had CK of 5373 U/L; elevated tetradecenoylcarnitine led to the diagnosis [26]. Metabolic decompensations diminish with age, while muscle pain becomes predominant as physical activity increases [26].

The late-onset episodic myopathic form, probably the most frequent, presents with intermittent exercise-induced rhabdomyolysis, cramps or muscle pain and exercise intolerance, without hypoglycaemia during symptoms; diagnosis may be delayed until adulthood [3], resembling CPT2 deficiency [26]. Triggers include intense exercise, fasting, cold and fever [3]. One woman developed her first exercise-induced symptoms at 19 years, with markedly elevated CK [26].

Most newborns identified by screening are asymptomatic at diagnosis [3]. With early care, cognitive development is similar to that of the general population (developmental or intelligence quotient ≥85), although motor and language delays and cases of cardiomyopathy on an MCT diet have been described; screening prevents hypoglycaemia in patients with residual activity, but not hypoglycaemia or cardiac complications in those with very low residual activity [3]. The 2026 guideline reports that nine of 24 individuals asymptomatic at diagnosis later developed symptoms [33]. The French PNDS stresses that the three phenotypes form a continuum, that expression in the same patient may change with age, that residual enzyme activity appears to predict clinical severity, that some patients with the late-onset muscular form have cardiomyopathy and that moderate muscular symptoms have been described in heterozygotes [10].

3.3 LCHAD and trifunctional protein deficiencies

The two entities form a continuum: LCHAD deficiency typically presents with a severe to intermediate phenotype and TFP deficiency with a severe to mild phenotype [4]. In the series of 50 patients with LCHAD deficiency of den Boer and colleagues, the mean age at presentation was 5.8 months (1 day to 26 months), seven (15%) presented in the neonatal period, 39 (78%) with hypoketotic hypoglycaemia and 11 (22%) with chronic problems (failure to thrive, feeding difficulties, cholestatic liver disease or hypotonia); 82% of those who had an acute crisis had already shown non-specific chronic symptoms, and mortality was 38%, always before or within three months of diagnosis [40]. Episodes often begin at the end of the first year, with the first prolonged fast, usually due to intercurrent illness heralded by vomiting, and many patients were labelled as Reye syndrome [21]. In the French PNDS synthesis, based on the same series, the presenting hypoketotic hypoglycaemia was accompanied by hepatic dysfunction in 79%, coma in 56%, seizures in 38%, apnoeas in 23% and sudden death or arrhythmias in 9–21%, with mortality of 30–40% at diagnosis; about one patient in five presented with chronic manifestations only, and associated chronic symptoms included hepatomegaly (60%), hepatic dysfunction (80%), cholestasis (30%), feeding difficulties (55%), growth retardation (73%), hypotonia (64%), psychomotor delay with microcephaly (27%) and cardiomyopathy (36%). The PNDS also notes that preterm delivery, often induced by gestational steatosis, is more frequent than in the general population and that retinopathy develops in most patients but is rarely present at diagnosis [10, 40].

The severe neonatal form, more common in TFP deficiency, presents in the first days with a Reye-like syndrome—encephalopathy (lethargy, poor feeding, seizures, apnoea, coma), hypoketotic hypoglycaemia, hepatomegaly with steatosis and elevated transaminases, lactic acidosis and sometimes hyperammonaemia—and progressive dilated cardiomyopathy with arrhythmias and heart failure, carrying very high mortality [4]. In den Boer's TFP deficiency series, 42% had rapidly progressive deterioration, and eight of nine died of cardiac disease within two months [21, 41]. Among five Japanese patients with TFP deficiency, two presented in the first days with lactic acidaemia, hypoglycaemia and hyperammonaemia and died of cardiac arrest, two had hepatic presentations and rhabdomyolysis in late childhood, and one developed muscle pain, weakness and rhabdomyolysis at 15 years [21, 42].

The intermediate childhood (hepatic) form, the most common LCHAD deficiency presentation, consists of fasting- or infection-triggered decompensation with hypoketotic hypoglycaemia, lactic acidosis, elevated transaminases and CK, vomiting, lethargy and hepatomegaly, potentially preceded by muscle weakness, feeding difficulties and hypotonia; untreated patients develop dilated or hypertrophic cardiomyopathy, long QT, cirrhosis, cholestasis, developmental delay and poor weight gain [4]. Dilated cardiomyopathy may first appear during a crisis even in treated patients [4]. Electrocardiography may show sinus tachycardia, long QT or ventricular tachycardia, and echocardiography dilatation and poor contractility; pericardial effusion and tamponade have been described [21]. Cholestasis with impaired vitamin D 25-hydroxylation caused hypocalcaemia and a tonic–clonic seizure at two months, and several authors have described hypoparathyroidism [21].

The mild late-onset (neuromyopathic) form is typical of mild TFP deficiency and rare in LCHAD deficiency: weakness, exercise intolerance, hypotonia and episodic rhabdomyolysis triggered by prolonged exercise, cold, fasting or infection, with diffuse pain, profound weakness, myoglobinuria and CK above five times the upper limit [4]. CK may reach 15,000–165,000 IU/L, and patients may adopt a “frog-leg” position [21].

Peripheral neuropathy. This is a complication unique to these two deficiencies among the fatty acid oxidation disorders. In the study by Grünert and colleagues (8 patients with LCHAD deficiency and 11 with TFP deficiency), overall prevalence was 58%, slightly higher in TFP deficiency (70% versus 50%), with significantly earlier onset (median 4.7 versus 15.3 years); 45.5% had sensorimotor neuropathy, 27.3% pure motor and 27.3% pure sensory, and in four patients isolated neuropathy was the first and only manifestation, with falsely negative newborn screening [43]. Electrophysiology classifies it as axonal with secondary demyelination; in patients with fulminant acute onset the symptoms may be partially reversible, and early diagnosis and treatment do not prevent it in all cases [43]. The first sign is loss of the Achilles reflex, followed by sensory deficit and impaired heel walking; the upper limbs are spared until later [33]. Patients may toe-walk, with equinus deformity, and reflexes may be absent from childhood [21]. A phenotype of fever-associated periodic paralysis has been described in a thermosensitive TFP deficiency [33]. In the late-onset form of TFP deficiency, according to the PNDS, neuropathy affects more than half of patients, may be present at diagnosis or precede the other manifestations and progresses like Charcot-Marie-Tooth disease; in these mild adult forms the acylcarnitine profile may be normal outside crises, and patients with hypocalcaemia and hypoparathyroidism have been described [10].

Retinopathy. Much more frequent in LCHAD deficiency, it progresses through four stages: (1) normal fundus or diffuse hypopigmentation; (2) pigment accumulation in the fovea; (3) macular pallor and peripheral migration of pigmentary changes; (4) posterior pole atrophy with further peripheral migration [4, 44]. Visual loss begins at stage 3, so retinopathy may go undetected without fundus imaging and electroretinography; approximately half of patients with LCHAD deficiency have retinopathy by two years [4]. In a series of 28 children, granular pigmentation appeared between four months and five years; the two oldest survivors (16 and 31 years) had progressive chorioretinal atrophy, axial myopia, scotomas and posterior staphylomas, and all four long-term survivors had lens opacities [21]. In the Swedish cohort of 12 patients, over 80% developed abnormal or subnormal retinal function, more pronounced in those with neonatal symptoms and attenuated by strict dietary management [45].

Other manifestations. Hypoparathyroidism, neonatal respiratory distress syndrome and necrotising enterocolitis are rare [4]. Six of ten patients had anaemia and thrombocytopenia; intelligence is usually normal, but prolonged hypoglycaemia may cause cognitive impairment or epilepsy [21].

3.4 Maternal complications: acute fatty liver of pregnancy and HELLP syndrome

Heterozygous women carrying a fetus with LCHAD or TFP deficiency have a high risk of gestational liver disease, mainly HELLP syndrome (haemolysis, elevated liver enzymes and thrombocytopenia) and acute fatty liver of pregnancy (AFLP), estimated at 15–25% of these pregnancies [4, 12]. Ibdah and colleagues studied 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency: 19 had isolated LCHAD deficiency (8 homozygous for Glu474Gln (historical numbering, = NM_000182.5:c.1528G>C p.(Glu510Gln)) and 11 compound heterozygous with this variant), and 79% of the heterozygous mothers had acute fatty liver or HELLP syndrome during pregnancy; none of the five children with complete TFP deficiency carried the variant, and none of their mothers had liver disease [25]. Among women with acute fatty liver, 10–25% carry a fetus with LCHAD deficiency; in HELLP syndrome this proportion is below 1% [21]. The 2026 guideline cites a series with acute fatty liver in 49% and HELLP in 11% of pregnancies with affected fetuses and an Austrian series in which four of 14 infants with LCHAD deficiency were born to mothers with HELLP; conversely, heterozygosity for the common variant did not significantly increase the risk of HELLP in the Dutch population and was not found in 88 Austrian infants of mothers with HELLP [33]. The practical consequence is bidirectional: an obstetric emergency may reveal the disease in the newborn, and diagnosis in a child identifies a mother to be monitored in future pregnancies [4, 33]. The PNDS estimates that fetal LCHAD deficiency with the common variant accounts for more than 20% of the aetiologies of acute fatty liver of pregnancy, whereas the association is exceptional in the other beta-oxidation defects, although rare cases have been described in heterozygous mothers of fetuses with CPT1A deficiency [10].

3.5 Primary carnitine deficiency

Without treatment, the spectrum comprises five groups: (1) metabolic decompensation between three months and two years, with hypoketotic hypoglycaemia, feeding refusal, irritability, lethargy, hepatomegaly, elevated transaminases and hyperammonaemia, triggered by fasting or common illnesses (upper respiratory infection, gastroenteritis); (2) cardiac and skeletal myopathy between two and four years; (3) reduced exercise endurance or worsening arrhythmias during pregnancy; (4) adult fatigue; (5) absence of symptoms [5]. Approximately half of untreated patients have the infantile metabolic presentation, and the other half childhood myopathy, with dilated cardiomyopathy, hypotonia, weakness and elevated CK [5]. The first described patient presented at three months with coma and flaccidity after prolonged overnight fasting, arterial pH 7.17, blood glucose 0.39 mmol/L (7 mg/dL), cerebrospinal fluid glucose 0.2 mmol/L, ammonia 338 µmol/L and elevated transaminases; she sustained severe brain injury [18]. Absence of ketonuria and dicarboxylic aciduria, together with elevated uric acid and CK, guides diagnosis; misleading ketonuria may nevertheless appear at the height of hypoglycaemia [18].

Cardiomyopathy is the other classical presentation and may develop in any patient lacking diagnosis and treatment: it was the most frequent initial complaint in a series of 15 patients and was present in all of the first 20 described patients, with median cardiac onset at three years [18]. Echocardiography shows increased cardiac volume and left ventricular wall thickening, although cardiomyopathy has also been described as characteristically dilated [18]; approximately two-thirds of childhood cases have dilated or hypertrophic cardiomyopathy between one and four years, and electrocardiography may show short QT with peaked T waves [34]. The Oxford Desk Reference emphasises marked T-wave abnormalities and endocardial fibroelastosis, and the lifesaving effect of L-carnitine treatment [13]. Cardiomyopathy responds poorly to standard treatment and may be fatal without carnitine; PCD is associated with QT interval shortening and severe arrhythmias [5]. In nine patients, diagnostic delay was one to six years after initial symptoms, during which all developed cardiomyopathy [18]. Muscle weakness or hypotonia may also occur, sometimes in isolation, with lipid storage myopathy and, exceptionally, severe peripheral neuropathy [18].

In adults, PCD may manifest as potentially fatal events after an asymptomatic life, with arrhythmias and sudden death; in the Faroe Islands an odds ratio of 54.3 was estimated for the association between sudden death and untreated PCD [5]. In the structured review by Crefcoeur and colleagues (166 articles, 757 patients), 621 had a diagnosis confirmed genetically or functionally; in these, cardiac symptoms (mainly cardiomyopathy) were the most prevalent (23.8%), and neurological (7.1%), hepatic (8.4%) and metabolic (9.2%) symptoms occurred mainly in early childhood; 16 of 194 adults had symptom onset in adulthood and six (3.1%) suffered a serious event without any prior symptom (five cardiac, one coma) [14]. Many women were diagnosed after their child's newborn screening showed low carnitine: about half reported fatigue and the other half were asymptomatic, one had dilated cardiomyopathy and another arrhythmias [5, 46, 47]. Pregnancy increases energy consumption and lowers plasma carnitine, and may reveal or worsen the disease [5]. The PNDS places cardiomyopathy (dilated and/or hypertrophic, with heart failure and often muscle weakness) between six months and five to seven years of age, reports associated anaemia at any age and describes rhabdomyolysis, triggered by exertion or infection, as a possible presenting manifestation in adults, with muscle enzymes sometimes persistently raised outside crises; in adults, the disease may also present with ventricular arrhythmia, sometimes lethal, possibly preceded by short QT (more rarely long QT) and usually without underlying cardiomyopathy, and hypertrophic cardiomyopathy has exceptionally been described in heterozygous adults [10].

Diet contributes to clinical expression: the first patient had changed to carnitine-free soy formula four weeks earlier, a 12-year-old boy who died suddenly after surgery ate a predominantly vegetarian diet, and a newborn of a vegetarian mother died at five days [18]. Pivalate-containing antibiotics, whose pivalate is excreted conjugated to carnitine, may precipitate symptoms [12].

3.6 Rhabdomyolysis: a shared manifestation

Rhabdomyolysis occurs in VLCAD, LCHAD and TFP deficiencies and, less frequently, PCD. Triggers include prolonged or intense exercise, cold, fasting, fever and infections [3, 4]. CK above five times the upper reference limit suggests rhabdomyolysis (reported range 1000 to 100,000 IU/L), and admission CK above 15,000 IU/L increases acute kidney injury risk [4]. The 2026 guideline defines rhabdomyolysis as CK activity above 1000 U/L [33]. Pain may begin during or after exercise and extend to muscles that were not exercised; in moderate or severe episodes, myoglobinuria may cause acute renal failure requiring dialysis [12]. Recurrent rhabdomyolysis is a long-term problem in some patients with VLCAD deficiency, and no current treatment completely prevents it [12].

4. Clinical Recognition and Warning Signs

Recognition rests on five scenarios. The first is hypoketotic hypoglycaemia in an unwell infant or child: in a hypoglycaemic patient, absence of urinary ketones indicates hypoketosis, but ketonuria may be misleading, requiring measurement of free fatty acids and 3-hydroxybutyrate in blood collected during the episode [20]. Hyperuricaemia and elevated CK, rarely included in paediatric biochemistry panels, are warning signs for a fatty acid oxidation defect [20]. The second is Reye-like syndrome (hypoglycaemia, hepatomegaly, elevated transaminases and hyperammonaemia): most patients presenting with Reye syndrome today have a fatty acid oxidation defect, even when liver biopsy shows typical microvesicular steatosis [20]. The third is cardiomyopathy or arrhythmia in an infant, particularly with hypotonia, hepatomegaly or pericardial effusion; the Oxford Desk Reference includes plasma carnitine, dried blood spot acylcarnitine profiling, glucose, lactate, ammonia (elevated in carnitine deficiency and fatty acid oxidation defects) and lactate dehydrogenase, often markedly elevated in these defects, in the investigation of all childhood cardiomyopathies [13]. The fourth is exercise-induced rhabdomyolysis in adolescents or young adults, particularly if recurrent or associated with myoglobinuria, and peripheral neuropathy with pigmentary retinopathy, suggesting LCHAD or TFP deficiency [4, 33]. The fifth is sudden infant death or an acute life-threatening episode: fatty acid oxidation defects should be considered in these settings [33].

Table sources: [3–5, 13, 20, 33].

Children with LCHAD deficiency often have non-specific chronic symptoms before their first crisis (poor weight gain, feeding difficulties, cholestasis, hypotonia), requiring consideration of the diagnosis even without typical decompensation [40]. Late episodes are often preceded by leg pain [21]. In PCD, diagnostic delay is usual without screening, and the disease should be considered at any age when low plasma carnitine has no identified cause [5, 18].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Newborn screening

Screening for fatty acid oxidation disorders is performed by analysis of acylcarnitines and free carnitine in dried blood spots by tandem mass spectrometry; the target disorders vary between countries, and some screen only for MCAD deficiency [12]. Screening for long-chain defects is more sensitive when sampling occurs on the second or third day of life, during catabolism; because acylcarnitines may normalise later, an abnormal initial profile should be followed by enzymatic or genetic confirmation rather than by repeating the profile [12]. Screening may miss mild forms of CPT2, multiple dehydrogenase and TFP deficiencies, and for VLCAD deficiency and PCD there is a high false-positive rate [12]. In France, newborn screening for MCAD deficiency began on 1 December 2020, and the HAS opinion of 3 February 2020 recommended extending it to LCHAD deficiency and PCD; at the time of the PNDS (2021), the start date of these two screening programmes had not been set and their algorithms were being developed [10].

VLCAD. Screening quantifies C14:1, C14:2, C14 and C12:1 and the C14:1/C2 and C14:1/C16 ratios [3]. Although thresholds vary with age, method and laboratory, C14:1 above 1 µmol/L on the initial test strongly suggests disease and should be treated as such; values above 0.8 µmol/L suggest disease but also occur in carriers and healthy individuals [3]. C14:1/C2 may be more sensitive than C14:1 alone at the cost of overdiagnosis, and thresholds below 0.25 µmol/L generate false positives [26]. Marked weight loss on the sampling day may falsely elevate C14:1 and C14:1/C2; samples obtained after feeding or intravenous glucose may be normal [3]. Postanalytical tools from Region 4 Stork / CLIR (Collaborative Laboratory Integrated Reports) refine interpretation [3, 33]. A substantial proportion of positive screens represent carriers [3, 35].

LCHAD and TFP. Screening quantifies 3-hydroxypalmitoylcarnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH), with confirmation by plasma acylcarnitine profiling and urinary organic acids [4]. High endogenous long-chain acylcarnitine concentrations in erythrocytes make dried blood spots less reliable than plasma [21]. Four patients with isolated neuropathy as their sole manifestation had negative screening [43].

PCD. Free carnitine (C0) is measured in blood collected at 24–72 hours of life; a low value may identify an affected newborn, an affected mother (through placental carnitine transfer), or both [5]. Positive predictive value is low (4.7% in California), and results are influenced by maternal carnitine deficiency, prematurity, pivalate-containing antibiotics and other inherited metabolic disorders; New Zealand discontinued screening because of low sensitivity and positive predictive value [5]. In California between 2005 and 2012, review included 14 newborns with PCD, 14 maternal cases (PCD in six, glutaric aciduria type 1 in five, MCAD deficiency in two, cobalamin C in one) and 154 false positives; truly affected newborns could have C0 near the threshold and plasma carnitine near the lower limit during the first two weeks. Maternal total plasma carnitine and newborn total urinary carnitine were the best predictors, but without a discriminatory rule, making molecular testing essential [48]. In the Faroe Islands, a threshold of 5 µmol/L non-butylated C0 identified all c.95A>G homozygotes [8]. France introduced PCD screening in early 2023 with its own algorithm [7]. A positive screen requires assessment of the newborn and mother as soon as possible, no later than the third day [5].

Immediate management after a positive long-chain screen. During confirmation, clinically assess the newborn, teach caregivers to avoid prolonged fasting and monitor reduced intake, vomiting or lethargy, and, if the newborn is unwell, admit for fluid resuscitation, intravenous glucose (10% dextrose or higher), and nutritional and cardiac assessment [3, 4]. The 2026 guideline recommends fasting precautions with intervals no longer than three hours in suspected newborns while awaiting confirmation [33]. For PCD, if no specialist is available, start oral levocarnitine while awaiting confirmation (see section 7.5) [5].

5.2 Biochemical profiles

Sources: Saudubray, table 12.2 [12]; GeneReviews [3–5]; Atlas, table 35.1 [18].

In the Atlas, patient plasma ranges were 0.76–13.28 µmol/L for C14:1 in VLCAD deficiency (control 95th percentile: 0.18), 0.12–0.60 µmol/L for C16-OH and 0.14–0.86 µmol/L for C18:1-OH in LCHAD deficiency (controls 0.02 and 0.01) [20]. Over 85% of patients with LCHAD deficiency were identified by C18:1-OH above the 95th percentile combined with elevation of two other hydroxylated long-chain species [21]. C14:1 carnitine above 1 µmol/L correlates closely with confirmed disease; below this value, patients, carriers and healthy individuals cannot be clearly distinguished [26].

Abnormalities are more pronounced under stress but may be attenuated or masked by intravenous glucose or an MCT diet, and profiles may be completely normal in forms with high residual activity (mild VLCAD or TFP deficiencies)—sometimes becoming apparent only after overnight fasting, exercise or carnitine loading [12]. LCHAD and TFP profiles are identical, as are profiles of severe CACT and CPT2 deficiencies; terminal or post-mortem samples often show multiple elevated species resembling multiple dehydrogenase deficiency [12]. Urinary organic acids are often normal between crises; during crises, medium- and long-chain dicarboxylic acids appear with little or no ketosis [12, 26]. Quantification is essential in LCHAD deficiency because 3-hydroxydecanedioic acid and other dicarboxylic acids also occur during ketosis, albeit at lower concentrations [21].

The French PNDS adds practical rules for sampling and interpretation. Samples for metabolic investigation should be collected during the crisis (blood before correction of blood glucose, urine as close as possible to the episode) or, failing this, after a physiological fast appropriate for age, in the newborn immediately before a feed; a profile collected outside a crisis may be subtle or normal and should be repeated if suspicion is strong, possibly after carnitine supplementation if the initial profile is poor in acylcarnitines. Urinary free carnitine is of interest only when PCD is suspected, and the choice of matrix matters: in CPT1A deficiency the dried blood spot profile is preferred, in CPT2 and CACT deficiencies the plasma profile. For VLCAD deficiency, the PNDS uses the C14:1/C16 and C14:1/C12:1 ratios, with C6–C14 dicarboxylic aciduria; for LCHAD and TFP deficiencies, elevation of C14-OH, C16-OH, C16:1-OH, C18-OH and C18:1-OH, with C6–C14 dicarboxylic and 3-hydroxydicarboxylic aciduria; in PCD, very low free carnitine in blood with paradoxically preserved urinary excretion, other acylcarnitines low and organic acids without dicarboxylic aciduria, except during hypoglycaemia [10]. Annex 2 of the PNDS lists the situations and substances that modify the acylcarnitine profile independently of any beta-oxidation defect:

Source: HAS PNDS, annex 2 [10].

In PCD, plasma free and total carnitine are usually below 5 µmol/L but may be higher neonatally, reflecting maternal status [12]; in 20 patients, total carnitine ranged from 0 to 9 µmol/L (18 below 4.2), compared with control values of 40–60 µmol/L [18]. Clinical diagnosis rests on plasma or tissue carnitine reduced at least five- to tenfold (<5–8 µmol/L versus normal 25–50), renal reabsorption below 90% with normal renal function and no organic acid or fatty acid oxidation abnormalities causing secondary deficiency, impaired fibroblast transport, and response to supplementation [34]. Free, acylated and total carnitine below 10% of control values are highly suggestive [5]. During a fasting test (now rarely necessary), the first patient developed hypoglycaemia at 12 hours with free fatty acids 2.22 mmol/L and persistently low 3-hydroxybutyrate at 0.27 mmol/L; after carnitine, she fasted for 24 hours without hypoglycaemia, with 3-hydroxybutyrate 2 mmol/L [18].

Source: Atlas, table 35.1 [18].

5.3 Molecular diagnosis

The 2026 guideline recommends genetic testing in all suspected cases (strong recommendation), confirmation of a positive screen using molecular and enzymatic or functional analysis, and next-generation sequencing, through a panel or single gene, as follow-up to metabolic screening; it is not yet recommended for primary newborn screening [33].

VLCAD. Diagnosis is established by a specific acylcarnitine pattern and/or biallelic pathogenic ACADVL variants [3]. Sequencing detects 95–97% of variants; intragenic deletions are rare (one described) [3]. In a study systematically measuring enzyme activity in 108 individuals, all 55 with activity of 0–24% had both variants identified by sequencing, but only 57% in the affected/carrier overlap group (activity 25–27%) had two variants [3, 49]. A single variant with strong clinical suspicion requires functional testing; finding one variant does not prove carrier status [3, 26].

LCHAD and TFP. Diagnosis is established by elevated long-chain 3-hydroxyacylcarnitines and/or excretion of 3-hydroxydicarboxylic acids, with biallelic variants in HADHA (LCHAD) or HADHA/HADHB (TFP) [4]. Sequence HADHA first and, if negative, HADHB, adding deletion/duplication analysis when only one variant is found; two large deletions in HADHA and two in HADHB have been described in TFP deficiency [4]. A persistently abnormal profile with only one identified variant supports a presumptive diagnosis [4].

PCD. SLC22A5 sequencing detects approximately 95% of variants and deletion/duplication analysis approximately 5%; sequencing should include the 5′ UTR (c.-149G>A accounted for 14% of pathogenic variants in a cohort of 236 individuals) [5, 38]. Approximately 15% of variants lie outside exons [34]. When molecular tests are negative but suspicion persists, fibroblast carnitine transport testing confirms diagnosis [5]. Biallelic variants of uncertain significance, or one pathogenic variant and one of uncertain significance, neither establish nor exclude diagnosis [5].

5.4 Enzymatic and functional studies and severity assessment

Assay of VLCAD activity (palmitoyl-CoA oxidation) in lymphocytes, fibroblasts, liver, heart, muscle or amniocytes, preferably with product separation by high-performance liquid chromatography or tandem mass spectrometry, confirms the diagnosis; lymphocytes can be prepared from 1–2 mL of fresh EDTA blood, with results within a few days [3, 12]. Residual activity above 20% is compatible with mild or late-onset disease, or even lifelong absence of symptoms, and a long-chain fatty acid oxidation flux above 90% of normal predicts absence of symptoms without intervention [33]. In fibroblasts incubated with labelled palmitate, severe patients accumulate C14 and less severe patients shift accumulation to C12 (the so-called in vitro probe) [3, 26]. In LCHAD/TFP deficiency, the enzyme assay in lymphocytes or fibroblasts distinguishes isolated LCHAD deficiency from deficiency of all three activities [4]; direct assay of LCHAD with anti-SCHAD antibody usually gives less than 10% of control [21]. The C18-OH/(C14-OH+C12-OH) ratio and oxidation flux correlate with severity, unlike LCHAD and LCKAT activities [33]. In PCD, carnitine uptake by fibroblasts or lymphoblasts is below 10% of control in patients and below 40% in some heterozygotes [18]. The PNDS defines the indications for in vitro functional investigations (incubation of fibroblasts or lymphocytes with a stable-isotope-labelled long-chain fatty acid, which reproduces fasting at the cellular level without exposing the patient, or assay of a specific enzyme activity): before genetic testing, in the presence of an atypical acylcarnitine profile or strong clinical suspicion with repeatedly uninformative metabolic investigation; after genetic testing, in the presence of variants of uncertain significance or a single heterozygous variant; the decision is taken jointly by clinicians and laboratory specialists, and the list of laboratories performing them is available on the G2M network website [10].

5.5 Post-mortem and prenatal diagnosis

Post-mortem bile acylcarnitines identified patients initially classified as sudden infant death [20], and among 313 sudden infant death autopsies, three were attributed to transporter deficiency based on hepatic steatosis and very low liver carnitine [18]. Post-mortem profile interpretation is difficult, and genetic testing clarifies diagnosis for counselling [33]. Prenatal diagnosis is preferably molecular when familial variants are known; all fatty acid oxidation enzymes are expressed in chorionic villi and amniocytes, and impaired carnitine uptake has been demonstrated in amniocytes [12, 18, 33].

5.6 Investigation algorithm

Sources: [3–5, 12, 33].

The French PNDS defines the minimum required in an emergency: blood glucose (a capillary value is confirmed on venous blood) and testing for ketone bodies in blood and/or urine by dipstick, whose discordance with the duration of fasting characterises these defects; these are supplemented by CK, transaminases, lactate, ammonia, electrolytes with bicarbonate, urea, creatinine, prothrombin time and factor V, which assess severity and guide diagnosis. The results of specialised metabolic investigation may be urgent and justify contacting the laboratory. The fasting test is contraindicated and is acceptable only as a last resort in a specialised setting [10].

6. Differential Diagnosis

Differential diagnosis is organised by presentation. Most fatty acid oxidation defects can be distinguished by their acylcarnitine profiles [4], and the Atlas hypoketotic hypoglycaemia algorithm uses ketogenesis, blood and urine free and esterified carnitine concentrations, and acylcarnitine species (C6–C10:1 for MCAD; C12–C18 for VLCAD; hydroxylated C12–C18 for LCHAD; C16–C18 for CPT2) [20].

Table sources: [3–5, 12, 13, 20, 50].

Three points deserve emphasis. First, MCAD deficiency shares hypoketotic hypoglycaemia but does not cause cardiomyopathy, myopathy, neuropathy or retinopathy, and in it MCT are contraindicated — which is why confirmation of the type of defect precedes any prescription of medium-chain oil [4, 12]. Second, the differential diagnosis of cardiomyopathies with multisystem involvement includes primary mitochondrial diseases; LCHAD and VLCAD deficiencies may present with arrhythmias, cardiomyopathy and sudden cardiac arrest, and the clinical overlap with respiratory chain disorders is real [4, 50]. Third, low free carnitine on newborn screening should be interpreted in the light of maternal causes (PCD, glutaric aciduria type 1, MCAD, cobalamin C, vegan diet) and of prematurity, which reduces carnitine through lower placental transfer in the third trimester and renal tubular immaturity [5, 12, 48].

The French PNDS describes in detail the remaining carnitine cycle and beta-oxidation defects, which enter the differential diagnosis of the four entities in this article and share much of their treatment [10]:

Source: HAS PNDS, sections 4.2 and 4.4 and annex 1 [10].

7. Treatments and Risk Management Strategies

7.1 Principles and organisation of care

Treatment of the long-chain defects rests on four pillars: avoiding prolonged fasting, adapting the diet to severity (restriction of long-chain fat with a source of medium-chain fat), having a written emergency protocol and monitoring organ complications [30, 33]. In PCD, the pillar is continuous oral levocarnitine, together with prevention of fasting and the emergency protocol [5]. The 2026 guideline proposes classifying each patient into three severity categories, reassessed over time: mild/attenuated (no symptoms or previous decompensations, normal clinical and laboratory assessment and concordant genotype or functional data), moderate or indeterminate (asymptomatic or mildly symptomatic with persistent biochemical abnormalities, uncertain molecular results or inconclusive or unavailable functional study) and severe (neonatal or infantile presentation, cardiomyopathy, hypoketotic hypoglycaemia, liver disease, hyperammonaemia, recurrent rhabdomyolysis, hospital admission, or genetic or functional findings of severe disease); CACT, LCHAD and TFP deficiencies are usually considered severe [33]. Treatment planning, family education and prevention of the adverse effects of the diet (malnutrition, growth failure) require a multidisciplinary team coordinated by a reference centre for inherited metabolic disorders [3, 4]. The editorial commentary on the guideline warns of two opposite risks: overtreatment, with unnecessary restrictive diets, of newborns with mild defects detected by screening, and persistence of severe symptoms in some patients despite early diagnosis and treatment [11]. The French PNDS sets out the objectives on the basis of the two disease mechanisms, energy deficiency and accumulation of toxic derivatives: restoring energy production with alternative substrates and limiting accumulation by reducing exogenous (diet) and endogenous (fasting lipolysis) supply. It assigns to the attending physician the liaison with the reference or competence centre, checking that the patient always carries a written emergency protocol, monitoring of growth, development and vaccination and management of common illnesses according to the centre's instructions; and it includes therapeutic education, with individual and group sessions directed first at the parents and then, progressively, at the child, which strengthens adherence particularly in adolescence and prepares for pregnancy [10].

7.2 Fasting prevention

No data define safe fasting intervals in otherwise healthy infants with these defects; recommendations derive from reviews and expert opinion, particularly the VLCAD deficiency literature [33].

Sources: [4, 33].

After the first year, persistent preprandial hypoglycaemia in LCHAD/TFP deficiency warrants consideration of night feeds or uncooked cornstarch at 1 g/kg at bedtime [4]; the Atlas describes 1.5–2 g/kg at bedtime for preschool children with VLCAD and LCHAD deficiencies [21, 26]. However, the 2026 guideline prefers a nutritious complex carbohydrate energy source to uncooked cornstarch (weak recommendation), and considers cornstarch generally unnecessary in VLCAD deficiency when patients are well, avoid excessive fasting and meet energy requirements [33]. Severe disease may require continuous overnight enteral feeding [12, 26]; gastrostomy, preferred for prolonged use, is indicated for severe feeding difficulties, chronic vomiting or feeding refusal [33]. Adolescents and adults should not fast for more than 12 hours overnight [26].

The French PNDS proposes, as a guide and for patients without anorexia or digestive disturbance, recommended and maximum fasting durations common to all beta-oxidation defects, to be shortened in severe forms [10]:

Source: HAS PNDS, table 3 [10].

In the most severe forms, in which these durations cannot be achieved, the PNDS resorts to overnight enteral feeding by nasogastric tube or gastrostomy with a glucose delivery rate of at least 10 mg/kg/min in infants, falling to 5 mg/kg/min in adolescents and adults, and also in children who do not keep to the feeding schedule or do not take the whole ration orally. Uncooked cornstarch may allow overnight feeding to be stopped or the daytime fast to be lengthened from 12 to 24 months of age, if digestive tolerance and severity allow, but its introduction should be assessed in hospital with free fatty acids, lactate and acylcarnitines, without relying on the absence of hypoglycaemia [10]. The maximum of 14 hours above 6 years is more permissive than earlier sources (see section 7.16).

7.3 Diet: long-chain fat, medium-chain fat and essential nutrients

Medium-chain fatty acids enter mitochondria independently of carnitine and bypass long-chain enzymes, so MCT may replace part of the long-chain fat in VLCAD, LCHAD, TFP, CACT, CPT1 and CPT2 deficiencies; an MCT diet resolved cardiomyopathy in several patients with VLCAD and LCHAD deficiencies [12]. A diet providing 5–10% of calories as long-chain fat and MCT at 30% of total calories (85–90% of fat calories) was associated with regression of hypertrophic cardiomyopathy in VLCAD deficiency [26]. MCT and triheptanoin are contraindicated in MCAD, ETF and ETF dehydrogenase deficiencies, where medium-chain fatty acids cannot be oxidised [12]. MCT do not fully replace long-chain fatty acid metabolism and carry risks of gastrointestinal intolerance, excess energy intake and essential fatty acid imbalance [33]. Neither neuropathy nor retinopathy appears to benefit from MCT and dietary management [21], and modified diet did not prevent retinopathy in LCHAD/TFP deficiency [33].

Source: [33].

For VLCAD deficiency, Van Calcar and colleagues' nutrition guideline, adopted by GeneReviews, stratifies energy percentages by age and severity [3, 32]:

Source: GeneReviews, table 7, adapted from Van Calcar et al. [3, 32]. Total protein at or above the age-specific reference intake; energy requirements calculated using the Institute of Medicine equation [3].

For LCHAD/TFP deficiency, GeneReviews proposes approximately 30% of energy as fat, 7–15% as long-chain fat and 15–25% as MCT, considering MCT central to treatment [4]. The Atlas describes MCT at 1.5 g/kg, a multivitamin containing all fat-soluble vitamins, and vegetable or walnut oil within the 10% long-chain fat allowance to provide essential fatty acids [21]. DHA supplementation increased blood concentrations, with electrophysiological evidence of visual improvement in four patients; an 11-year-old boy with neuropathy had improved nerve conduction after 12 months of cod liver oil, but no difference was found in other patients [21]. VLCAD GeneReviews suggests DHA at 60 mg/day in infants and young children and 100 mg/day in older individuals, and arachidonic acid at 0.5–1.2% of energy [3].

The French PNDS sets a common framework for all long-chain defects (VLCAD, LCHAD/TFP, CPT1, CPT2, CACT): normal energy intake for age, carbohydrates (preferably complex) providing at least 50–55% of energy, long-chain fat up to 10% of energy, supplemented by MCT at 20–25%, for a total fat of 25–30%, and protein restriction only in hyperammonaemia. Essential fatty acids (linoleic and alpha-linolenic) are provided by walnut or soya oil, a sunflower and rapeseed blend, or direct DHA supply, and are covered by MCT-rich infant formulas (Monogen®, Lipistart®); fat-free formulas and skimmed milk are alternatives, and MCT are available as aqueous emulsion, oil, margarine and powder. A diet low in natural fat requires supplementation with fat-soluble vitamins (A, D, E and possibly K) and coverage of the other vitamins, minerals and trace elements. In LCHAD and TFP deficiencies, whose enzymes take part in endogenous DHA synthesis, the PNDS recommends DHA systematically, 190 mg/day below 20 kg and 380 mg/day above, usually as omega-3 acid ethyl esters (Omacor®), and accepts it in the other deficiencies when deficiency is documented [10]. These uniform targets correspond to the severe forms of the 2026 guideline and do not provide for the unrestricted diet of the mild forms, and the DHA dose is about three times that of the international guideline (see section 7.16).

Breastfeeding. The 2026 guideline recommends including breast milk wherever possible: exclusively in infants with mild or late-onset disease (for example, asymptomatic screen-detected VLCAD deficiency); combined with modified medical food (15–30% of energy as long-chain fat and 10–30% as medium-chain fat, total fat 35–55%) in moderate disease; and in severe disease, discontinue breastfeeding and use medical food or modular formula providing total fat of 40–50% (10–15% long-chain and 35–40% medium-chain), with skimmed breast milk potentially included [33]. A newborn with CACT deficiency treated with triheptanoin mixed into breast milk skimmed using a portable cream separator (residual long-chain fat 6–7% of calories) had regression of cardiomyopathy without further decompensations in the first year [33]. Historical concerns about breastfeeding partly derive from sudden deaths in two breastfed infants with CACT deficiency [33].

Exercise. Restriction of exercise is not necessary, and regular practice is in fact beneficial; the guideline recommends prescribing an exercise programme for all patients [33]. Ten to 20 minutes before exertion, energy should be provided: medium-chain fatty acids (0.5–1 g/kg), triheptanoin (0.5 g/kg) or complex carbohydrates with or without protein (moderate quality of evidence) [33]. The GeneReviews chapter on VLCAD deficiency recommends MCT oil at 0.5 g/kg of lean body mass 20 minutes before exercise and avoidance of extreme exertion (for example, military training), which can unmask the disease in asymptomatic adults [3]. In children with LCHAD/TFP deficiency, MCT before exertion improved metabolic stability and reduced episodes of rhabdomyolysis; combined with juice, they reduced 3-hydroxyacylcarnitines by about 30% and tripled 3-hydroxybutyrate [33]. The PNDS recommends regular physical activity, particularly in the late-onset muscular forms, to preserve muscle mass and limit excess weight: never start exertion while fasting, take complex carbohydrates and/or MCT (possibly 3-hydroxybutyrate) beforehand and sugary drinks or foods during prolonged exertion, prohibit excessive exertion in patients with severe muscle involvement, and avoid alcohol and tobacco [10].

7.4 Triheptanoin (Dojolvi®)

Mechanism. Triheptanoin is a synthetic triglyceride containing three seven-carbon fatty acids (odd-chain medium-chain fat). Oxidation produces acetyl-CoA and propionyl-CoA; the latter enters the tricarboxylic acid cycle as succinyl-CoA, replenishing cycle intermediates lost in these defects (anaplerotic effect), whereas acetyl-CoA from even-chain MCT compensates only for oxaloacetate and citrate deficiency [4, 12, 33].

Regulatory status. The FDA approved triheptanoin in June 2020 [3]; the current label (version of 10 June 2025) indicates it as a source of calories and fatty acids for the treatment of adult and paediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders [51]. According to the editorial commentary on the 2026 guideline, it is approved in the United States, Canada, Brazil, Japan, Mexico and Kuwait, but not by the European Medicines Agency (EMA), and a controlled trial is under way in Europe to meet EMA requirements [11]. In the European Union, triheptanoin received orphan medicinal product designations for VLCAD deficiency (EU/3/15/1508, June 2015), LCHAD deficiency (EU/3/15/1524) and TFP deficiency (EU/3/15/1525), both from July 2015, but orphan designation is not a marketing authorisation [52]. In Brazil, triheptanoin is registered as a new medicine with the National Health Surveillance Agency (ANVISA; registration no. 1.3964.0003, holder Ultragenyx Brasil Farmacêutica), and the package insert for healthcare professionals published in the Electronic Package Insert Database (Bulário Eletrônico) on 4 September 2025 has the same indication as the US label: source of calories and fatty acids for paediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders [53].

Dosing according to the label. Before calculating the dose, the prescribed daily caloric intake (DCI) is determined; the patient should be under the care of a specialist experienced in the dietary management of the disease [51]. The daily target dose is up to 35% of the total prescribed DCI, divided into at least four doses, mixed into semi-solid or liquid foods, or into a medical food or formula, at meals or snacks; the caloric value is 8.3 kcal/mL and the daily volume is rounded to the nearest millilitre [51]. In patients not taking MCT, treatment starts at about 10% of DCI in at least four doses and is increased by about 5% of DCI every 2–3 days up to the target; in those taking another MCT product, this is stopped before the first dose and triheptanoin is started at the last tolerated daily volume of MCT, with the same titration scheme [51]. If the target is not tolerated, the maximum tolerated dose is maintained; in case of gastrointestinal effects, dose reduction or smaller, more frequent doses are considered [51]. A missed dose is taken as soon as possible, keeping intervals of 3–4 hours, or omitted if all doses cannot be taken that day; newborns may need a higher fat intake and therefore more triheptanoin [51]. In the trials, doses ranged from 12% to 41% of DCI, corresponding to 0.7–6.0 g/kg/day in children and 0.5–1.3 g/kg/day in adults [51]. The 2025 Brazilian package insert agrees with the US label on the target dose (up to 35% of DCI in at least four doses, 8.3 kcal/mL), on the transition from another MCT product (last tolerated daily volume and increases of about 5% of DCI every 2–3 days), on the tolerance and missed-dose rules and on the range of doses in the trials; it differs in the titration of patients without prior MCT, described as an increase of about 10% up to 35% of DCI over 2 to 3 weeks, without the 5% step every 2–3 days of the 2025 US label, and states that safety and efficacy are established from the neonatal period [51, 53]. The reference dose is that of the 2026 guideline, and the US and Brazilian labels serve as comparison [33, 51, 53]. The French PNDS, which predates the guideline, proposes triheptanoin in the long-chain defects at 25–35% of total energy (or by weight-based calculation), adjusted to clinical benefit and biological results, replacing MCT when these are insufficient or from the outset in severe forms, particularly neonatal ones; even-chain MCT are stopped at once or progressively, the patient is switched to fat-free milk or formula with coverage of essential fatty acids, and the dose is split into 4 to 6 doses, well emulsified in low-fat foods, and may be incorporated into enteral feeding and the emergency regimen; initial digestive intolerance, more frequent in older patients, improves with time. It advises against triheptanoin, as against MCT, until the precise diagnosis has been established [10].

Precautions and adverse effects. The label has no contraindications. It should be avoided in patients with pancreatic insufficiency (hydrolysis depends on pancreatic enzymes) and should not be administered through polyvinyl chloride (PVC) tubes, with regular monitoring of tube function [51]. In the safety population of 79 patients (4 months to 63 years), the most frequent reactions were abdominal pain (60%), diarrhoea (44%), vomiting (44%) and nausea (14%), with median onset at 7.3 weeks; gastrointestinal reactions led to dose reduction in 35% and 12% of patients in studies 1 and 2 [51]. There are no data in pregnant women; in animal studies, embryo-fetal effects were attributed to reduced food intake due to taste aversion, and a pregnancy safety study exists [51]. The Brazilian package insert, unlike the US label, contraindicates use in patients allergic to triheptanoin; it classifies it in pregnancy risk category C, requires avoidance of combination with pancreatic lipase inhibitors and of administration in pancreatic insufficiency, prohibits polystyrene or PVC containers and tubes and reports, in in vitro studies, that heptanoate increases the free fraction of valproic acid about twofold [53].

Clinical evidence. In Gillingham and colleagues' double-blind randomised trial (32 patients with CPT2, VLCAD, TFP or LCHAD deficiencies, 20% of energy as triheptanoin or trioctanoin for four months), the triheptanoin group increased left ventricular ejection fraction by 7.4% and reduced ventricular mass by 20%, with lower heart rate at the same exercise workload, but no differences in energy expenditure, phosphocreatine recovery, body composition or rhabdomyolysis incidence [54]. In the UX007 phase 2 trial (29 patients aged 0.8 to 58 years, target 25–35% of DCI), 12-minute walking distance increased by 28% at 18 weeks and power output by 60% at 24 weeks, neither statistically significant, with significant improvement in the adult SF-12v2 physical component; 62% had treatment-related adverse effects, predominantly gastrointestinal [55]. In the open-label CL202 extension (75 patients), annualised major clinical event rates (rhabdomyolysis, hypoglycaemia, cardiomyopathy) fell from 1.76 to 0.96 events/year in the rollover group (P = 0.0319), with a 66% reduction in median duration, and from 2.33 to 0.71 events/year in treatment-naïve patients (P = 0.1072), with an 80% duration reduction [56]. In 10 patients (8 infants) with moderate to severe cardiomyopathy despite MCT, switching to triheptanoin through emergency or compassionate use was followed within 2 to 21 days by an ejection fraction increase from 12–45% to 33–71%, normalising in nine [57]. Triheptanoin was less effective for rhabdomyolysis than other symptoms [3]. The 2026 guideline considers it a treatment option for symptomatic patients (moderate evidence, strong recommendation) and for acutely ill children, including those receiving MCT [33]; it describes two published regimens: complete MCT replacement at 2–4 g/kg/day (up to 35% of calories), or 1–2 g/kg/day alongside MCT, the latter outside label instructions requiring MCT discontinuation [33, 51]. The phase 3 trial NCT05933200 is comparing triheptanoin with even-chain MCT for reducing major clinical events in paediatric patients (active, not recruiting; completion expected August 2027) [58].

7.5 Levocarnitine

Primary carnitine deficiency. Levocarnitine treats the underlying cause and is highly effective: it restores plasma and hepatic free carnitine, prevents hypoglycaemic crises and cardiomyopathy, and heart failure responds within weeks to months, with normalisation of cardiac volume [12, 18]. Developmental delay or seizures caused by previous hypoglycaemia persist without progression; mild proximal weakness may persist, and muscle carnitine remains below 5% of normal [12, 18]. Disease rapidly recurs after treatment withdrawal [34]. Carnitor® (levocarnitine) is FDA-approved for primary systemic carnitine deficiency and acute and chronic treatment of inherited metabolic disorders with secondary carnitine deficiency [59].

Source: official Carnitor® labels (oral, 2024; injectable, 2023) [59].

In Portugal, the SmPC for levocarnitine oral solution (Disocor® 1000 mg/10 mL, approved by INFARMED on 29 December 2023), indicated for carnitine deficiency resulting from inborn errors of metabolism, defines the daily oral dose by age: 150 mg/kg from 0 to 2 years, 100 mg/kg from 2 to 6 years, 75 mg/kg from 6 to 12 years and 2–4 g/day above 12 years and in adults, depending on severity, with no other maximum dose defined [60]. The paediatric dose of the Portuguese label is thus higher than the US dose below 2 years (150 mg/kg/day versus 50–100 mg/kg/day) and coincides with the US upper limit from 2 to 6 years. In Brazil there is no approved dosing for comparison: in ANVISA's open medicines data, downloaded on 31 October 2026, there is no active registration of any medicine containing levocarnitine, alone or in combination, and the three single-ingredient levocarnitine products in the database are inactive (Levocarnin®, from Abbott, with registration expired in March 2005; Carnitan®, from Marjan, expired in February 2005; and Carnitine, from Probiótica, expired in September 2012); the Electronic Package Insert Database returns no package insert when searched for levocarnitine [61]. The sources consulted do not describe the route of access to levocarnitine in Brazil or its provision in the Unified Health System (SUS).

In PCD, the dose recommended by GeneReviews is 100–200 mg/kg/day orally divided into three doses, adjusted to plasma carnitine, also as presumptive treatment after a positive screen if no specialist is available; in a crisis, 100 mg/kg/day divided into four doses orally or intravenously [5]. Compared with the labels, this dose often exceeds the paediatric range of the US label (50–100 mg/kg/day, maximum 3 g/day) and, above 150 mg/kg/day or outside the corresponding age bands, also that of the Portuguese SmPC, falling in those cases outside the label conditions [59, 60]. Saudubray indicates 100 mg/kg/day in three or four doses [12], the Atlas reports 50–150 mg/kg/day orally, with doses up to 400 mg/kg recommended by some authors, limited by intestinal tolerance [18], and the cardiogenetics chapter reports 100–400 mg/kg/day adjusted to plasma carnitine [34]. In the acute crisis, the Atlas prefers the intravenous route (100–300 mg/kg), because of greater bioavailability and to avoid the diarrhoea of high oral doses [20]. The French PNDS proposes in PCD 100–200 mg/kg/day orally in three to four doses, allowing higher doses, with the aim of keeping residual free carnitine above 20 µmol/L, and the same dose as curative treatment when suspicion is strong in the acute phase; in France, levocarnitine is available as Levocarnil® solution for injection (1 g/5 mL, by continuous or divided infusion) and oral solution (1 g/10 mL), and the injectable form can be given orally, bearing in mind that it is twice as concentrated [10]. This dosing coincides with that of GeneReviews.

Adverse effects. Gastrointestinal effects (nausea, vomiting, abdominal cramps, diarrhoea) depend on the rate of ingestion and improve with slow intake, dilution and dose reduction; fishy body odour results from bacterial metabolism to trimethylamine [5, 59]. GeneReviews reports that oral metronidazole at 10 mg/kg/day for 7–10 days and/or dose reduction usually resolve the odour (off-label use) [5]. The PNDS proposes, as an alternative, adding riboflavin at 50–100 mg/day to reduce the odour [10]. The label also describes seizures, with increased frequency in patients with pre-existing epilepsy, hypersensitivity reactions (rash, urticaria, facial oedema; anaphylaxis after intravenous administration, mainly in haemodialysis patients), increased INR in patients on warfarin and accumulation of trimethylamine and trimethylamine N-oxide in severe renal impairment [59].

Long-chain defects. The use of carnitine in VLCAD, LCHAD and TFP deficiencies is controversial because of concern that it increases long-chain acylcarnitines, which are potentially arrhythmogenic [12, 26]. In VLCAD-deficient mice, supplementation increased acylcarnitines in muscle and liver without restoring free carnitine [26]. In LCHAD deficiency, about half of the patients in the largest series were treated with carnitine with no demonstrable harmful effect [21], and in a series of 50 patients there were no differences in morbidity between the 12 treated with 50–100 mg/kg/day and the rest [33]; in a triheptanoin trial, 50 of 52 patients received 100 mg/kg/day (maximum 1000 mg/day) without evident adverse effects [33]. The 2026 guideline concludes that there is no evidence for supplementation or for adverse effects and that, if total and free carnitine are very low, a low dose (10 mg/kg/day for 4–6 weeks) may be considered, with monitoring and discontinuation when they normalise, with no maximum dose defined in the source [33]. The GeneReviews chapter on VLCAD deficiency reports 10–25 mg/kg/day in three or four doses when free carnitine is below 10 µmol/L, to be avoided during acute illness [3], and that on LCHAD/TFP deficiency 25–50 mg/kg/day in three doses only in documented deficiency [4]. These doses in patients with long-chain defects are lower than those of the label and should be understood as expert recommendations. The French PNDS is more liberal: it regards oral supplementation of 10–50 mg/kg/day as usual in the deficiencies with accumulation of long-chain acylcarnitines (CACT, CPT2, VLCAD, LCHAD, TFP), acknowledging that no study has assessed its efficacy and safety; in the acute phase it proposes 10–50 mg/kg/day intravenously or enterally, with caution and a preference for delaying initiation in the presence of arrhythmia or long QT; and the G2M network emergency certificate allows, in CACT deficiency, maintenance doses up to 200–600 mg/kg/day [10]. The later 2026 international guideline restricts carnitine to very low concentrations (see section 7.16).

7.6 Emergency protocols

Written emergency plans, updated frequently, should be held by parents, primary care and schools and carried when travelling; they include warning signs, home regimens and hospital instructions, and can be generated in several languages at www.emergencyprotocol.net [3, 33]. Parents or the local hospital should contact the reference centre when temperature exceeds 38.5 °C, vomiting, diarrhoea or other intercurrent illness signs occur, or new neurological symptoms develop [3]. Admission indications include cold sweats and other hypoglycaemia signs, vomiting, anorexia, drowsiness, lethargy, seizures, abdominal or muscle pain, dark urine, bradycardia or tachycardia, arrhythmias and pallor; laboratory indications include hypoglycaemia, hyperammonaemia, elevated CK and deteriorating cardiac function [33].

Sources: GeneReviews [3–5]; 2026 guideline [33].

Saudubray summarises acute treatment physiology: hormonal changes during illness induce lipolysis and fatty acid oxidation, and decompensation is prevented by providing enough glucose to stimulate insulin and suppress lipolysis; glucose drinks should begin at the first sign of illness and be repeated every 2–3 hours, with meals reintroduced within 24–48 hours. In hospital, intravenous glucose should at least match physiological hepatic production (3–12 mg/kg/min, age-dependent); hypoglycaemia is a late event, and treatment should start promptly regardless of blood glucose [12]. The Atlas recommends glucose solutions of 10% or higher even in normoglycaemic patients, for example during rhabdomyolysis, and letters specifying the need for intravenous glucose even with normal glucose on arrival [20, 26]. Metabolic specialists manage hospitalisation with intravenous glucose and electrolytes; evidence is insufficient to recommend acute carnitine (unless deficient) or riboflavin [33]. Some series continue intravenous infusion until CK begins to fall, without data defining a stopping threshold [33].

The French PNDS and the G2M network emergency certificate “VLCAD, LCHAD, CPT2, CACT, TFP and multiple dehydrogenase deficiencies”, annexed to the PNDS, quantify the correction of hypoglycaemia and the glucose delivery rate [10]:

Source: HAS PNDS, section 4.6.2, table 2 (basal requirements according to Bier, 1977) and G2M emergency certificate [10].

To avoid hyperglycaemia, the PNDS suggests starting the infusion at about two thirds of the target and increasing it over a few hours, and preferring insulin to reducing the glucose rate; in the text of the protocol insulin is started at 0.2 IU/kg/h, with a target blood glucose of 1–1.5 g/L, whereas the emergency certificate indicates 0.01 IU/kg/h adjusted hourly for blood glucose of 1–1.8 g/L if blood glucose exceeds 2 g/L with glycosuria, and reduction of the sugar supply by 20–25% only if hyperglycaemia persists despite 0.05 IU/kg/h. Normalisation of hyperlactataemia serves as a marker of recovery of aerobic metabolism. In heart failure, concentrated solutions via a central line allow volume to be limited. The certificate also requires the emergency investigations to be taken without delaying the infusion (capillary and venous blood glucose, CK, ammonia, electrolytes with potassium and calcium, urea, creatinine, blood gases, lactate, transaminases, GGT, prothrombin time and factor V; electrocardiogram, BNP, troponin and echocardiogram if there are cardiac signs), hypovolaemia to be corrected with Ringer's lactate or normal saline at 10 mL/kg (maximum 500 mL) in the absence of cardiac signs, intravenous lipids to be avoided as contraindicated, potassium to be added only after exclusion of rhabdomyolysis (CK <1000 IU/L and no renal failure), the usual L-carnitine to be maintained (intravenous if the oral route is impossible) but stopped in the presence of arrhythmia, and, if infusion is impossible, the same solutions and rates to be given by nasogastric tube. It defines as signs of severity, with transfer to intermediate or intensive care, neurological impairment or ammonia above 200 µmol/L in the newborn and 150 µmol/L in children and adults, arrhythmias or electrocardiographic signs of hyperkalaemia (potassium >7 mmol/L, with discontinuation of levocarnitine), CK above 15,000 IU/L (hydration of 3 L/m²/day), haemodynamic or renal failure and severe liver failure (prothrombin time <50% or factor V <30%); monitoring includes continuous monitoring and electrocardiogram, blood glucose every 4 hours and repeat tests between 12 and 24 hours if the initial investigations are normal [10].

Enteral feeding, preferably continuous, is resumed as soon as digestive tolerance and haemodynamics allow, without lipids and, if there is significant hyperammonaemia, without protein (glucose 30% or maltodextrin in water, or skimmed milk); the emergency regimen is normocaloric, high-carbohydrate and low-fat, with suspension of essential fatty acid supplements and the same glucose rate. In the acute phase, synthetic ketone bodies (sodium 3-hydroxybutyrate, 400–900 mg/kg/day orally) may be used, weighing the sodium load in severe heart failure, whereas MCT and triheptanoin are introduced only after the type of defect has been confirmed [10]. In hyperammonaemia, energy recovery is usually sufficient when ammonia is below two to three times normal and the patient is conscious; in the most severe forms, the PNDS applies the treatment of urea cycle defects: protein suspension for 24–48 hours, sodium benzoate or sodium phenylacetate + benzoate (Ammonul®) with a loading dose of 250 mg/kg over 90–120 minutes and maintenance of 250–500 mg/kg/day by continuous infusion (phenylbutyrate orally only, at the same dosage), with the maxima of the consensus table that the PNDS reproduces from the urea cycle defects protocol (sodium benzoate: 6 g in the 2-hour load and 12 g/24 h in maintenance, or 5.5 g/m²/day above 20 kg; sodium phenylacetate: 12 g/24 h), switch to the oral route with Ammonaps®, Pheburane® or Ravicti® and, as an alternative, carglumic acid (Carbaglu®) with a 100 mg/kg load and 100–250 mg/kg/day in four doses, with no maximum dose defined in the PNDS; extracorporeal clearance is discussed in the presence of signs of severity or lack of improvement. The G2M certificate starts sodium benzoate without waiting for confirmation when ammonia exceeds 150 µmol/L in children or 100 µmol/L in adults, with 250 mg/kg over 2 hours (maximum 8 g, above the 6 g of the consensus table) and then 250 mg/kg/24 h (maximum 12 g/24 h), noting that each gram contains 7 mEq of sodium [10]. Hepatocellular failure, secondary and usually rapidly resolving, is treated with supportive measures (fresh frozen plasma, albumin) and is not an indication for liver transplantation [10].

7.7 Rhabdomyolysis

Rhabdomyolysis requires abundant hydration and, according to the GeneReviews chapter on VLCAD deficiency, urinary alkalinisation, to protect the kidney from myoglobinuria [3]. In LCHAD/TFP deficiency, GeneReviews recommends, in children, 10% dextrose with electrolytes at twice maintenance, with urine output above 3 mL/kg/h; in adults, an initial infusion of 400 mL/h adjusted for a urine output of about 200 mL/h; nephrology consultation and haemodialysis if there is acute kidney injury; and avoidance of hypotonic fluids without glucose (such as 0.45% saline), which promote catabolism and worsen rhabdomyolysis [4]. Hyperglycaemia resulting from dextrose is treated with insulin [4]. In recovery from severe and recurrent episodes, physiotherapy and exercise rehabilitation are recommended [33]. The PNDS adds to non-specific treatment (hyperhydration and urinary alkalinisation) analgesia and monitoring of renal function and potassium, with extracorporeal clearance if there is acute kidney injury, and combines it with the high-carbohydrate, low-fat regimen as specific treatment [10].

7.8 Agents and circumstances to avoid; anaesthesia and surgery

Avoid fasting (including preparation for and recovery from surgery or sedation), myocardial irritation (for example, cardiac catheterisation), dehydration, diets high in long-chain fat, ketogenic or low-carbohydrate weight-loss diets, and volatile anaesthetics or those delivering high doses of long-chain fatty acids, such as propofol and etomidate [3]. A retrospective analysis found no adverse effects from propofol during short procedures in LCHAD/TFP deficiency, and a combination of midazolam, thiopental, fentanyl and remifentanil was successfully used in a patient with LCHAD deficiency [4]. Vaccination is safe, but adequate caloric intake should be ensured afterwards [4]. Controlled weight loss is possible through long-chain fat and calorie restriction, with MCT and overnight uncooked cornstarch [3]. Planned procedures, including dental procedures, should be discussed with the reference centre in advance to arrange perioperative management; patients with PCD who must fast or cannot tolerate oral intake should be admitted for intravenous glucose [3, 5]. In PCD, also avoid fasting beyond age-appropriate intervals, catabolic illnesses (maintain vaccinations, wear masks indoors and recognise symptoms early), and inadequate caloric intake during other stresses [5]; pivalate-containing antibiotics reduce carnitine [12].

The French PNDS details anaesthesia, which should be prepared with the reference centre. Fasting is limited and compensated by continuous glucose infusion at least equal to basal requirements (6–8 mg/kg/min in children and 2.2 mg/kg/min in adults, more if fasting is prolonged): in practice, 10% glucose with electrolytes at 100–150 mL/kg/day from birth to 6 years, 80–120 mL/kg/day in children and 2.5–4 L/day in adolescents and adults (or 1–1.5 L/day of 30% glucose in adults), with rapid switch to the oral route and insulin, rather than rate reduction, if there is hyperglycaemia. Propofol, whose excipient is a lipid emulsion, is avoided or used only as a bolus at induction; etomidate is avoided, because it contains propylene glycol or a lipid emulsion depending on the formulation; ketamine is avoided at anaesthetic doses, because it stimulates the sympathetic system and catecholamines. Halogenated gases, thiopental, midazolam and opioids can be used safely; depolarising muscle relaxants may raise CK, which is also a marker of postoperative decompensation, and non-depolarising agents are used with neuromuscular monitoring; no complications have been described with non-steroidal anti-inflammatory drugs, paracetamol or local or regional anaesthesia. Premedication, prevention of hypothermia and multimodal analgesia reduce perioperative stress [10]. The G2M network emergency certificate prohibits acetylsalicylic acid and valproic acid, requires the indication for corticosteroid therapy lasting more than three days to be weighed (without precluding hydrocortisone when resuscitation requires it) and advocates all vaccines, including influenza vaccine [10]. In the presence of excess weight, any weight-loss diet or bariatric surgery may be dangerous and requires prior advice from the reference centre [10].

7.9 Heart, neuropathy and retinopathy

Cardiomyopathy may regress with adequate carbohydrate-rich energy intake, long-chain fat restriction and MCT or triheptanoin; sodium D,L-3-hydroxybutyrate has been used to improve cardiac function, with a risk of sodium overload, and arrhythmias are treated with non-specific drugs [33]. Successful heart transplantation has been described in TFP and CPT2 deficiencies, although timely diagnosis and strict dietary management are expected to make it unnecessary [4, 33]. Severe ventricular arrhythmia, particularly with long QT, may cause sudden death; pacemakers or implantable defibrillators have been suggested but not studied [33]. Early diagnosis and strict diet may delay neuropathy and retinopathy onset or slow progression without completely preventing them [4, 62]; DHA supplementation is advised if concentrations are low, with uncertain prophylactic effects on retinopathy (weak recommendation) [33]. In PCD, cardiomyopathy responds to levocarnitine, but patients starting treatment late may not recover completely [5, 63].

7.10 Pregnancy

Women with long-chain defects. Pregnancy may improve biochemical profiles in the second and third trimesters because the fetus and placenta contribute to fatty acid oxidation, but delivery and the puerperium are catabolic states carrying risks of rhabdomyolysis and myoglobinuria [3, 64]. The 2026 guideline recommends a carbohydrate-rich diet with 10–25% of energy as long-chain fat, supplementation with medium-chain fat or triheptanoin, and frequent meals; during labour and until diet resumes, 10% dextrose in 0.45% saline at 1.35–1.5 times maintenance; and postpartum CK and symptom monitoring because of rhabdomyolysis risk and postpartum heart failure described in VLCAD deficiency [33]. For VLCAD deficiency, GeneReviews recommends nutritional review monthly or each trimester, carnitine and CK at every visit, acylcarnitines weekly to monthly, essential fatty acids at least once, echocardiography before conception or as soon as pregnancy is recognised, and halving vitamin A supplementation without discontinuation [3]. In LCHAD deficiency, increased third-trimester MCT and peripartum dextrose infusion have enabled successful pregnancies [4, 65].

Heterozygous pregnant women with an at-risk fetus. Women heterozygous for HADHA or HADHB variants, including presumed carriers, should be monitored for HELLP syndrome and acute fatty liver, with liver function tests at each visit in the first two trimesters and more frequently in the third, by a maternal–fetal medicine and medical genetics team [4]. The 2026 guideline recommends this surveillance (moderate evidence, strong recommendation), advises against screening pregnant women with HELLP or acute fatty liver for LCHAD in the absence of other risk factors, and recommends testing children born to mothers with these complications [33].

Women with PCD. All pregnant women with PCD, including asymptomatic women, require close plasma carnitine monitoring, increasing supplementation as needed to maintain normal levels [5]. The Atlas considers treatment of asymptomatic mothers detected through their child's screening prudent, particularly in a subsequent pregnancy [18].

Recommendations of the French PNDS. Pregnancy is possible in all these diseases, but should be planned because of the risk of decompensation; the first trimester is critical because of nausea and vomiting, requiring closer monitoring and adaptation of the diet; in the long-chain defects, caloric intake increases by 350–400 kcal in the second and again in the third trimester; delivery and the immediate postpartum period, at greater risk (particularly of rhabdomyolysis), require continuous intravenous glucose during labour, switch to the oral route and repeated biochemical monitoring; breastfeeding requires a high caloric intake; and in PCD maternal free carnitine should be monitored during pregnancy, adjusting the dose to prevent deficiency in the mother and fetus [10].

7.11 Investigational treatments

The investigational nature of these approaches contrasts with triheptanoin, which is an approved medicine. Creatine reduced muscle pain and CK in a single patient [21], and riboflavin (75–100 mg/day) had no benefit in LCHAD deficiency [21]. The French PNDS allows oral creatine at very variable doses (3–20 g/day) for muscle symptoms, acknowledging that it has never shown efficacy, and proposes sodium 3-hydroxybutyrate (compounded preparation) orally in severe forms at 300–1000 mg/kg/day (maximum 2600 mg/kg/day) in 4 to 6 doses, with long-term efficacy described on cardiac and cerebral involvement in CACT, CPT2 and multiple dehydrogenase deficiencies and with no heart failure attributed to the sodium load in treated patients [10].

7.12 Actionability (ClinGen)

The ClinGen Actionability Working Group classified VLCAD deficiency (report AC126) as moderately actionable in children and of limited actionability in adults; trifunctional protein complex defects (AC1039) as moderately actionable in children for HADHA and HADHB, with adult classification pending; and primary systemic carnitine deficiency (AC1047) as strongly actionable in children and moderately actionable in adults [9]. Report AC1039 scored two outcome/intervention pairs, both addressing morbidity from metabolic decompensation: dietary management with illness protocols (score 9CA) and triheptanoin (9CC) [9].

7.13 Comparative regulatory status

Accurate interpretation of regulatory status requires distinguishing four levels: peer-reviewed publication, sponsor announcement or preliminary results, regulatory opinion (for example, from the EMA Committee for Medicinal Products for Human Use), and authorisation decision (FDA or European Commission). Orphan designation or a positive opinion does not constitute authorisation, and authorisation does not guarantee marketing, reimbursement or access in each country.

7.14 Clinical trials: overview and interpretation limits

Studies using a pretreatment comparator (CL202, Korean study) are subject to regression to the mean because patients enter after a period with many events, and to concurrent management changes; reductions in annualised event rates should be considered alongside residual rates (approximately one event annually in CL202 rollover patients). The only randomised trial compared triheptanoin with trioctanoin (both medium-chain fats), lasted four months, used doses below the label target and found no rhabdomyolysis difference; echocardiographic improvements occurred in patients with normal baseline function. The bezafibrate trial was negative despite in vitro evidence. Ranking treatments by indirect comparison across these studies is unjustified.

7.15 Portuguese and Brazilian experience

At Centro Hospitalar Universitário de São João (Porto), two boys with VLCAD deficiency (12 years) and LCHAD deficiency (8 years) and recurrent rhabdomyolysis had fewer admissions (6 → 2 and 4 → 1) and lower peak CK during the 18 months after triheptanoin initiation compared with the preceding 18 months, but gained 13 kg and 7 kg, without major adverse effects—a two-case series with no population-level inference [71]. At the Lisbon reference centre (Centro Hospitalar Universitário de Lisboa Central), among 23 patients with metabolic myopathies followed from 2009 to 2022, seven had fatty acid oxidation defects, including three with LCHAD deficiency diagnosed through newborn screening [72]. No published Brazilian clinical series specific to these four entities were found in the consulted databases (Europe PMC, PubMed).

7.16 Divergences between the French PNDS and the other guidelines

The HAS PNDS (text of June 2021) predates the 2026 international guideline, was developed by expert opinion and covers all beta-oxidation defects together; the 2026 guideline, with adapted GRADE methodology and Delphi consensus, is the reference for this article when the two diverge, and the labels serve as comparison for doses [10, 33]. The differences with practical consequences are as follows:

Sources: HAS PNDS [10]; others as indicated.

8. Reproductive Options and Family Counselling

All four entities are autosomal recessive. If both parents are heterozygous, each sibling of an affected individual has, at conception, a 25% probability of being affected, 50% of being an asymptomatic carrier, and 25% of inheriting neither variant; children of an affected individual are obligate carriers unless the other parent is a carrier or affected; each sibling of either parent has a 50% carrier probability [3–5]. Parental molecular testing confirms heterozygosity; if only one parent carries a variant and parentage is confirmed, consider a de novo variant in the proband or parental mosaicism, and with apparent homozygosity consider a deletion missed by sequencing or uniparental isodisomy [3, 5]—a mechanism described in TFP deficiency through chromosome 2 uniparental disomy [21].

Entity-specific considerations. ACADVL and SLC22A5 variant carriers are asymptomatic [3, 5], although SLC22A5 heterozygotes may have low carnitine and benign cardiac hypertrophy [34, 39]. Women carrying HADHA or HADHB variants do not develop the disease but risk HELLP syndrome and acute fatty liver when the fetus is affected; discuss this before every pregnancy and provide obstetric surveillance [4]. In PCD, an apparently healthy parent may have biallelic variants and should then be referred for treatment; carrier testing is recommended for partners of carriers or affected individuals, particularly with shared ancestry, as in the Faroe Islands [5].

Disclosure of the diagnosis. The French PNDS recommends a dedicated consultation, in line with HAS recommendations, by a physician familiar with the disease, if possible with both parents and in the presence of a psychologist and possibly a dietitian, in two stages: first, explanation of the suspected diagnosis and the life-threatening risks; then, once the disease is confirmed, the complications, the follow-up plan and the therapeutic options; the same consultation offers genetic counselling for future pregnancies and family testing, which is then carried out in a separate consultation [10].

At-risk relatives. Test all siblings regardless of age, as many patients are asymptomatic in childhood: use molecular testing if familial variants are known; otherwise, in VLCAD deficiency, acylcarnitine profiling may lack sensitivity and lymphocyte enzyme testing or fibroblast studies may be needed; in LCHAD/TFP deficiency, assess acylcarnitines, carnitine and organic acids; in PCD, measure plasma free carnitine and, if low, fibroblast uptake [3–5]. At-risk newborns without prenatal diagnosis should be tested alongside newborn screening [3–5]. The 2026 guideline permits awaiting delivery and measuring acylcarnitines in cord blood or, preferably, a newborn sample within 24 hours, maintaining feeding and observation; cord blood metabolites may show little abnormality because of maternal clearance [33]. Biochemical profiles do not reliably identify carriers [3, 4].

Prenatal and preimplantation diagnosis. Once familial variants are identified, molecular prenatal diagnosis (the 2026 guideline's recommended method) and preimplantation genetic testing are available [3–5, 33]; biochemical assays in amniocytes or chorionic villi are alternatives when genetics is inconclusive [12, 33]. Decisions are personal and should be discussed before pregnancy through non-directive counselling; DNA banking is recommended for probands without a confirmed molecular diagnosis [3, 5].

Genetic test limitations and reporting. Targeted sequencing does not generally detect exon deletions or duplications, deep intronic variants or regulatory variants (such as SLC22A5 c.-149G>A, requiring inclusion of the 5′ UTR) [5, 38]; a negative result or single variant does not exclude diagnosis with a convincing biochemical or clinical phenotype and requires functional studies [3, 33]. Reports should specify gene, versioned reference transcript—ACADVL NM_000018.4, HADHA NM_000182.5, SLC22A5 NM_003060.4 [3–5]—HGVS nomenclature, zygosity, ACMG/AMP classification (for ACADVL, using ClinGen specifications version 2.1.0), and technical limitations. Where literature uses historical numbering, provide both: c.1528G>C p.(Glu510Gln), formerly E474Q; c.848T>C p.(Val283Ala), formerly V243A; c.709T>C p.(Cys237Arg), formerly C215R [3, 4]. The HADHB variants in isolated LCKAT deficiency were published without explicit reference to the current transcript and are cited here using original article numbering [21]. A variant of uncertain significance does not become pathogenic through treatment response or partial segregation; segregation is described as an investigational finding.

9. Special Considerations: Population Diversity and Epidemiology

VLCAD deficiency. GeneReviews estimates incidence at 1:30,000 to 1:100,000 births, with incomplete ascertainment; most screen-detected cases remain asymptomatic in early childhood [3]. It is the second most frequent fatty acid oxidation defect in Europe and the United States, with prevalence of 1:50,000 to 1:100,000, far above clinical detection rates [12]; the Atlas cites 1:85,000 and identifies it as the most common fatty acid oxidation defect in the Saudi population [26]. Orphanet-validated birth prevalences are 3.2/100,000 in Australia, 1.8/100,000 in the United States, 2.3/100,000 in Israel (4.3/100,000 in a specific population) and 0.45/100,000 in Czechia, with point prevalence of 2.0/100,000 in Germany [1]. p.Val283Ala predominates in patients of European ancestry [12, 35].

LCHAD and TFP deficiencies. Combined Australian, German and US screening data (5,256,999 newborns) yielded incidences of approximately 1:250,000 for LCHAD and 1:750,000 for TFP deficiency [6, 21]; these figures apply to each entity, rather than all carriers of HADHA variants. The c.1528G>C allele shows a marked founder effect in northern and central Europe: carrier frequencies of 1:173 in Estonia, 1:217 in Poland and 1:240 in Finland, and 1:73 in the Kashubian population of Pomerania (Poland), with estimated local LCHAD deficiency prevalence of 1:16,900 [4, 73–75]. Orphanet records LCHAD birth prevalences of 2.0/100,000 in Sweden, 1.24 in Czechia, 1.09 in Estonia, 0.84 in Poland, 0.5 in Germany and Israel, and 0.4 in Australia and the United States [1]. c.1528G>C has not been described in Japanese or Korean populations [4], and a series of 14 Japanese patients with complete TFP deficiency had a molecular spectrum distinct from that in Caucasian populations [76]. For TFP deficiency, Orphanet reports approximately 100 published cases and unknown worldwide prevalence [1].

Primary carnitine deficiency. Newborn screening incidences were 1:348,333 in Australia and New Zealand, 1:121,609 in North America, 1:127,912 in Europe (excluding Denmark, Greenland and the Faroe Islands), and 1:50,386 in Asia; one study suggested 1:17,456 in China [5]. In the Faroe Islands, screening of 26,462 people (55% of the population) identified 89 patients, giving prevalence of 1:297, the highest reported [8]. In Japan, a heterozygote frequency of 1.01% in Akita Prefecture led to estimated incidence of 1:40,000 [39]. The cardiogenetics chapter describes incidence of approximately 1:40,000 with carrier frequency of approximately 1%, and 1:142,000 in US screening [34]. These figures represent screening incidences, inflated by maternal cases and affected by low positive predictive value, rather than clinical prevalences [5, 48].

Portugal and Brazil. Portuguese and Spanish screening programmes (over 1.6 million newborns) showed that the Iberian Peninsula has one of Europe's highest fatty acid oxidation defect prevalences (1:7,914 across the group), and Portugal the highest reported (1:6,351), influenced by MCAD deficiency in the Roma community [77]; this frequency concerns the group and must not be applied to individual entities. Expanded Portuguese screening, introduced in 2004 with 99.8% coverage, also detected maternal cases, including carnitine transporter deficiency [78]. In Brazil, Law No. 14.154/2021 included fatty acid beta-oxidation disorders in the second stage of expansion of the National Newborn Screening Programme [79], and triheptanoin is approved nationally [11]. No published prevalence data specific to these four entities in Brazil, the rest of Latin America or Africa were found in the consulted sources.

France. The PNDS estimates that most of these deficiencies have a birth incidence of the order of 1:100,000 or lower, versus 1:15,000 to 1:20,000 for MCAD deficiency [10]. Patients are followed in the reference and competence centres for inherited metabolic disorders, coordinated by the G2M rare disease health network, which provides the emergency certificates, the updated list of centres and functional investigation laboratories and recommendations for transition. These diseases are included in ALD 17 (long-term condition), with exemption from patient co-payment and 100% coverage of related care, to which support from the family allowance fund (CAF) and the departmental centre for persons with disabilities (MDPH) may be added, with support from a social worker. Schooling takes place in the local school, with an individualised reception plan (PAI) or personalised schooling plan (PPS) that provides for the diet, snacks or packed meals and any adaptations of sport, which is not contraindicated; in working life, adaptations may be justified by muscle weakness or visual impairment (LCHAD/TFP). There is no patient association specific to these deficiencies in France; the PNDS lists the association No Myolyse and the Alliance Maladies Rares [10].

Networks and resources. The relevant European reference network is MetabERN (European Reference Network for Hereditary Metabolic Disorders), which collaborated on the 2026 guideline with INFORM (International Network for Fatty Acid Oxidation Research and Management) [11]. Patient organisations include the FOD Family Support Group (fodsupport.org) and United Mitochondrial Disease Foundation, listed by GeneReviews [3]; multilingual emergency protocols are available at www.emergencyprotocol.net [33].

10. Illustrative Clinical Case

10.1 Pregnancy in a woman with LCHAD deficiency (Shakerdi et al., 2022)

A 30-year-old woman had LCHAD deficiency diagnosed at six weeks after rapid weight loss and loss of consciousness, confirmed by HADHA c.1528G>C homozygosity [65]. She had recurrent decompensations with hypotonia, hypoglycaemia and respiratory failure requiring ventilation, axonal sensorimotor neuropathy (using a crutch for short distances and a wheelchair for longer distances), bilateral pigmentary retinopathy, grade III diastolic dysfunction and recurrent rhabdomyolysis (four admissions in the previous four years; peak CK 45,303 U/L). Before conception, she observed maximum fasting intervals of 4 h by day and 8 h overnight, long-chain fat below 10% of energy, MCT approximately 15%, DHA 200 mg/day, fat-soluble vitamins, carnitine 500 mg four times daily and overnight modified starch; pregabalin and topiramate were discontinued when pregnancy was confirmed [65].

A multidisciplinary team managed pregnancy with weekly laboratory tests (CK, AST, lactate dehydrogenase, urate, liver and kidney function, full blood count) and central venous access from nine weeks. Ejection fraction was 61%. Protein intake rose to approximately 15–17% and MCT to approximately 20% of energy; linoleic and eicosapentaenoic acid deficiencies were corrected with walnut oil. CK rose transiently after influenza vaccination, and the team chose not to vaccinate against pertussis—an individual decision that does not override the general recommendation that vaccination is safe with adequate caloric intake [4]. At 36 weeks, CK reached 2954 U/L with moderately elevated transaminases and no myoglobinuria; withholding long-chain fat and providing glucose polymers every 2–3 hours normalised CK within 48 hours, with insulin for hyperglycaemia. Mean CK during pregnancy was significantly lower than before pregnancy and postpartum. At 37 weeks, she underwent elective caesarean section under spinal anaesthesia at her preference (with no contraindication to vaginal delivery), with 15% peripartum dextrose; a 3.1 kg boy was born with Apgar score 9/10, monitored for hypoglycaemia without problems [65]. CK and ALT trends are shown in figure 1 of the original article (https://pmc.ncbi.nlm.nih.gov/articles/PMC9259390/).

The case illustrates biochemical improvement during the anabolic phase of pregnancy, late gestational and peripartum risks, and the value of preconception planning; individual decisions (caesarean delivery, omitted vaccination, regular carnitine) are not routine recommendations.

10.2 Primary carnitine deficiency across the lifespan (Crefcoeur et al., 2022)

An 18-month-old boy was admitted with a respiratory infection followed by congestive heart failure with a dilated, poorly contracting left ventricle; serum free carnitine was 1.4 µmol/L (reference 19–59) with increased urinary carnitine, and the diagnosis was confirmed by homozygosity for NM_003060.4:c.632A>G p.(Tyr211Cys) in SLC22A5 and fibroblast carnitine transport below 10% [63]. With diuretics and levocarnitine (500 mg three times daily), cardiac function normalised within three months. From the age of 13 he stopped taking the medication, at 20 he left the metabolic clinic and at 27 all care, with free carnitine of 4.0 µmol/L and an ejection fraction of 50%; he observed the Ramadan fast for years without symptoms. At 29, after a viral respiratory infection, he presented with severe heart failure with atrial fibrillation and severe mitral regurgitation, treated in intensive care with furosemide, enoximone and intravenous levocarnitine (6 g bolus and 6 g/day); he was discharged at two weeks with an ejection fraction of 30%, which rose to 55–57% with oral levocarnitine (1.5–3 g four times daily) in the following years [63]. At 38 he had free carnitine of 14 µmol/L, a mildly dilated ventricle and inability to work [63]. The doses in this report reflect the centre's practice and not the label instructions. The case shows the reversibility of cardiomyopathy even in adults, the risk of the paediatric–adult transition and the lifelong nature of treatment.

10.3 Cases illustrated in the Atlas

A girl with VLCAD deficiency was admitted at 12 months in shock, with undetectable glucose, a seizure and modest dicarboxylic aciduria; mass spectrometry showed elevated long-chain acylcarnitines, and hormonal abnormalities consistent with hypopituitarism resolved by six years [26]. Another child was diagnosed at two days because a sibling had died from a fatty acid oxidation defect (elevated C14:1, C16 and C18:1) [26]. A boy with LCHAD deficiency had hypoglycaemia from five months with hepatomegaly and steatosis; fasting and long-chain triglyceride loading caused hypoglycaemia, unlike MCT loading, and he later developed myoglobinuria with markedly elevated CK [21].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Before screening, most defects had significant mortality at presentation but a good prognosis after diagnosis; screening improves outcomes, although it identifies patients who would never have had symptoms [12]. After diagnosis, the prognosis is excellent in treated PCD [12], but the disease is lifelong and interruption of treatment is dangerous [34, 63]. Recurrent rhabdomyolysis persists as a problem in some patients with VLCAD deficiency [12]. LCHAD deficiency is more severe: about one third of patients died at presentation before screening, and there is a high risk of retinopathy and neuropathy and of high-risk pregnancy [12, 40]. Earlier diagnosis and a strict diet improved survival and the clinical course of LCHAD deficiency in Finland [80], prevent or reverse cardiomyopathy [81], but only delay neuropathy and retinopathy [43, 45, 62]. The neonatal forms of CACT, CPT2, TFP and multiple dehydrogenase deficiencies often present before screening results and are often fatal [12]. Some patients with TFP or LCHAD deficiency are wheelchair-dependent in adolescence, and patients with a formal exercise programme maintain better physical fitness [11]. Obesity may become a relevant problem [3]. The French PNDS adds hepatic fibrosis and chronic elevation of transaminases as possible complications, mainly in LCHAD and TFP deficiencies, sporadic hypoparathyroidism, chronic respiratory failure associated with myopathy and persistence of retinopathy and neuropathy despite omega-3 supplementation; in PCD, the long-term course is usually good if supplementation is not interrupted, whereas in CPT1A deficiency no specific complications have been described. Quality of life has been little studied in these diseases, and in the myopathic forms it shares determinants with non-metabolic myopathies [10].

11.2 Follow-up

Sources: [3–5].

The 2026 guideline recommends clinical, biochemical and nutritional surveillance according to its table 1 (including pro-BNP and troponin), regular cardiac monitoring with echocardiography, electrocardiography and Holter in VLCAD, CACT, early-onset CPT2 and LCHAD/TFP deficiencies, regular neurological examination with periodic nerve conduction studies in LCHAD/TFP, periodic retinal imaging (electroretinography, visual evoked potentials, optical coherence tomography, autofluorescence), and individual exercise prescriptions; acylcarnitines should be sampled under standardised conditions relative to meals and exercise [33]. Transition to adult care should be planned and multidisciplinary [3, 5].

Annex 4 of the French PNDS proposes a common monitoring schedule, to be adapted to severity, adherence and psychosocial context; the first visit is systematically held one month after diagnosis [10]:

In PCD, the acylcarnitine profile is of little use in follow-up, unlike residual free carnitine; in patients on oral 3-hydroxybutyrate supplementation some teams measure ketone bodies. Fasting tests are contraindicated, and tolerance of a longer fast, like exercise tests, is assessed only in a specialised setting, with free fatty acids, blood glucose, acylcarnitines and ammonia, without relying on the absence of hypoglycaemia, which is inconsistent and late. At each visit the fasting limits (including sleeping in late), the indications for exercise and the emergency sheets, transmitted to the attending physician and the local hospital, are reviewed; transition to adult services is prepared early, with the recommendations of the G2M network, bearing in mind that adult specialists are scarce [10]. The schedule for long-chain defects covers, in the PNDS, CACT and CPT2 deficiencies and multiple acyl-CoA dehydrogenase deficiency, but excludes CPT1A deficiency on two points: in this condition, regular measurement of free carnitine and of the acylcarnitine profile is not recommended, nor are annual echocardiogram and electrocardiogram, because the disease does not progress to cardiomyopathy, chronic myopathy or other specific late complications; monitoring may also be lightened in moderate late-onset forms and in riboflavin-responsive forms of multiple dehydrogenase deficiency, whose follow-up includes urinary organic acids [10].

12. Summary and Final Considerations

VLCAD, LCHAD, trifunctional protein and carnitine transport deficiencies impair use of long-chain fat as fuel during fasting, illness and exercise, presenting with hypoketotic hypoglycaemia and a Reye-like syndrome, cardiomyopathy and arrhythmias, and myopathy with rhabdomyolysis. Each has distinctive features: genotype–phenotype correlation and predominance of late myopathic forms in VLCAD deficiency; peripheral neuropathy, pigmentary retinopathy and maternal obstetric risk (HELLP and acute fatty liver) in LCHAD and TFP deficiencies, with the founder c.1528G>C allele in northern and central Europe; and, in primary carnitine deficiency, very low plasma carnitine with renal loss, cardiomyopathy and sudden death preventable with levocarnitine, and identification of affected mothers through newborn screening.

Acylcarnitine screening has transformed the epidemiology and prognosis, but requires molecular and functional confirmation, severity stratification and attention to the overtreatment of mild forms. The 2026 international guideline harmonised fasting intervals, long- and medium-chain fat targets, essential fatty acids, DHA, exercise, sick-day protocols and management of pregnancy, while acknowledging predominantly low-quality evidence. Triheptanoin (Dojolvi®) is approved in the United States and other countries, including Brazil, but not in the European Union, with a label dose of up to 35% of caloric intake in at least four doses and frequent gastrointestinal effects; the paediatric phase 3 trial is expected to be completed in 2027. Levocarnitine is mandatory in PCD, at doses often above those of the label, and reserved for documented deficiency in the long-chain defects. Emergency management rests on early intravenous glucose at a supraphysiological rate, without waiting for hypoglycaemia, and that of rhabdomyolysis on hydration with glucose-containing fluids. The 2021 French PNDS agrees with the international guideline on principles, but is more liberal on carnitine and DHA, applies the dietary targets for severe forms to all long-chain defects and provides the operational emergency tool (G2M network certificate) with glucose rates by age and severity thresholds [10].

13. References

1. Orphanet. Very long chain acyl-CoA dehydrogenase deficiency (ORPHA:26793); Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (ORPHA:5); Mitochondrial trifunctional protein deficiency (ORPHA:746); Systemic primary carnitine deficiency (ORPHA:158); Acute fatty liver of pregnancy (ORPHA:243367) [Internet]. Paris: INSERM; 2026 [accessed 4 October 2026]. Available at: https://www.orpha.net. Epidemiological data: Orphadata, en_product9_prev.xml (https://www.orphadata.com).
2. Online Mendelian Inheritance in Man (OMIM). #201475, *609575, #609016, #609015, #620300, *600890, *143450, #212140, *603377 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 4 October 2026]. Available at: https://omim.org.
3. Leslie ND, Saenz-Ayala S. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2009 May 28 [updated 2022 Jun 16; revised 2025 Aug 7]. 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/NBK6816/. PMID: 20301763.
4. Prasun P, LoPiccolo MK, Ginevic I. Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency. 2022 Sep 1. 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/NBK583531/. PMID: 36063482.
5. El-Hattab AW, Almannai M. Primary Carnitine Deficiency. 2012 Mar 15 [updated 2024 Dec 5]. 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/NBK84551/. PMID: 22420015.
6. Lindner M, Hoffmann GF, Matern D. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis. 2010 Oct;33(5):521-6. doi:10.1007/s10545-010-9076-8. PMID: 20373143.
7. Lefèvre CR, Labarthe F, Dufour D, Moreau C, Faoucher M, Rollier P, et al. Newborn Screening of Primary Carnitine Deficiency: An Overview of Worldwide Practices and Pitfalls to Define an Algorithm before Expansion of Newborn Screening in France. Int J Neonatal Screen. 2023 Feb 1;9(1):6. doi:10.3390/ijns9010006. PMID: 36810318.
8. Rasmussen J, Nielsen OW, Janzen N, Duno M, Gislason H, Køber L, et al. Carnitine levels in 26,462 individuals from the nationwide screening program for primary carnitine deficiency in the Faroe Islands. J Inherit Metab Dis. 2014 Mar;37(2):215-22. doi:10.1007/s10545-013-9606-2. PMID: 23653224.
9. ClinGen Actionability Working Group. Gene-condition actionability reports AC126 (Very long chain acyl-CoA dehydrogenase deficiency; released 2025 Aug 13), AC1039 (Disorders of the trifunctional protein complex; 2022 Feb 9) and AC1047 (Systemic primary carnitine deficiency disease; 2022) — paediatric and adult settings [Internet]. Available at: https://actionability.clinicalgenome.org/ac/.
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. Filière de santé maladies rares G2M. Saint-Denis La Plaine: HAS; 2021 Oct 14 (text of June 2021). Available at: https://www.has-sante.fr/jcms/p_3289772
11. Spiekerkoetter U, Vockley J. Treatment of Fatty Acid Oxidation Disorders Today: Emerging Personalized Treatment Strategies. J Inherit Metab Dis. 2026 Sep;49(5):e70255. doi:10.1002/jimd.70255. PMID: 42788480.
12. 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.
13. 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.
14. Crefcoeur LL, Visser G, Ferdinandusse S, Wijburg FA, Langeveld M, Sjouke B. Clinical characteristics of primary carnitine deficiency: A structured review using a case-by-case approach. J Inherit Metab Dis. 2022 May;45(3):386-405. doi:10.1002/jimd.12475. PMID: 34997761.
15. Karpati G, Carpenter S, Engel AG, Watters G, Allen J, Rothman S, et al. The syndrome of systemic carnitine deficiency. Clinical, morphologic, biochemical, and pathophysiologic features. Neurology. 1975 Jan;25(1):16-24. doi:10.1212/wnl.25.1.16. PMID: 234182.
16. Waber LJ, Valle D, Neill C, DiMauro S, Shug A. Carnitine deficiency presenting as familial cardiomyopathy: a treatable defect in carnitine transport. J Pediatr. 1982 Nov;101(5):700-5. doi:10.1016/s0022-3476(82)80294-1. PMID: 7131143.
17. Treem WR, Stanley CA, Finegold DN, Hale DE, Coates PM. Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts. N Engl J Med. 1988 Nov 17;319(20):1331-6. doi:10.1056/NEJM198811173192006. PMID: 3185635.
18. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Chapter 35, Carnitine transporter deficiency; p. 271–277.
19. Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet. 1999 Jan;21(1):91-4. doi:10.1038/5030. PMID: 9916797.
20. 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.
21. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Chapter 41, Long-chain L-3-hydroxyacyl-CoA dehydrogenase (trifunctional protein) deficiency; p. 310–316.
22. Wanders RJ, Duran M, Ijlst L, de Jager JP, van Gennip AH, Jakobs C, et al. Sudden infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase. Lancet. 1989 Jul 1;2(8653):52-3. doi:10.1016/s0140-6736(89)90300-0. PMID: 2567831.
23. Wanders RJ, IJlst L, Poggi F, Bonnefont JP, Munnich A, Brivet M, et al. Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem Biophys Res Commun. 1992 Nov 16;188(3):1139-45. doi:10.1016/0006-291x(92)91350-y. PMID: 1445348.
24. IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ. Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene. J Clin Invest. 1996 Aug 15;98(4):1028-33. doi:10.1172/JCI118863. PMID: 8770876.
25. Ibdah JA, Bennett MJ, Rinaldo P, Zhao Y, Gibson B, Sims HF, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med. 1999 Jun 3;340(22):1723-31. doi:10.1056/NEJM199906033402204. PMID: 10352164.
26. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Chapter 40, Very long-chain acyl-CoA dehydrogenase deficiency; p. 304–309.
27. Bertrand C, Largillière C, Zabot MT, Mathieu M, Vianey-Saban C. Very long chain acyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid oxidation in fibroblasts. Biochim Biophys Acta. 1993 Jan 22;1180(3):327-9. doi:10.1016/0925-4439(93)90058-9. PMID: 8422439.
28. Aoyama T, Uchida Y, Kelley RI, Marble M, Hofman K, Tonsgard JH, et al. A novel disease with deficiency of mitochondrial very-long-chain acyl-CoA dehydrogenase. Biochem Biophys Res Commun. 1993 Mar 31;191(3):1369-72. doi:10.1006/bbrc.1993.1368. PMID: 8466512.
29. Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. doi:10.1086/302261. PMID: 9973285.
30. Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H, et al. Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis. 2009 Aug;32(4):498-505. doi:10.1007/s10545-009-1126-8. PMID: 19452263.
31. Arnold GL, Van Hove J, Freedenberg D, Strauss A, Longo N, Burton B, et al. A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2009 Mar;96(3):85-90. doi:10.1016/j.ymgme.2008.09.008. PMID: 19157942.
32. Van Calcar SC, Sowa M, Rohr F, Beazer J, Setlock T, Weihe TU, et al. Nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD): An evidence- and consensus-based approach. Mol Genet Metab. 2020 Sep-Oct;131(1-2):23-37. doi:10.1016/j.ymgme.2020.10.001. PMID: 33093005.
33. Grünert SC, Bhattacharya K, Karall D, Langeveld M, Rohr F, Visser G, et al. International Guideline on the Diagnosis, Treatment, and Monitoring of Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD). J Inherit Metab Dis. 2026 Sep;49(5):e70251. doi:10.1002/jimd.70251. PMID: 42779363.
34. Linhart A. Metabolic Cardiomyopathy. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 151–166. doi:10.1007/978-3-030-45457-9_9.
35. Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. doi:10.1016/j.ymgme.2015.08.011. PMID: 26385305.
36. Spiekerkoetter U, Sun B, Khuchua Z, Bennett MJ, Strauss AW. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. Hum Mutat. 2003 Jun;21(6):598-607. doi:10.1002/humu.10211. PMID: 12754706.
37. Boutron A, Acquaviva C, Vianey-Saban C, de Lonlay P, de Baulny HO, Guffon N, et al. Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency. Mol Genet Metab. 2011 Aug;103(4):341-8. doi:10.1016/j.ymgme.2011.04.006. PMID: 21549624.
38. Ferdinandusse S, Te Brinke H, Ruiter JPN, Haasjes J, Oostheim W, van Lenthe H, et al. A mutation creating an upstream translation initiation codon in SLC22A5 5'UTR is a frequent cause of primary carnitine deficiency. Hum Mutat. 2019 Oct;40(10):1899-1904. doi:10.1002/humu.23839. PMID: 31187905.
39. Koizumi A, Nozaki J, Ohura T, Kayo T, Wada Y, Nezu J, et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999 Nov;8(12):2247-54. doi:10.1093/hmg/8.12.2247. PMID: 10545605.
40. den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. 2002 Jan;109(1):99-104. doi:10.1542/peds.109.1.99. PMID: 11773547.
41. den Boer ME, Dionisi-Vici C, Chakrapani A, van Thuijl AO, Wanders RJ, Wijburg FA. Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement. J Pediatr. 2003 Jun;142(6):684-9. doi:10.1067/mpd.2003.231. PMID: 12838198.
42. Purevsuren J, Fukao T, Hasegawa Y, Kobayashi H, Li H, Mushimoto Y, et al. Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency. Mol Genet Metab. 2009 Dec;98(4):372-7. doi:10.1016/j.ymgme.2009.07.011. PMID: 19699128.
43. Grünert SC, Eckenweiler M, Haas D, Lindner M, Tsiakas K, Santer R, et al. The spectrum of peripheral neuropathy in disorders of the mitochondrial trifunctional protein. J Inherit Metab Dis. 2021 Jul;44(4):893-902. doi:10.1002/jimd.12372. PMID: 33638202.
44. Tyni T, Kivelä T, Lappi M, Summanen P, Nikoskelainen E, Pihko H. Ophthalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy. Ophthalmology. 1998 May;105(5):810-24. doi:10.1016/S0161-6420(98)95019-9. PMID: 9593380.
45. Fahnehjelm KT, Liu Y, Olsson D, Amrén U, Haglind CB, Holmström G, et al. Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function. Acta Paediatr. 2016 Dec;105(12):1451-1460. doi:10.1111/apa.13536. PMID: 27461099.
46. Schimmenti LA, Crombez EA, Schwahn BC, Heese BA, Wood TC, Schroer RJ, et al. Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab. 2007 Apr;90(4):441-5. doi:10.1016/j.ymgme.2006.10.003. PMID: 17126586.
47. El-Hattab AW, Li FY, Shen J, Powell BR, Bawle EV, Adams DJ, et al. Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. Genet Med. 2010 Jan;12(1):19-24. doi:10.1097/GIM.0b013e3181c5e6f7. PMID: 20027113.
48. Gallant NM, Leydiker K, Wilnai Y, Lee C, Lorey F, Feuchtbaum L, et al. Biochemical characteristics of newborns with carnitine transporter defect identified by newborn screening in California. Mol Genet Metab. 2017 Nov;122(3):76-84. doi:10.1016/j.ymgme.2017.06.015. PMID: 28711408.
49. Hesse J, Braun C, Behringer S, Matysiak U, Spiekerkoetter U, Tucci S. The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). J Inherit Metab Dis. 2018 Nov;41(6):1169-1178. doi:10.1007/s10545-018-0245-5. PMID: 30194637.
50. Blank AC, Breur JMPJ, Fuchs SA, Koop K, Baas AF. Mitochondrial Cardiomyopathies. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 179–191. doi:10.1007/978-3-030-45457-9_11.
51. Ultragenyx Pharmaceutical Inc. DOJOLVI (triheptanoin) oral liquid. Prescribing information [Internet]. Revised 2025 Jun 10. Set ID 4cfeb8bd-143e-4dd7-bc34-b0bcda02460d. Available at: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4cfeb8bd-143e-4dd7-bc34-b0bcda02460d (accessed via openFDA, 4 October 2026).
52. European Medicines Agency. Orphan designations: triheptanoin EU/3/15/1508 (very long-chain acyl-CoA dehydrogenase deficiency), EU/3/15/1524 (long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency), EU/3/15/1525 (mitochondrial trifunctional protein deficiency); EU/3/20/2319 (REN001, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; withdrawn) [Internet]. Amsterdam: EMA; [accessed 4 October 2026]. Available at: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-15-1508.
53. Ultragenyx Brasil Farmacêutica Ltda. DOJOLVI (tri-heptanoína) líquido. Bula para profissionais de saúde (package insert for healthcare professionals) [Internet]. ANVISA registration no. 1.3964.0003. Brasília: Agência Nacional de Vigilância Sanitária, Bulário Eletrônico; published 2025 Sep 4 (file 1176711253). Available at: https://consultas.anvisa.gov.br/#/bulario/q/?nomeProduto=DOJOLVI (accessed 29 October 2026).
54. Gillingham MB, Heitner SB, Martin J, Rose S, Goldstein A, El-Gharbawy AH, et al. Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. J Inherit Metab Dis. 2017 Nov;40(6):831-843. doi:10.1007/s10545-017-0085-8. PMID: 28871440.
55. Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, et al. UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment. Mol Genet Metab. 2017 Apr;120(4):370-377. doi:10.1016/j.ymgme.2017.02.005. PMID: 28189603.
56. Vockley J, Burton B, Berry G, Longo N, Phillips J, Sanchez-Valle A, et al. Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study. J Inherit Metab Dis. 2021 Jan;44(1):253-263. doi:10.1002/jimd.12313. PMID: 32885845.
57. Vockley J, Charrow J, Ganesh J, Eswara M, Diaz GA, McCracken E, et al. Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders. Mol Genet Metab. 2016 Nov;119(3):223-231. doi:10.1016/j.ymgme.2016.08.008. PMID: 27590926.
58. ClinicalTrials.gov. NCT05933200 (Triheptanoin compared with even-chain MCT on major clinical events in pediatric patients with LC-FAOD; Ultragenyx); NCT03833128 (REN001 in fatty acid oxidation disorders; Reneo Pharma); NCT05411835 (Oral ketones and exercise in LC-FAOD; Oregon Health and Science University) [Internet]. Bethesda (MD): National Library of Medicine; [accessed 4 October 2026]. Available at: https://clinicaltrials.gov.
59. Leadiant Biosciences. CARNITOR (levocarnitine) tablets and oral solution; CARNITOR (levocarnitine) injection. Prescribing information [Internet]. Revised 2024 Oct (oral) and 2023 Nov (injectable). Available at: https://dailymed.nlm.nih.gov (set IDs d2133bc3-9c15-48bd-8b16-b8995a6a14cd and cf801cc4-775e-433d-9d32-e5d9a98981d3; accessed via openFDA, 4 October 2026).
60. Laboratório Medinfar – Produtos Farmacêuticos, SA. Disocor 1000 mg/10 ml solução oral (levocarnitina). Resumo das Características do Medicamento (Summary of Product Characteristics) [Internet]. Lisbon: INFARMED; approved 2023 Dec 29. Available at: https://extranet.infarmed.pt/INFOMED-fo/ (accessed 26 October 2026).
61. Agência Nacional de Vigilância Sanitária (ANVISA). Levocarnitine: medicine registrations (DADOS_ABERTOS_MEDICAMENTOS.csv) and Bulário Eletrônico search [Internet]. Brasília: ANVISA; accessed 31 October 2026. Available at: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv and https://consultas.anvisa.gov.br/#/bulario/
62. Fraser H, Geppert J, Johnson R, Johnson S, Connock M, Clarke A, et al. Evaluation of earlier versus later dietary management in long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein deficiency: a systematic review. Orphanet J Rare Dis. 2019 Nov 15;14(1):258. doi:10.1186/s13023-019-1226-y. PMID: 31730477.
63. Crefcoeur LL, Melles MC, Bruning TA, Pereira RR, Langendonk JG. Primary carnitine deficiency is a life-long disease. JIMD Rep. 2022 Nov;63(6):524-528. doi:10.1002/jmd2.12319. PMID: 36341172.
64. Mendez-Figueroa H, Shchelochkov OA, Shaibani A, Aagaard-Tillery K, Shinawi MS. Clinical and biochemical improvement of very long-chain acyl-CoA dehydrogenase deficiency in pregnancy. J Perinatol. 2010 Aug;30(8):558-62. doi:10.1038/jp.2009.198. PMID: 20668464.
65. Shakerdi LA, McNulty J, Gillman B, McCarthy CM, Ivory J, Sheerin A, et al. Management of pregnancy in a patient with long-chain 3-hydroxyacyl CoA dehydrogenase deficiency. JIMD Rep. 2022 Jul;63(4):265-270. doi:10.1002/jmd2.12284. PMID: 35822088.
66. Ørngreen MC, Madsen KL, Preisler N, Andersen G, Vissing J, Laforêt P. Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial. Neurology. 2014 Feb 18;82(7):607-13. doi:10.1212/WNL.0000000000000118. PMID: 24453079.
67. Shiraishi H, Yamada K, Oki E, Ishige M, Fukao T, Hamada Y, et al. Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan; 2nd report QOL survey. Mol Genet Metab Rep. 2019 Sep;20:100496. doi:10.1016/j.ymgmr.2019.100496. PMID: 31372341.
68. Bleeker JC, Visser G, Clarke K, Ferdinandusse S, de Haan FH, Houtkooper RH, et al. Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2020 Jul;43(4):787-799. doi:10.1002/jimd.12217. PMID: 31955429.
69. Vieira Neto E, Wang M, Szuminsky AJ, Ferraro L, Basu S, Zhao X, et al. Elamipretide Improves Mitochondrial Function in Mitochondrial Trifunctional Protein-Deficient Mice and Human Fibroblasts. J Inherit Metab Dis. 2026 Jan;49(1):e70132. doi:10.1002/jimd.70132. PMID: 41500837.
70. Yoon JH, Park JH, Kim D, Hwang S, Park J, Kim JH, et al. Long-term safety and efficacy of triheptanoin in Korean patients with long-chain fatty acid oxidation disorders: a prospective, open-label, single-center, phase II clinical study. BMC Med Genomics. 2026 May 16;19(1):112. doi:10.1186/s12920-026-02390-x. PMID: 42143327.
71. Santos H, Vieira A, Tenente J, Carriço A, Rodrigues E. 18 Months of Treatment with Triheptanoin in 2 Patients with Long Chain Fatty Acid Oxidation Disorders. Endocr Metab Immune Disord Drug Targets. 2023 Dec 13. doi:10.2174/0118715303279681231122104925. PMID: 38093447.
72. Rebelo M, Pires M, Azurara L, Câmara L, Pereira M, Ribeirinho A, et al. Metabolic Myopathies: Experience of a Reference Center of Inherited Metabolic Diseases. Endocr Metab Immune Disord Drug Targets. 2023 Oct 18. doi:10.2174/0118715303279208231012051937. PMID: 37859320.
73. Joost K, Ounap K, Zordania R, Uudelepp ML, Olsen RK, Kall K, et al. Prevalence of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency in Estonia. JIMD Rep. 2012;2:79-85. doi:10.1007/8904_2011_51. PMID: 23430857.
74. Piekutowska-Abramczuk D, Olsen RK, Wierzba J, Popowska E, Jurkiewicz D, Ciara E, et al. A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Poland. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S373-7. doi:10.1007/s10545-010-9190-7. PMID: 20814823.
75. Nedoszytko B, Siemińska A, Strapagiel D, Dąbrowski S, Słomka M, Sobalska-Kwapis M, et al. High prevalence of carriers of variant c.1528G>C of HADHA gene causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the population of adult Kashubians from North Poland. PLoS One. 2017;12(11):e0187365. doi:10.1371/journal.pone.0187365. PMID: 29095929.
76. Bo R, Yamada K, Kobayashi H, Jamiyan P, Hasegawa Y, Taketani T, et al. Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: a comparison with Caucasian cases. J Hum Genet. 2017 Sep;62(9):809-814. doi:10.1038/jhg.2017.52. PMID: 28515471.
77. 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.
78. 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.
79. Brazil. 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.
80. Immonen T, Turanlahti M, Paganus A, Keskinen P, Tyni T, Lapatto R. Earlier diagnosis and strict diets improve the survival rate and clinical course of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Acta Paediatr. 2016 May;105(5):549-54. doi:10.1111/apa.13313. PMID: 26676313.
81. De Biase I, Viau KS, Liu A, Yuzyuk T, Botto LD, Pasquali M, et al. Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency. JIMD Rep. 2017;31:63-71. doi:10.1007/8904_2016_558. PMID: 27117294.