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Specific fatty acid oxidation disorders

Specific fatty acid oxidation disorders
Author:
Jerry Vockley, MD, PhD
Section Editor:
Sihoun Hahn, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Oct 2022. | This topic last updated: Jan 11, 2022.

INTRODUCTION — Fatty acid oxidation disorders (FAODs) (table 1) are inborn errors of metabolism resulting in failure of mitochondrial beta-oxidation or the carnitine-based transport of fatty acids into mitochondria (figure 1). They are primarily categorized based upon the length of the fatty acid chain. FAODs lead to deficient energy production and produce widely variable clinical presentations ranging from mild hypotonia in adults to sudden death in infants [1].

This topic reviews the major types of FAODs and disease-specific management. A general overview of the clinical features, diagnosis, and management of FAODs is presented separately. (See "Overview of fatty acid oxidation disorders".)

LONG-CHAIN FATTY ACID OXIDATION DISORDERS — The long-chain fatty acid oxidation disorders (LCFAODs) include defects that affect the carnitine cycle or fatty acid beta-oxidation (figure 1). LCFAODs are typically associated with a more severe phenotype due to a greater energy deficit, with symptoms including cardiomyopathy, arrhythmia, skeletal myopathy, rhabdomyolysis, transaminitis, liver failure, and retinal degeneration. However, milder disease with adolescent or adult onset can occur.

Carnitine cycle defects — Carnitine is essential for long-chain fatty acid transport through the cell membrane and mitochondrial outer and inner membranes into the mitochondrial matrix where fatty acid oxidation occurs (figure 1). The carnitine transport cycle includes a sodium-dependent carnitine transporter that moves carnitine across the cell membrane and into the cytosol, a transferase (carnitine palmitoyltransferase 1 [CPT1]) that covalently links carnitine to the long-chain fatty acyl-CoA, an acylcarnitine translocase (carnitine-acylcarnitine translocase [CACT]) that transports carnitine and carnitine-fatty acid complexes across the mitochondrial membrane, and then a second transferase (carnitine palmitoyltransferase 2 [CPT2]) that removes the carnitine from the long-chain fatty acyl-CoA. Deficiency in any of these components disrupts the carnitine cycle.

Carnitine transporter deficiency — Carnitine transporter deficiency (CTD; also called primary systemic carnitine deficiency or carnitine uptake defect) is an autosomal-recessive disease caused by pathogenic variants in the solute carrier family 22 member 5 (SLC22A5) gene that encodes a high-affinity sodium-ion dependent organic cation transporter protein (OCTN2) expressed in heart muscle, kidney, lymphoblasts, and fibroblasts. CTD is characterized by hypoketotic hypoglycemia, hyperammonemia, liver dysfunction, cardiomyopathy, and skeletal hypotonia. Presentation during the neonatal period is uncommon. Cardiomyopathy may be the presenting sign in children or young adults.

Profoundly low plasma total and free carnitine levels (typically less than 10 micromol/L in plasma) are found. False-positive newborn screening (NBS) for low free carnitine levels may be due to neonatal nutritional deficiency or secondary to low maternal plasma carnitine levels from either dietary restriction (eg, vegan diet) or previously unrecognized maternal CTD. Measurement of maternal total and free carnitine levels are necessary when performing follow-up testing of an abnormal NBS. Maternal CTD may be clinically significant and benefit from carnitine supplementation, although some mothers may have been asymptomatic or have mild symptoms that were not clinically recognized. Diagnostic confirmation through DNA sequencing of the SLC22A5 gene is typically adequate, although analysis of fibroblast carnitine uptake is available [2].

Treatment of CTD involves supplementation with carnitine, usually at doses of at least 100 to 200 mg/kg/day, adjusted as necessary to obtain normal total and free plasma carnitine levels. Fasting avoidance and frequent feeding are generally recommended. Outcomes are positive with improvements in cardiomyopathy, hypoglycemia, and rhabdomyolysis.

Carnitine palmitoyltransferase 1A deficiency — The CPT1 enzyme has three different isoforms encoded by different genes. Deficiency of only CTP1A, expressed in the liver and kidney, has been described. Carnitine palmitoyltransferase 1A deficiency (CPT1AD) is an autosomal-recessive disorder that typically presents in early childhood with hypoketotic hypoglycemia and liver dysfunction, which may quickly progress to liver failure and hepatic encephalopathy. Cardiomyopathy or skeletal myopathy is not seen, although renal tubular acidosis has been reported during episodes of acute decompensation [3]. Symptoms are often triggered by fasting or by a concurrent infection, fever, or gastrointestinal illness, and onset of symptoms is typically rapid [4].

A milder phenotype associated with a common CPT1A variant, c.1436C>T (p.P479L), occurs in circum-Arctic populations and North American Hutterites, although it is still associated with higher infant mortality and impaired fasting intolerance [5-8]. The frequency of this allele in the Inuit and Inuvialuit populations that reside in northern coastal regions is 0.44 [5].

An adult-onset myopathy is less common, and neonatal hypoglycemia is rare [9]. Acute fatty liver of pregnancy can develop in female carriers if the fetus is homozygous for a pathogenic variant in CPT1A [4,10].

Diagnostic laboratory findings include elevated total and free plasma carnitine levels with low long-chain acylcarnitines; an elevated C0/(C16+C18) ratio improves specificity in NBS. Confirmatory testing is through the demonstration of mutations in the CPT1A gene or enzyme activity in skin fibroblasts.

Treatment includes fasting avoidance, a low-fat diet with medium chain triglyceride (MCT; medium chain fatty acids) supplementation or triheptanoin, and supportive care during illness. Carnitine supplementation has not been therapeutic. (See 'Dietary management of LCFAODs' below and 'L-carnitine supplementation in LCFAODs' below and "Overview of fatty acid oxidation disorders", section on 'Common elements of treatment'.)

Patients with CPT1AD can have a normal outcome, but some suffer neurologic impairment from repeated episodes of metabolic decompensation [3,11]. Liver function tests and glucose should be monitored during times of illness or reduced caloric intake. Pregnant individuals who are carriers should be monitored for acute fatty liver of pregnancy. (See "Acute fatty liver of pregnancy".)

Carnitine-acylcarnitine translocase deficiency — Carnitine-acylcarnitine translocase deficiency (CACTD) is an autosomal-recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the solute carrier family 25 member 20 (SLC25A20) gene that most often presents with severe neonatal symptoms including ventricular dysrhythmias, cardiomyopathy, hypoglycemia, hyperammonemia, and sudden death [12,13]. More chronic symptoms include hypoglycemia, vomiting, gastroesophageal reflux, and mild chronic hyperammonemia as well as severe skeletal myopathy and mild hypertrophic cardiomyopathy. Early diagnosis and treatment can be beneficial, although significant morbidity including profound developmental delay, seizures, and other complications occur despite NBS [12,14-16]. Milder disease associated with higher residual enzyme activity has been reported [17]. However, enzyme activity does not necessarily correlate with disease severity [18].

Affected individuals have elevated C16-, C16:1-, C18-, and C18:1-acyclarnitine levels with low free carnitine levels on diagnostic testing and NBS. DNA sequencing of the SLC25A20 confirms the disease.

Treatment includes avoidance of prolonged fasting; use of a low-fat, high-carbohydrate formula (a fat-restricted diet is not necessary); MCT or triheptanoin supplementation; and carnitine supplementation (100 to 200 mg/kg/day). Treatment is successful in preventing or reversing symptoms in some cases but is dependent upon compliance. Despite NBS, the mortality rate remains high and the prognosis poor in most infants [12,16]. Surviving patients may suffer profound developmental delay, seizures, and other complications [14,15]. (See 'Dietary management of LCFAODs' below and 'L-carnitine supplementation in LCFAODs' below and "Overview of fatty acid oxidation disorders", section on 'Common elements of treatment'.)

Carnitine palmitoyltransferase type 2 deficiency — A severe, neonatal form of carnitine palmitoyltransferase type 2 deficiency (CPT2D) presents with hypotonia, cardiomyopathy, arrhythmias, seizures, and multiple congenital anomalies (dysmorphic facies, renal cysts, brain malformations) and may result in death during the first days to months of life [19]. However, the majority of affected individuals have a later-onset form that presents in the second or third decade of life with exercise intolerance and attacks of rhabdomyolysis, which can lead to kidney failure and death [11]. CPT2D results in an identical acylcarnitine pattern as CACTD, with elevations of C16- and C18:1-acylcarnitines on NBS or diagnostic testing. Treatment is also the same. Confirmatory sequencing of the gene, CPT2, verifies the diagnosis [20]. Most later-onset patients carry a common mutation resulting in a higher residual enzyme activity [20]. (See 'Carnitine-acylcarnitine translocase deficiency' above.)

Beta-oxidation defects — Intramitochondrial beta-oxidation defects involve the following enzymes (figure 1):

Very long-chain acyl-coenzyme A dehydrogenase (VLCAD)

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD)

Trifunctional protein (TFP)

Medium-chain acyl-coenzyme A dehydrogenase (MCAD)

Multiple acyl-coenzyme A dehydrogenase:

Electron transfer flavoprotein dehydrogenase (ETFDH)

Electron transfer flavoprotein A and B (ETFA and ETFB)

Short-chain acyl-coenzyme A dehydrogenase (SCAD)

Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD)

Myopathy and cardiomyopathy occur in most of the LCFAODs. Transient hepatic dysfunction has been documented in younger patients at times of catabolic crisis but is uncommon outside of infancy. Deficiencies in VLCAD, LCHAD, and TFP are reviewed in this section, and the others are discussed below. (See 'Medium- and short-chain fatty acid oxidation disorders' below.)

Very-long-chain acyl-CoA dehydrogenase deficiency — Historically, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) was estimated to affect between 1 in 100,000 to 1 in 120,000 individuals, but NBS studies suggest the prevalence is as high as 1 in 42,500 [21]. VLCAD is highly expressed in the liver, heart, and skeletal muscle. When this enzyme is completely or partially deficient, phenotypes vary from severe cardiomyopathy and death in the first few days of life, to recurrent hypoketotic hypoglycemia, or to adolescent or adult presentations with myopathy and/or rhabdomyolysis [22-27]. Cardiomyopathy and arrhythmias have been reported in 48 and 52 percent, respectively [28].

A delay in diagnosis may result in detection after the first critical illness or on postmortem biochemical evaluation [29]. Plasma acylcarnitine profile shows elevations of C14:1-, C14-, C16:1-, and C16-acylcarnitines levels, with low secondary free carnitine levels in some infants. During an acute metabolic decompensation, urine organic acid analysis may demonstrate longer-chain dicarboxylic aciduria. Most patients with VLCADD in the United States and other developed countries are detected through NBS by acylcarnitine profiling. Confirmation by sequencing and deletion/duplication analysis of the acyl-CoA dehydrogenase, very long chain gene (ACADVL) is recommended, but the identification of mild or benign DNA variants represents a significant challenge. Individuals with a single variant are heterozygous, unaffected carriers, although the presence of a second, undetected variant is still possible. Patients with two compound heterozygous variants may have a reduced risk of developing symptoms, although the degree of severity of these symptoms may still be as significant as those with known severe variants. Pathogenic variants leading to milder disease have been identified, especially through NBS [21]. Leukocyte enzyme assay or fatty acid oxidation probe analysis may be helpful to determine treatment when a single heterozygous or novel heterozygous variants are found and/or there are persistent acylcarnitine elevations inconsistent with the genotype [30].

Treatment follows the general principles for management of LCFAODs including prolonged fasting avoidance, dietary fat restriction, and MCT or triheptanoin supplementation [31]. In the past, supplementation with L-carnitine was a proposed therapy for FAODs, but this therapy has become more controversial. Symptomatic infants should discontinue breastfeeding (due to the high fat content in breast milk) and start MCT-containing formula or triheptanoin [32]. Breastfeeding may be supplemented with MCT-containing formula in patients with milder or asymptomatic forms of VLCADD. (See 'Dietary management of LCFAODs' below and 'L-carnitine supplementation in LCFAODs' below and "Overview of fatty acid oxidation disorders", section on 'Common elements of treatment'.)

Long-chain 3-hydroxyacyl-CoA dehydrogenase and trifunctional protein deficiency — The mitochondrial trifunctional protein is a hetero-octamer that includes four alpha and four beta subunits encoded by two genes (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [TFP], alpha and beta subunits [HADHA and HADHB]) with three enzymatic activities: long-chain enoyl-CoA hydratase, LCHAD, and 3-ketoacyl-CoA thiolase. The term "isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency" (LCHADD) indicates that only the dehydrogenase activity of the protein is deficient, caused by one specific pathogenic variant in the HADHA gene. Deficiency of all three enzymes is termed trifunctional protein deficiency (TFPD) and results from pathogenic variants in either the HADHA or HADHB genes. Both LCHADD and TFPD are autosomal-recessive disorders. The prevalence of LCHADD ranges from 1 in 110,000 to 150,000; TFPD is much rarer.

The most severe forms of LCHADD and TFPD may present with a rapidly progressive neonatal cardiomyopathy [33,34]. Infants may later develop recurrent hypoketotic hypoglycemia with acute catabolic illness resulting in liver dysfunction (a Reye-like syndrome), cardiomyopathy, myopathy, and rhabdomyolysis. Cholestasis may be present. Surviving individuals with LCHADD or TFPD may experience skeletal myopathy (65 percent), a slowly progressing peripheral neuropathy (21 percent), and pigmentary retinopathy (43 percent) [33]. Peripheral neuropathy in TFPD is earlier in onset and more severe than in those with LCHADD. Some patients may have severe liver disease with fibrosis in addition to necrosis and steatosis. Older children, adolescents, and adults may develop recurrent rhabdomyolysis during illness.

The majority of moderate-to-severe cases are identified by NBS. Diagnostic elevations of C16:1-OH-, C16-OH-, C18:1-OH-, and C18-OH-acylcarnitines are seen on plasma acylcarnitine analysis. Urine organic acid analysis shows longer-chain 3-hydroxydicarboxylic acids. Enzymatic diagnosis can be made in leukocytes or in skin fibroblasts, but a combination of clinical features, biochemical abnormalities, and HADHA or HADHB mutation analysis is often sufficient. A c.1528G>C mutation causing an amino acid substitution p.E510Q in the TFP-alpha subunit accounts for approximately 90 percent of all LCHADD.

Treatment of LCHADD and TFPD involves avoidance of prolonged fasting, dietary fat restriction, and MCT or triheptanoin supplementation. A low-fat diet and MCT supplementation decrease plasma hydroxyacylcarnitine levels and substantially reduce the risk of metabolic decompensation, but patients on this diet still require supplementation with essential fatty acids and fat-soluble vitamins [35]. Supplementation with docosahexaenoic acid (DHA) may reduce the progression of retinal disease but typically does not prevent it. Patients continue to require prophylactic emergency management during illnesses and supportive care pre- and postoperatively. L-carnitine supplementation is controversial. (See 'Dietary management of LCFAODs' below and 'L-carnitine supplementation in LCFAODs' below and "Overview of fatty acid oxidation disorders", section on 'Common elements of treatment'.)

Outcomes have improved with early diagnosis through NBS and timely institution of therapy, but morbidity and mortality are not entirely prevented, especially in TFPD patients [12,33,34,36]. The survival rate for TFPD is poorer than for LCHADD [12,33].

Dietary management of LCFAODs — The diet of patients with long-chain fatty acid oxidation disorder (LCFAOD) should be high in carbohydrates and low in long-chain fats [37]. Avoiding essential fatty acid deficiency requires supplementation with essential fatty acids. Patients are also supplemented with MCT oil to provide a substrate for beta-oxidation.

The strictness of the diet may vary depending upon disease severity. In severe VLCADD, for example, the dietary total fat is limited to 25 to 30 percent of total calories with one-third long-chain fatty acid content, and discontinuation of breastfeeding may be necessary [32,37]. In contrast, in milder cases of VLCADD, neonates may be allowed a more liberal goal of 30 to 40 percent of total calories from fat, including some breastfeeding. There is risk of essential fatty acid deficiency with these dietary restrictions. Thus, levels must be monitored through periodic measurement of essential fatty acid profile and appropriate supplementation provided as necessary.

MCT, including triheptanoin, can be used in patients with LCFAODs because medium-chain fatty acids can enter mitochondria directly, thereby circumventing the block in long-chain fatty acid oxidation. MCT oil or triheptanoin typically should provide 20 to 25 percent of total energy from the diet [32]. The dose of MCT oil is 0.5 g/kg per day in three divided doses, which can be gradually increased to 1 to 1.5 g/kg per day. Excess MCT oil, however, can be converted into long-chain fats in adipocytes, which limits the effectiveness of this treatment. In one small study, most patients with an LCHADD remained without episodes of metabolic decompensation when on a low-fat diet with supplemental MCT, essential fatty acids, and fat-soluble vitamins and demonstrated decreased plasma hydroxyacylcarnitines [35]. In patients with LCHADD or TFPD, preexercise "loading" with MCT oil reduced long-chain hydroxyacylcarnitines by 30 percent and increased beta-hydroxybutyrate levels threefold compared with those not given MCT oil [38]. MCT supplementation was associated with a reversal of cardiomyopathy in CACTD and VLCADD [14,39,40]. However, even highly compliant patients with VLCADD may still exhibit significant muscle weakness, muscle pain, and/or myoglobinuria [33]. Triheptanoin, a seven carbon triglyceride, was approved to treat LCFAODs and provides improved clinical outcomes compared with standard MCT oil [31,41-44].

A higher-protein diet has been investigated in patients with LCHADD and TFPD due to the increased incidence of overweight and obesity observed by some groups. While short-term studies have found a higher-protein diet to be safe and well tolerated and resulted in lowered energy intake and increased energy expenditure as compared with the standard high-carbohydrate diet, further long-term safety and efficacy studies are needed [45].

L-carnitine supplementation in LCFAODs — Oral carnitine supplementation is controversial. Patients with long-chain fatty acid oxidation disorder (LCFAOD) may develop secondary carnitine deficiency, but there is no published beneficial evidence of long-term carnitine supplementation [32]. Thus, carnitine supplementation is given only if secondary carnitine deficiency is found, which is almost always the case with CTD and CACTD but is less commonly so for the other LCFAODs.

Long-chain hydroxyacylcarnitines may exert a toxic effect by inducing cardiac arrhythmia, and, while carnitine supplementation induced production of acylcarnitines in VLCAD knockout mice, it did not replenish low free carnitine levels [46,47]. Additionally, carnitine supplementation in long-chain acyl-CoA dehydrogenase (LCAD) knockout mice did not result in long-chain acylcarnitine accumulation or affect cardiac function [48].

MEDIUM- AND SHORT-CHAIN FATTY ACID OXIDATION DISORDERS — Defects that involve intramitochondrial beta-oxidation of medium- and short-chain fatty acids include medium-chain acyl-coenzyme A dehydrogenase (MCAD), multiple acyl-coenzyme A dehydrogenase (made up of electron transfer flavoprotein dehydrogenase [ETFDH] and electron transfer flavoprotein [ETF]), short-chain acyl-coenzyme A dehydrogenase (SCAD), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) deficiencies (figure 1).

Medium-chain acyl-CoA dehydrogenase deficiency — Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common FAOD in White Northern Europeans and North Americans. While nearly all MCADD is detected now on newborn screening (NBS), later presentations still occur in older individuals. Historically, MCADD had a high mortality rate and was associated with sudden unexplained infant deaths, with survivors having subsequent neurologic injury, but earlier diagnosis and treatment due to NBS have dramatically improved mortality and morbidity [49,50].

Clinical presentations commonly include hypoketotic hypoglycemia with liver dysfunction and hepatomegaly during an infection, with vomiting, poor oral intake, dehydration, lethargy, and seizures. The presentation is similar to Reye syndrome and leads to death from brain edema and hyperammonemia. Severe lethal presentations with sudden infant death may occur, including in the first few days of life prior to availability of NBS results. Patients who are identified with "mild" or "asymptomatic" MCADD on NBS should still be considered at risk and receive long-term follow-up [49].

Reported chronic complaints include muscle weakness, fatigue, and poor exercise intolerance, although these complaints were not associated with abnormal cardiac function [51]. Others have reported arrhythmia [51,52].

NBS with acylcarnitine profiling reveals elevated C6-, C8-, C10-, and C10:1-species with an increased C8/C10:1 ratio. Urine acylglycine analysis may show elevation of propionylglycine, suberylglycine, and hexanoylglycine. Confirmation through DNA sequencing of acyl-CoA dehydrogenase, C-4 to C-12 straight chain (ACADM) is available, with a common mutation, c.985A>G, accounting for 70 percent of mutant alleles in individuals of Northern European ancestry.

Infants may continue to breastfeed or receive breast milk or standard infant formulas as appropriate to meet standard infant nutritional needs with introduction of solid foods later as per standard infant feeding guidelines [53]. Treatment focuses upon avoidance of prolonged fasting, especially during intercurrent illness. A diet high in carbohydrates and low in fat is recommended. Patients should avoid excessive dietary sources of medium-chain triglycerides (MCTs) such as manufactured MCT oil and coconut oil. Carnitine supplementation may be necessary in those patients with MCADD who have low free carnitine levels.

Multiple acyl-CoA dehydrogenase deficiency — Multiple acyl-CoA dehydrogenase deficiency (MADD; also known as glutaric acidemia type 2 [GA2]) is the result of a defect of electron transfer from all of the acyl-CoA dehydrogenases through their physiologic electron acceptor (ETF to ETFDH) and finally to coenzyme Q10 in complex III of the mitochondrial electron transport chain. ETF is made up of two subunits: ETFA and ETFB. Mutations in ETFA and ETFB, as well as the ETFDH gene, disrupt the flow of reducing equivalents and, thus, oxidative phosphorylation. Riboflavin is a precursor of the essential flavin adenine dinucleotide (FAD) cofactor for each of these enzymes, and riboflavin deficiency (including genetic defects in riboflavin synthesis or cellular transport) may mimic MADD. Riboflavin-responsive mutations of each of the above genes have also been described, most frequently in ETFDH.

Clinical presentations of MADD have an overlapping spectrum of symptoms that fall into three main categories: neonatal presentation with or without congenital anomalies and a later-onset form. The severe neonatal form can present with metabolic crisis, including metabolic acidosis, nonketotic hypoglycemia, and hyperammonemia; additional features include hypotonia, cardiomyopathy, hepatomegaly, "sweaty feet" odor, coma, and neonatal death [54]. A rapidly progressing hypertrophic cardiomyopathy often occurs in the neonatal-onset forms, and the risk for sudden death is great even with prior detection through NBS [54,55]. Congenital malformations include enlarged polycystic kidneys, rocker-bottom feet, inferior abdominal musculature defects, hypospadias and chordee, hypotonia, cerebral cortical dysplasia, and gliosis [56]. Dysmorphic features include telecanthus, malformed ears, macrocephaly, a large anterior fontanel, a high forehead, and a flat nasal bridge. The physical features resemble those seen in severe carnitine palmitoyl-transferase 2 deficiency (CPT2D). (See 'Carnitine palmitoyltransferase type 2 deficiency' above.)

The later-onset form of MADD does not have congenital malformations but rather a lifelong risk of acute intermittent episodes that consist of vomiting, dehydration, hypoketotic hypoglycemia, and acidosis, with hepatomegaly or a lipid storage myopathy in some older individuals. Episodes of acute decompensation may be triggered by infection, fever, surgery, low-energy diets or weight loss, alcohol, and pregnancy. Most of these patients develop chronic myopathic symptoms including exercise intolerance, myalgias, muscle weakness, and muscle atrophy [57]. Associated secondary muscle coenzyme Q10 deficiency, primarily in adulthood, has been reported in some patients with ETFDH mutations [58,59]. Later-onset forms of disease are more likely to be riboflavin responsive.

A diagnosis of MADD is suspected with the combination of increased anion gap metabolic acidosis, lactic acidosis, hypoketotic hypoglycemia, and hyperammonemia. A "sweaty feet" odor of isovaleric acid may be present. Diagnostic testing demonstrates elevations of metabolites from short-, medium-, and long-chain fatty acids; branched-chain amino acid; and sarcosine metabolism due to the various acyl-CoA dehydrogenase enzymes involved. Plasma acylcarnitine testing and NBS show elevations of C4-, C5-, C5DC-, C6-, C8-, C10:1-, C12-, C14-, C14:1-, C16-, C16:1-, C18-, C18:1-, C16-OH-, C16:1-OH-, C18-OH-, and C18:1-OH-acylcarnitines. Urine organic acid testing demonstrates elevations of ethylmalonic acid; glutaric acid; 3-hydroxyisovaleric acid; lactic acid; medium- and long-chain dicarboxylic acids; and isovalerylglycine, isobutyrylglycine, and 2-methylbutyrylglycine. Ketone bodies, including acetoacetic acid and 3-hydroxybutyric acids, are minimal or undetectable. Liver dysfunction leads to elevated serum transaminases and prolonged prothrombin time and partial thromboplastin times. Renal tubular dysfunction results in generalized aminoaciduria. Confirmation should include DNA sequencing of the genes ETFA, ETFB, and ETFDH. If normal, genes of riboflavin synthesis or transport should be interrogated. Enzyme testing is also available from liver biopsy or fatty acid oxidation probe analysis in fibroblasts but may not be necessary. Several ETFDH variants lead to a milder, riboflavin-responsive phenotype with correction of clinical and biochemical parameters in some individuals with at least one these alleles [60].

The complex treatment plan for MADD requires a low-protein and low-fat diet; avoidance of prolonged fasting; and supplementation with carnitine, riboflavin (50 mg three times a day in young children and 100 mg three times a day in older children and adults), and glycine (150 mg/kg/day divided three times a day). Patients with MADD due to ETFDH pathogenic variants who have coenzyme Q10 deficiency can additionally be treated with a coQ10 supplement (dose in children is 4 to 20 mg/kg per day given once a day or in two divided doses). Metabolic formulas have to be individually designed to meet nutritional goals. Acute decompensation should be treated promptly with intravenous (IV) glucose and carnitine to restore anabolism, with close monitoring of cardiac, hepatic, and renal function. Ketone bodies represent a source of energy that patients with MADD can metabolize, and small trials of treatment with 4-hydroxybutyrate have shown some success, especially relative to cardiac function. However, larger studies are necessary to confirm initial results. (See 'L-carnitine supplementation in LCFAODs' above.)

Short-chain acyl-CoA dehydrogenase deficiency — Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is diagnosed through elevations of C4-acylcarnitine and urinary ethylmalonic acid and butyrylglycine. Individuals with mild, moderate, and severely decreased enzyme function may be identified on NBS. Prior reports found that decreased SCAD enzyme activity was associated with a wide variety of symptoms including failure to thrive, poor feeding, hypotonia, and seizures. Subsequently, up to 14 percent of the normal population was found to be compound heterozygous or homozygous for one of two common polymorphisms (c.511C>T and c.625G>A) in the acyl-CoA dehydrogenase, C-2 to C-3 short chain gene (ACADS) that reduce enzyme activity and lead to the biochemical abnormalities of SCADD but are of no physiologic consequence [61]. Rarer inactivating alleles have been described, including a common one in Ashkenazi Jews. Currently, all infants with SCADD detected on NBS have been reported to remain asymptomatic, leading many to consider SCADD to be a benign biochemical phenotype rather than a clinically relevant inborn error of metabolism [62]. Chronic treatment seems inadvisable, although the need for carnitine or riboflavin supplementation, or other acute management during illness, is unclear [63].

Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency — 3-hydroxyacyl-CoA dehydrogenase, encoded by HADH, catalyzes the NAD+ dependent oxidation of 3-hydroxyacyl-CoA for C4 to C10 substrates [64,65]. Unlike the trifunctional protein (TFP), SCHAD has only one enzymatic function. Most patients with proven SCHAD pathogenic variants have recurrent hypoglycemia that is associated with diazoxide-responsive hyperinsulinism [66-71]. Thus, short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (SCHADD) should be classified as a congenital hyperinsulinism syndrome. Symptoms are typically precipitated by stressors, fasting, or dietary protein [71]. Protein sensitivity and hyperinsulinism are related to a nonenzymatic function of the SCHAD protein, which interacts with glutamate dehydrogenase (GDH) in pancreatic islet cells to downregulate GDH activity, leading to gain of activity insulin sensitivity. To date, among cases with proven HADH variants, skeletal and cardiomyopathies have not been present, differentiating this disorder from the longer-chain defects in trifunctional protein. All patients with SCHADD have presented within the first year of life. Late diagnosis can result in seizures and intellectual disability due to recurrent hypoglycemia [70]. Short- and medium-chain 3-hydroxyacylcarnitines may be elevated during episodes of hypoglycemia and on NBS. Treatment reflects recognition and management of hypoglycemia with frequent feedings and/or continuous IV dextrose in crisis and diazoxide or other therapies that are used in other forms of congenital hyperinsulinism syndromes.

SUMMARY

Fatty acid oxidation disorders (FAODs) (table 1) are inborn errors of metabolism resulting in failure of mitochondrial beta-oxidation or the carnitine-based transport of fatty acids into mitochondria (figure 1). They are primarily categorized based upon the length of the fatty acid chain. FAODs lead to deficient energy production and produce widely variable clinical presentations ranging from mild hypotonia in adults to sudden death in infants. (See 'Introduction' above and "Overview of inherited disorders of glucose and glycogen metabolism".)

Carnitine is essential for long-chain fatty acid transport through the cell membrane and mitochondrial outer and inner membranes into the mitochondrial matrix where fatty acid oxidation occurs. Defects that cause FAODs result from deficiency of components in the carnitine cycle or beta-oxidation. (See 'Carnitine cycle defects' above and 'Beta-oxidation defects' above.)

The long-chain fatty acid oxidation disorders (LCFAODs) are typically associated with a more severe phenotype due to a greater energy deficit, with symptoms including cardiomyopathy, arrhythmia, skeletal myopathy, rhabdomyolysis, transaminitis, liver failure, and retinal degeneration. They have the highest rates of morbidity and mortality, particularly when untreated or diagnosed after signs and symptoms of disease have developed. However, milder disease with adolescent or adult onset occurs. Treatment with triheptanoin reduces the morbidity and mortality of LCFAODs. (See 'Long-chain fatty acid oxidation disorders' above.)

The diet of patients with LCFAODs should be high in carbohydrates and low in long-chain fats. Avoiding essential fatty acid deficiency requires supplementation with essential fatty acids. Patients are also supplemented with medium chain triglyceride (MCT) oil to provide a substrate for beta-oxidation. (See 'Dietary management of LCFAODs' above.)

Medium- and short-chain fatty acid oxidation disorders have a wide spectrum of severity and age of onset. Overall, outcomes of these disorders have improved with early diagnosis and treatment due to newborn screening (NBS). (See 'Medium- and short-chain fatty acid oxidation disorders' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges J Lawrence Merritt II, MD, who contributed to an earlier version of this topic review.

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Topic 115918 Version 6.0

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