Long-chain fatty acid oxidation defects

Jerry Vockley MD PhD

Neurogenetic Disorders

Updated 09.12.2024
Released 11.07.2004
Expires For CME 09.12.2027

Long-chain fatty acid oxidation defects

Author: Jerry Vockley MD PhD

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Editor: Deepa S Rajan MD

Long-chain fatty acid oxidation defects

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Introduction

Overview

Very long-chain acyl-CoA dehydrogenase and mitochondrial trifunctional protein (including isolated long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiencies are recessively inherited inborn errors of mitochondrial fatty acid oxidation. They have a wide range of manifestations, from clinically asymptomatic to severe hypertrophic cardiomyopathy, cardiac arrhythmias, or acute life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting or physiologic stress (75; 76; 81). In infancy, the presentation can mimic sudden infant death syndrome. Milder variants primarily affect skeletal muscle and manifest in adolescence or early adulthood as chronic weakness, pain, recurrent rhabdomyolysis, or acute or chronic cardiomyopathies. Newborn screening and treatment with triheptanoin have dramatically improved patient outcome. Insights into clinical presentation, etiology, pathophysiology, diagnostic work-up, treatment, and pregnancy are presented in this article. The authors describe novel diagnostic tools and clinical trials on potential new management strategies for these fatty oxidation disorders.

Key points

	• Mitochondrial fatty acid oxidation is the central metabolic pathway for generation of substrates for ATP production, especially in liver, heart, and skeletal muscle.
	• Fatty acid-oxidation disorders can present with acute, life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting.
	• Milder variants manifest in adolescence or early adulthood as chronic muscle weakness, pain, recurrent rhabdomyolysis, or acute or chronic cardiomyopathies.
	• Newborn screening has significantly reduced morbidity and mortality.

Historical note and terminology

Mitochondrial fatty acid oxidation plays a major role in energy production and homeostasis. Very long-chain acyl-CoA dehydrogenase (VLCAD) and mitochondrial trifunctional protein (including isolated long-chain 3-hydroxyacyl CoA dehydrogenase, LCHAD) deficiencies, are recessively inherited inborn errors of mitochondrial fatty acid oxidation resulting in overlapping clinical phenotypes.

VLCAD deficiency was first identified independently by two groups (02; 05). In retrospect, all of the patients initially described with long-chain acyl-CoA dehydrogenase deficiency appear to have had defects in VLCAD (24; 74). Two disorders of the trifunctional protein (TFP) complex associated with the inner mitochondrial membrane have been described: isolated LCHAD deficiency and a deficiency of all three enzymatic components (TFP deficiency) (21; 32).

The long-chain fatty acid oxidation disorders are best detected by grass chromatography/mass spectrometry analysis of urinary organic acids or acylcarnitine profile analysis of dry blood spots or plasma utilizing tandem mass spectrometry (54). Distinguishing elevated metabolic markers (acylcarnitines) for VLCAD deficiency are C14 and C14:1 carnitine species, and for TFP and LCHAD deficiencies, increased hydroxy forms of C16:0H and C18:1 carnitine species. Urinary analysis will show elevated dicarboxylic acids during illness.

Clinical manifestations

Presentation and course

Defects of the fatty acid oxidation often present in early infancy with acute, life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting (75; 76; 81). Hepatopathy and rhabdomyolysis can be present. Symptoms tend to become milder with age, and hypoglycemia is uncommon after early childhood. Thereafter, recurrent rhabdomyolysis becomes the prominent symptom. Cardiomyopathy and cardiac arrhythmias can appear at any age. Later-onset disease, primarily recurrent rhabdomyolysis, is described in adolescence or early adulthood. Neuropsychiatric outcome is normal unless neurologic damage secondary to a hypoglycemic or hypoxic event has occurred.

VLCAD deficiency. Impairment of long-chain fat metabolism can result in severe organ dysfunction, especially of the heart, liver, and skeletal muscle (75; 76; 81). Clinical findings include hepatomegaly, hepatocellular disease, cardiomegaly, cardiomyopathy, and muscular hypotonia. In early studies, clinical onset of the disease was usually within 4 months of birth; 75% died within 2 months of onset, and all patients had liver dysfunction (04). Three overlapping clinical phenotypes of VLCAD deficiency have been described: (1) a severe, early-onset presentation with cardiomyopathy and hepatopathy; (2) a hepatic phenotype that usually manifests in infancy with recurrent episodes of hypoketotic hypoglycemia; and (3) a milder, later-onset myopathic form with episodic muscle weakness, myalgia, and myoglobinuria (55). However, there is considerable clinical overlap in patients, and cardiomyopathy can occur at any age. In addition, diagnosis through newborn screening leads to milder disease and is identifying an increasing number of individuals who are completely asymptomatic until adolescence or early adulthood. In the neonatal period, patients with VLCAD deficiency often develop hypoglycemia, irritability, and lethargy, precipitating evaluation for sepsis. Because these patients respond rapidly to glucose infusion, they can be discharged without diagnosis, and a more severe event can occur later.

Isolated LCHAD deficiency. Most patients with isolated LCHAD deficiency present with hepatopathy and fasting-induced hypoketotic hypoglycemia in the first weeks to months of life, whereas others present with cardiomyopathy (usually hypertrophic) or myopathy with recurrent rhabdomyolysis later in childhood (55). Pigmentary retinopathy (19) occurs as patients age, as does peripheral sensory-motor polyneuropathy (13). More than 80% of the patients develop pathological or subnormal retinal function and severe neonatal symptoms not purely related to poor clinical metabolic control (31). The first sign of polyneuropathy usually appears between the ages of 6 to 12 years, and despite early initiation of therapy with good compliance, most patients develop neuropathy. Patients identified by newborn screening have better outcomes than those diagnosed symptomatically. In addition, LCHAD deficiency predisposes the heterozygote mother of an affected baby to develop acute fatty liver of pregnancy or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndromes (87).

TFP deficiency. The most common clinical presentations are early hypoketotic hypoglycemia, cardiomyopathy, or sudden infant death (50). Severe peripheral neuropathy is nearly universal, though milder symptoms are occasionally seen. Variable clinical phenotypes range from a severe neonatal presentation with cardiomyopathy, liver failure, and early death; a hepatic form with recurrent hypoketotic hypoglycemia; and a milder, later-onset neuromyopathic phenotype with episodic myoglobinuria. Retinopathy is unusual (19). Episodic worsening of neuropathy with subsequent improvement has been reported (23).

Prognosis and complications

VLCAD deficiency. Patients with early-onset disease typically present with chronic hypertrophic cardiomyopathy and pericardial effusion between 2 and 5 months of age (82; 79; 41). Historically, they died early (04). Chronic complications like hypertrophic cardiomyopathy can also develop in more mildly affected patients and improve with treatment (56). The mild form of very long-chain acyl-CoA has an excellent prognosis with early diagnosis and treatment. Because fasting tolerance improves with age, the risk of episodes of coma decreases in later childhood and adulthood but with a concomitant increase in episodes of rhabdomyolysis. Some patients identified by newborn screening are asymptomatic early with milder late onset of rhabdomyolysis in adolescence or early adulthood, and long-term outcome is improved in general with newborn screening (49; 41). However, in one study, newborn screening had a clear beneficial effect on the prevention of hypoglycemic events in patients with some residual enzyme activity, but not in patients with low residual enzyme activity (06). Acute decompensations and sudden deaths occur in these patients despite expanded newborn screening (33; 41). Outcome with triheptanoin treatment, a newly approved therapy, is improved (77; 76; 80). The oldest patients identified by newborn screening are now in their early thirties.

Isolated LCHAD deficiency. Clinical features and outcomes for patients with LCHAD deficiency are similar to those with VLCAD deficiency, though LCHAD-deficient patients uniquely develop a pigmentary retinopathy as well as a peripheral neuropathy. Although early mortality rate was initially high, newborn screening and early treatment have improved outcome (28; 14; 41). Peripheral neuropathy is milder than in TFP deficiency but worsens with age. Cardiac and muscular symptoms, but not retinopathy or neuropathy, improve with triheptanoin treatment (77; 76; 80). The oldest patients identified by newborn screening are now in their early thirties.

TFP deficiency. Patients with early-onset TFP deficiency with cardiac involvement typically die in the first weeks to months of life despite early identification and immediate interventions (58). Peripheral neuropathy is almost universally severe. Newborn screening has had less impact on clinical outcome, though triheptanoin treatment can prolong life (55). Regardless of age of onset, few patients survive to their third decade of life.

Clinical vignette

A 32-year-old patient developed acute-onset severe pain in all extremities and trunk muscles during his work as a gardener. Pain treatment with diclofenac was ineffective, and the muscle symptoms progressed. The department of neurology in the hospital was consulted.

First diagnostic tests. Routine investigations showed elevated transaminases (AST 5089 U/L, normal < 50 U/L; ALT 1456 U/L, normal < 50 U/L), a massive increase of creatine kinase (CK 225,133 U/L, normal < 170 U/L), myoglobin (MG 251,000 µg/L normal < 55 µg/L), lactate dehydrogenase (LDH 3100 U/L, normal < 240), and a moderate elevation of CRP (27.4 mg/L, N < 10 mg/L). Furthermore, renal function parameters were significantly elevated (creatinine 4.3 mg/dl, normal < 1.25 mg/dl; urea 144 mg/dl normal, < 55 mg/dl; potassium 5.69 mmol/L, normal 3.6-5.2 mmol/L).

Management and course. The patient was dialyzed continuously for 6 days in an intensive care unit. Because of increasing transaminases and creatine kinase and the suspicion of autoimmune myopathy, the patient was treated with high doses of steroids, with improvement of symptoms and laboratory values. Because of a language barrier, the complete medical history of this patient was not adequately obtained immediately. The use of a professional interpreter later revealed recurrent episodes of rhabdomyolysis during childhood in the patient and his two older sisters (34 and 35 years old). Further metabolic investigations were performed.

Metabolic investigations. Acylcarnitine profile in plasma revealed an elevation of long-chain acylcarnitines and long-chain L3-hydroxy-acylcarnitines, typical for LCHAD and TFP. Enzymatic analysis in blood confirmed the diagnosis. Genetic investigation confirmed that the patient was homozygous for the common isolated LCHAD deficiency variant. Note that newborn screening was not available when the patient was a neonate.

Management and course. High-dose steroid treatment was interrupted. The patient rapidly recovered with anabolic treatment using intravenous glucose. He received an emergency protocol letter and was educated in detail about his disease and the need for early intervention in the face of symptoms.

Biological basis

Etiology and pathogenesis

Metabolic pathway of fatty acids and ketone bodies

Long-chain fatty acids (C16-C20) are stored as triglycerides in fat tissue. When required, fatty acids are released by lipases and activated toward coenzyme A (CoA) in the cytosol by thiokinases. Complete oxidation is possible onl...

Following import into the mitochondrial matrix, the beta-oxidation spiral shortens fatty acid-CoA esters by two carbon atoms (one molecule acetyl-CoA) in sequential cycles of four enzymatic steps involving chain length–specific enzymes at each step. The flavin adenine dinucleotide (FAD)-dependent acyl-CoA dehydrogenases (VLCAD, long-chain acyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; and SCAD, short-chain acyl-CoA dehydrogenase) catalyze the first step, generating an enoyl-CoA product (62). For long-chain substrates, the next three enzymatic reactions are contained on the TFP: an enoyl-CoA hydratase, an NAD+-dependent dehydrogenase (LCHAD), and a ketoacyl-CoA thiolase (38). Additional medium- and short-chain 3-hydroxyacyl-CoA dehydrogenases (MCHAD, SCHAD) and ketothiolase activities exist as individual enzymes (38). Even-chain fatty acids are oxidized to acetyl-CoA, which can enter the tricarboxylic acid cycle (TCA cycle, also known as the Krebs cycle) or be used for ketone synthesis, used by extrahepatic tissue (muscle, brain) as an energy source, particularly during fasting or insulin deficiency. Odd-chain fatty acids additionally yield propionyl-CoA at the final cycle, which enters the Krebs cycle. Reducing equivalents generated by the dehydrogenases are transferred to the respiratory chain, either via FAD-containing electron-transfer flavoprotein (ETF) and ETF-coenzyme Q-oxidoreductase (ETF-QO; also known as ETF dehydrogenase, ETFDH) to coenzyme Q or via NADH+ and H+ to complex I (07; 22).

Biochemistry. VLCAD is the first matrix enzyme of the beta-oxidation spiral. It is loosely bound to the inner mitochondrial membrane and is unique among the acyl-CoA dehydrogenases in its size, structure, and intramitochondrial distribution. Whereas the other acyl-CoA dehydrogenases are homotetramers of a 43 to 45 kD subunit, VLCAD is a 154 kD dimer of a 70 kD subunit (62).

The severity of clinical phenotypes of human very long-chain acyl-CoA deficiency can be distinguished to some extent biochemically using acylcarnitine profiles generated from patient fibroblast cell cultures exposed to various fatty acid substrates (20). In severe very long-chain acyl-CoA deficiency due to null mutations with no residual enzyme activity, accumulation of longer-chain (C14-C16) acylcarnitine species has been observed after substrate loading. In contrast, cell lines derived from individuals with milder clinical phenotypes accumulate C12-C14 substrates.

The TFP is a heterotetrameric (alpha2-beta2) enzyme associated with the inner mitochondrial membrane. It contains LCHAD, 2-enoyl-CoA hydratase, and 3-ketoacyl-CoA thiolase activities for the degradation of long-chain L-3-hydroxyacyl-CoA thioesters. The first two enzymatic steps (dehydrogenase and hydratase) reside in the alpha-subunit and the thiolase activity in the beta-subunit of the TFP. A fourth enzymatic function involved in cardiolipin synthesis, monolysylcardiolipin acyltransferase (contained on the alpha subunit), has been described (63).

It has been demonstrated that the enzymes of long-chain fatty acid oxidation both functionally and physically interact with those of the respiratory chain supercomplexes (84; 85). The LCHAD domain of TFP interacts with the NADH binding matrix arm of respiratory chain complex I. VLCAD intern interacts with TFP, presumably through the beta-subunit, though this has not yet definitively been proven.

Pathobiochemistry. Mitochondrial fatty acid oxidation is the central metabolic pathway for production of reducing equivalent for ATP production in the heart and skeletal muscle (75). Mitochondrial fatty acid oxidation disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to metabolic stress such as fasting, exercise, or intercurrent viral illness. The early onset of cardiac phenotypes in mitochondrial fatty acid oxidation disorders is caused by a switch in energy-producing substrate utilization from glucose in the fetal period to fatty acids postnatally. The perinatal cardiac substrate switch is paralleled by an increase in mitochondrial fatty acid oxidation protein expression (58). Symptoms in long-chain fatty acid oxidation disorders can be caused by reduction in blood sugar, decreased energy production, or accumulation of long-chain acylcarnitines hypothesized to have cellular toxicity. A hyperinflammatory state with macrophage pre-activation has been demonstrated in VLCAD deficiency, exacerbation of which seems to correlate with episodes of rhabdomyolysis (71).

Patients with long-chain fatty acid oxidation disorders have a reduced ability to oxidize palmitate in fibroblasts or to dehydrogenate palmitoyl-CoA in fibroblast extracts. Although ETF appears to circulate free in the mitochondrial matrix, ETFDH interacts with the cor2 subunit of complex III (84; 85). These physical interactions optimize the catalytic efficiency of reducing equivalents from substrate to the respiratory chain and subsequent generation of ATP through complex V.

Genetics. The ACADVL gene encoding VLCAD is on chromosome 17p11.13-p11.2, comprised of 20 exons (01). Hundreds of mutations in the ACADVL gene have been characterized, and numerous variants of uncertain significance are reported in ClinVar (10). There is some genotype-activity correlation, and one common mutation (c.848T> C; p.V283A) identified in approximately 20% of newborns identified through screening is a mild variant that predicts onset of recurrent rhabdomyolysis in adolescence or young adulthood with little risk of hypoglycemia or cardiomyopathy. HADHA and HADHB genes are located in opposite orientations on chromosome 2p23.3 and are transcribed from a common promotor. A common mutation, 1528G>C (E510Q), in HADHA is responsible for nearly all isolated LCHAD deficiency (30). Other mutations in HADHA and those in HADHB typically lead to complete TFP deficiency. Only a few cases of isolated long-chain 3-oxoacyl-CoA thiolase deficiency with a mutation in HADHB have been reported (12).

Pathophysiology. Mouse models of long-chain fatty acid enzymes have been generated to explore their pathophysiology (09; 18). In addition to VLCAD, a second enzyme, long-chain acyl-CoA dehydrogenase (LCAD) is involved in long-chain fatty acid oxidation in mice. Deletion mouse models of both enzymes have been made (09). Additionally, a mouse with a point mutation on the beta-subunit of TFP has been described (35). Because of the existence of two long-chain acyl-CoA dehydrogenases, deletion of either one alone does not completely reproduce human symptoms (09). Both show inconsistent development of cardiomyopathy and mild muscular weakness but develop only mild hypoglycemia with fasting or stress and do not exhibit rhabdomyolysis. Sensitivity to cold exposure is a sign of global bioenergetic deficit. Increased susceptibility to arrhythmia in the absence of systolic dysfunction occurs in mice with homozygous deletion of VLCAD in the absence of exogenously imposed stress, potentially due to lipotoxicity because of lipid deposition, but also energy deficiency with secondary respiratory impairment. Although the murine model of VLCAD deficiency has a less severe phenotype than in humans, essential biochemical characteristics of the human disease are replicated. During stress, they exhibit increased long-chain acylcarnitines (C14-C18) and decreased free carnitine in blood correlated with the severity of the clinical manifestations (59). Furthermore, it was demonstrated that changes in blood free carnitine levels did not correlate with carnitine homeostasis in liver and skeletal muscle. Carnitine supplementation resulted only in an increase of long-chain acylcarnitine production and had no effect on carnitine concentrations in tissues of these mice (40). Biochemical evidence of impaired gluconeogenesis suggests an additional underlying pathophysiologic mechanism of hypoglycemia in VLCAD (55). Interestingly, long-term use of medium-chain triglyceride (MCT) oil had severe cardiac adverse effects in mice in contrast to humans (66).

A TFP-deficient mouse model also recreated many symptoms found in human patients (35). The mouse had a c.1210T>A point mutation leading to an M404K substitution and demonstrated decreased weight gain and cardiac arrhythmias, which ranged from a prolonged PR interval to a complete atrioventricular dissociation. Sudden death often occurred between 9 and 16 months of age. Histopathological studies showed multifocal cardiac fibrosis and hepatic steatosis. A deletion of a portion of the gene for the alpha-subunit of TFP was used to create a model of complete TFP deficiency (29). The TFP-deficient fetuses accumulated long-chain fatty acid metabolites. The knock-out mice suffered from neonatal hypoglycemia; sudden death; severe dysfunction of the heart, liver, and diaphragm; and uniform mortality within hours postnatally. Analysis of the histopathologic changes showed rapid development of hepatic steatosis after birth and then necrosis and acute degeneration of the cardiac and diaphragmatic myocytes.

Many studies of cells derived from patients with VLCAD and LCHAD/TFP deficiency have been reported. Fibroblasts are the most frequently studied and, in general, reproduce the abnormal acylcarnitine accumulation seen in deficient mice and humans, along with impairment of whole cell oxygen consumption, increased accumulation of reactive oxygen species, and abnormal accumulation of complex lipids. VLCAD enzyme levels in patient-derived fibroblasts reflect the severity of patient symptoms, as does expression of synthetic mutant alleles in ACADVL knockout HEK293 cells (10). Most mutations in the HADHA and HADHB genes lead to loss of both TFP subunits, consistent with the interpretation that the presence of both protein subunits is necessary for enzyme stability (69). The HADHA E510Q mutation, which alters a catalytic important residue in the substrate binding pocket, appears to inactivate the LCHAD activity of the alpha-subunit without destabilizing the structure of the enzyme (39; 89).

Postmortem studies of human eye and brain from patients with LCHAD deficiency support the hypothesis that mitochondrial fatty acid beta-oxidation is involved in the metabolism of the retinal pigment epithelium, the cell layer that is most severely and primarily affected (68). Additionally, the accumulation of long-chain 3-hydroxyacylcarnitines in cultured LCHAD retinal pigmentary epithelial cells suggests direct toxicity of these metabolites on cells (19).

Long-chain acyl-CoA esters have been shown to inhibit the mitochondrial ATP/adenosine diphosphate carrier (70), the dicarboxylate carrier (25), and the pyruvate dehydrogenase complex (46). However, the relevance to human disease remains unclear. Uncoupling of oxidative phosphorylation in cells by accumulated long-chain 3-hydroxy fatty acids has been demonstrated (65). Multiple bioenergetic defects, accumulated reactive oxygen species, and alterations in mitochondrial fusion and fission have been demonstrated in VLCAD-deficient cells (51). The lack of mature cardiolipin in TFP-deficient cardiomyocytes results in mitochondrial abnormalities in vitro and has been postulated to be an important pathophysiologic mechanism of cardiac arrhythmias in TFP-deficient patients (45).

Differential diagnosis

Confusing conditions

The clinical presentation of fasting-induced vomiting, lethargy, and coma with hypoketotic hypoglycemia is typical for all mitochondrial fatty acid oxidation disorders. Most long-chain fatty acid oxidation disorders also cause heart and skeletal muscle involvement (cardiomyopathy, arrhythmia, hypotonia, and rhabdomyolysis). Biochemical screening with blood acylcarnitine profiling and urine organic acids should suggest the diagnosis, which can be confirmed by genetic testing.

Hypoglycemia is seen in many other disorders. It is most important to ascertain urine and serum samples at the time of hypoglycemia. One clue to mitochondrial fatty acid oxidation disorders is the finding of inappropriately low levels of urinary ketones despite high levels of free fatty acids. The duration of fasting and the age of onset are similar to ketotic hypoglycemia of hypopituitarism. The relative longer period of fasting required to induce illness, the mild degree of acidemia, and modest hepatomegaly help to distinguish long-chain acyl-CoA dehydrogenase deficiencies from glycogen storage disorders (types I, III, IX and 0) and gluconeogenic defects (pyruvate carboxylase deficiency, phosphoenolpyruvate carboxykinase deficiency, and fructose-1,6-bisphosphatase deficiency). Other inborn errors of metabolism presenting with hypoglycemia and coma include organic acidurias, which are usually associated with more severe acidemia than mitochondrial fatty acid oxidation disorders, and disorders of galactose or fructose metabolism (galactosemia or hereditary fructose intolerance). Organic acidurias can be distinguished by their distinctive urine organic acid profiles.

Hypoketotic hypoglycemia can be artificially induced by ingestion of oral hypoglycemic drugs or insulin administration. Patients with hyperinsulinism due to a mutation of glutamate dehydrogenase (hyperinsulinism and hyperammonemia syndrome) can present with similar degrees of hyperammonemia together with hypoketotic hypoglycemia. The hyperammonemia seen in long-chain mitochondrial fatty acid oxidation disorders due to liver dysfunction can suggest a urea cycle disorder, but elevation of blood ammonia is usually milder, and attacks of illness are often provoked by prolonged fasting rather than by protein feeding.

Myoglobinuria as seen in long-chain mitochondrial fatty acid oxidation disorders is characteristic of a number of inherited metabolic myopathies: carnitine palmitoyltransferase II, phosphorylase deficiency (McArdle disease, glycogenosis type V), short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, and other genetic diseases (17). Much more common causes are strenuous exercise, chronic alcoholism, toxic agents, and trauma.

An acute presentation of long-chain mitochondrial fatty acid oxidation disorders with an overwhelming lactic acidosis mimics a primary respiratory chain disorder whereas primary respiratory chain disorders can mimic mitochondrial fatty acid oxidation disorders including hypoketotic hypoglycemia. A plasma acylcarnitine profile should always be included in the diagnostic workup of infantile lactic acidemia.

Diagnostic workup

Initial studies in the case of a suspected fatty acid oxidation disorder should include glucose, lactate, ammonia, electrolytes, creatine kinase, blood gases, blood acylcarnitine profile analysis, and urine organic acid analysis, preferably obtained at the time of symptoms. A typical constellation of metabolic indicators of a defect in fatty acid oxidation includes hypoglycemia, minimal acidemia, elevated blood urea nitrogen, hyperammonemia, elevated liver transaminases and creatine kinase, and inappropriately low ketones in blood and urine (75; 76; 81). Urine organic acid analysis, which reveals both saturated and unsaturated dicarboxylic aciduria (adipic, suberic, sebacic acids), is direct evidence for insufficient mitochondrial fatty acid oxidation but less sensitive than blood acylcarnitine profiling. Dicarboxylic aciduria occurs in various amounts and patterns in different fatty acid oxidation disorders. Peroxisomal disorders and dietary medium-chain triglyceride can provoke secondary dicarboxylic aciduria in urine. During severe metabolic derangement, lactic aciduria can be excessive. Secondary carnitine depletion with low plasma and tissue levels is common in fatty acid oxidation disorders, and plasma free and total carnitine can give important hints. The C14:1-carnitine C14:1/C2 ratio is characteristic of VLCAD deficiency, whereas accumulation of long-chain unsaturated and 3-hydroxy-long-chain acylcarnitines are characteristic of LCHAD/TFP deficiencies. However, caution is necessary when well samples are analyzed as they may be normal, especially in LCHAD deficiency. When a diagnosis of a fatty acid oxidation disorder is suspected, follow-up functional studies are available in limited geographic areas and include fibroblast or white blood cell acylcarnitine profiling or enzyme analysis. Molecular testing is more broadly available and, thus, the usual diagnostic test. Variants of uncertain significance and noncoding mutations can still leave a diagnosis in question (10).

Management

Treatment of all long-chain fatty acid oxidation disorders is similar (75; 76; 81).

Intercurrent illness and emergency treatment. Because fatty acid oxidation is utilized during times of increased physiologic stress, intercurrent illness represents a high-risk time for metabolic decompensation to occur. Excess exercise, fasting, and psychological stress can also incite episodes; however, in some instances, it is not possible to identify the cause of a metabolic episode. Treatment of acute episodes in fatty acid oxidation disorders is aimed at quickly reversing the catabolic state that is responsible for stimulating the pathways of lipolysis and fatty acid oxidation. At the first appearance of symptoms, patients and parents should institute a home sick day regimen and should take/give small extra feedings of carbohydrates during the day and night at least every 4 to 6 hours. If solid foods are refused, an oral solution with 10% dextrose can be given to provide the equivalent of the 1.5-fold maintenance rate to stimulate anabolism. Urine dip sticks for hemoglobin can be used to identify occult myoglobinuria.

If home management is not successful or the patient is unable to tolerate oral fluids, the patient should promptly report to the hospital for intravenous glucose infusion, typically at the 1.5-fold maintenance rate in order to stimulate insulin secretion and suppress adipose tissue lipolysis. A thorough evaluation should be performed for an underlying intercurrent that requires treatment. A thorough cardiac exam and EKG should also be performed to assess for arrhythmias or signs of cardiomyopathy, in which case an echocardiogram should follow with appropriate cardiac intensive care. Blood ammonia, CPK, and electrolytes with creatine should be measured. Ammonia conjugating agents for mild hyperammonemia are typically not required as it will reverse readily when an anabolic state is reestablished. If rhabdomyolysis is present, intravenous fluid infusion should continue until the blood CPK level begins to fall and the patient is taking oral fluids and feeds. Here, the added risk is for acute tubular necrosis due to myoglobin toxicity. Intravenous fluids can then be weaned as oral intake increases. Discharge can be considered when a steady downward trend in blood CPK level is established and oral intake has returned to normal.

Chronic treatment. Dietary treatment of these disorders consists of the use of medium-chain triglycerides at 20% to 30% of total dietary calories to bypass the metabolic block and frequent feeds to avoid catabolism. Fasting should not exceed 8 to 10 hours. Triheptanoin, an odd medium-chain triglyceride, provides both acetyl-CoA and propionyl-CoA to counter a tricarboxylic acid cycle depletion that occurs in these diseases. It has been shown in clinical trials to reduce the incidence of rhabdomyolysis and cardiomyopathy compared to medium-chain triglyceride (MCT) oil and nearly eliminates the risk of hypoglycemia (78). With the use of either MCT oil or triheptanoin, intake of long-chain natural fats should be reduced to less than 20% of total calories to maintain caloric balance. With reduced natural long-chain fat intake, an essential fatty acid supplement should be added to the diet to prevent nutritional deficiency. There is no role for uncooked cornstarch in fatty acid oxidation disorders.

Carnitine, which is often severely decreased during intercurrent illness, may be supplemented. However, the use of carnitine supplementation in VLCAD deficiency has been controversial, particularly because of the fear that long-chain acylcarnitines will accumulate and provoke arrhythmias (08). However, intravenous or oral carnitine has been used in individual patients in both phenotypes of VLCAD deficiency without any apparent cardiac side effects despite high plasma levels of long-chain acylcarnitines (14). Carnitine supplementation (30 to 50 mg/kg per day) should be considered if free carnitine in the well state drops to less than 10 µM. In LCHAD/MCT deficiency, supplementation of docosahexanoic acid, a fatty acid essential for proper development of the eye and the nervous system, appears to slow but not stop progression of symptoms (34).

Patients should be supplied with an emergency card, letter, or bracelet containing instructions for emergency measures and phone numbers. Logistics of rational therapeutic measures should be repeatedly evaluated by the specialist team with the family and the primary care physicians.

Experimental treatments. Fibrate medications, acting as an agonist of peroxisome proliferator-activated receptors (PPAR), have been proposed as therapeutic. Bezafibrate or fenofibric acid has been shown to increase palmitate oxidation capacities in cultured patient-derived fibroblasts in some studies, but not in others (15). The effect might be genotype specific (16). An open-label study appeared to improve outcome in patients with VLCAD deficiency, but a double-blinded placebo-controlled study failed to show a difference in treatment groups and an uncontrolled trial in two TFP patients (48; 52; 61). A PPARdelta agonist has been shown to be more effective in reversing cellular metabolic defects in VLCAD patient-derived cells, as has mitochondrial targeted antioxidants (11). The former is now in clinical trials. Dantrolene has been proposed as a treatment for or prevention of rhabdomyolysis, but it has not been studied beyond a case report (83). Treatment of VLCAD-deficient fibroblasts with S-nitroso-N-acetylcysteine or a mitochondrial targeted antioxidant have been reported to improve cellular bioenergetics and/or acylcarnitine profile and beta-oxidation capacity (64).

Gene and mRNA therapy. Expression of VLCAD mRNA under the control of an adeno-associated virus (AAV) vector in patient-derived fibroblasts and VLCAD-deficient mice has been shown to increase activity of VLCAD and reduce disease-specific metabolites in cells in a variety of mouse tissues, as well as improve signs of whole-body bioenergetics (44; 36; 92). Transfected fibroblasts showed correction of the metabolic block as demonstrated by normalization of C14- and C16-acylcarnitine species in cell culture media and restoration of VLCAD activity in cells. Transfection of a human synthetic mRNA into patient-derived fibroblasts similarly improved cellular metabolic defects, whereas the same mRNA encased in lipid nanoparticles and injected into VLCAD-deficient mice lead to high-level liver expression of the enzyme (but not in heart or muscle) with improved signs of whole-body bioenergetics (91).

Outcomes

Historically, outcome in patients with long-chain fatty acid oxidation disorders has been poor, with up to 70% mortality before the age of 10 years and significant morbidity in survivors (03). The institution of newborn screening for these disorders has changed this picture dramatically (41). Although some babies can present prior to newborn screening results with a typically high mortality rate, screen-positive babies with early institution of therapy now nearly uniformly not only survive the newborn period but thrive. In addition, approval of triheptanoin has significantly improved outcomes in these disorders (77; 76; 81; 80; 75). In patients with VLCAD deficiency, intermittent rhabdomyolysis remains the primary long-term morbidity, though sudden death in adulthood, especially in patients with cardiomyopathy, has been reported. In isolated LCHAD deficiency, progressive retinopathy appears to be slowed, but not resolved, in early diagnosed and treated patients (19). Chronic progressive neuropathy remains a debilitating problem, though improvement with intensive physical therapy as well as spontaneous exacerbation and improvement have also been reported (23; 67). Long-term outcome in patients with severe TFP deficiency remains poor, with rare survival beyond 20 years of age.

Special considerations

Pregnancy

Obligate heterozygote mothers carrying a fetus with a long-chain fatty acid oxidation disorder (especially isolated LCHAD deficiency) are at increased risk for developing acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and reduced platelets (HEELP) syndrome, but little is known about the pathophysiologic mechanism of these problems (53; 27). Moreover, the risk to a baby born to a mother with these problems is low (47). The only effective therapy if the symptoms become life-threatening is delivery of the baby, following which the mother recovers rapidly. Fetuses affected with a long-chain fatty acid oxidation disorder can develop prenatal cardiomyopathy leading to severe neonatal disease (57). Prenatal diagnosis by amniotic fluid metabolite or genetic testing of a chorionic villus sample or amniocytes is possible (74). Successful pregnancies have been reported in women with VLCAD and isolated LCHAD deficiency but can lead to a false positive newborn screen in an unaffected baby (43; 90).

Anesthesia

Some special precautions must be taken in patients with long-chain fatty acid oxidation disorders before anesthesia. To avoid prolonged fasting, intravenous glucose-electrolyte infusion (8 to 12 mg/kg per min in infants) should be given throughout the perioperative fasting period to prevent activation of fatty acid oxidation (72). The time interval between the last meal and start of the glucose infusion should not exceed 3 hours. Ringer lactate should be avoided because of lactic acidosis. Drugs stimulating lipolysis and fatty acid oxidation, such as epinephrine and other beta-cell agonists, theoretically have been proposed to pose a hazard for patients with fatty acid oxidation disorders. Enflurane has been reported to increase free fatty acids during perioperative stress caused by minor elective surgery (37). A premedication with morphine, flunitrazepam, and promethazine had no effect on the plasma concentrations of free fatty acids (26). Propofol infusion syndrome, a rare but frequently fatal complication in critically ill children given long-term propofol infusions, results from an impaired fatty acid oxidation and inhibition of the respiratory chain at several points (88). Also, it is typically delivered in a high long-chain lipid solution that could be problematic if a patient is catabolic. However, safe use of propofol for short duration procedures in patients with long-chain fatty acid oxidation disorders has been reported (42). Avoidance of volatile anesthetics has been suggested, but there have been no specific reports of toxicity (86).

References

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Author

Jerry Vockley MD PhD

Dr. Vockley of the University of Pittsburgh School of Medicine has no relevant financial relationships to disclose.
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Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Georg F Hoffmann MD
Marina A Morath MD
Jennifer Friedman MD

Patient Profile

Age range of presentation: 0 month to 44 years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: None selectively affected
Occupation groups selectively affected: None selectively affected

ICD & OMIM codes

ICD-10: Disorders of fatty acid oxidation: E71.3
ICD-11: Disorders of mitochondrial fatty acid oxidation: 5C52.01
OMIM: Very long-chain acyl-CoA dehydrogenase deficiency: #201475

Mitochondrial trifunctional protein, alpha subunit: *600890

Mitochondrial trifunctional protein, beta subunit: *143450

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Long-chain fatty acid oxidation defects

Differential Diagnosis

hypoketotic hypoglycemia
other mitochondrial fatty acid oxidation disorders
plasma membrane carnitine transporter defect
carnitine palmitoyltransferase I deficiency
carnitine palmitoyltransferase II deficiency
- acylcarnitine translocase deficiency
- medium-chain acyl-CoA dehydrogenase deficiency
- HMG synthase deficiency
- HMG lyase deficiency
- electron transfer flavoprotein deficiency
- ketotic hypoglycemia of hypopituitarism
- glycogen storage disorders (types I, III, and 0)
- gluconeogenic defects
- pyruvate carboxylase deficiency
- phosphoenolpyruvate carboxykinase deficiency
- fructose-1,6-bisphosphatase deficiency
- organic acidurias
- disorders of galactose or fructose metabolism (galactosemia, hereditary fructose intolerance)
- hypoketotic hypoglycemia artificially induced by ingestion of oral hypoglycemic drugs or insulin administration
- hyperinsulinism due to a mutation of glutamate dehydrogenase (hyperinsulinism and hyperammonemia syndrome)
- urea cycle disorder
- defects of carnitine transport
- carnitine and acylcarnitine translocase
- short-chain-3-hydroxyacyl-CoA dehydrogenase deficiency
- glutaric aciduria type II
- McArdle disease
- glycogenosis type V
- strenuous exercise
- chronic alcoholism
- toxic agents
- trauma
- primary respiratory chain disorders

Also Relevant

Carnitine palmitoyltransferase 1A deficiency
Carnitine palmitoyltransferase II deficiency
Carnitine-acylcarnitine translocase deficiency
Medium-chain acyl-CoA dehydrogenase deficiency
Myoglobinuria
- Sudden infant death syndrome

Clinical Categories

Neurogenetic Disorders

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Mitochondrial Disorders

Long-chain fatty acid oxidation defects

Introduction

Overview

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Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

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Editor

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Patient Profile

ICD & OMIM codes

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Also in This Category

Carnitine palmitoyltransferase II deficiency

Pyruvate carboxylase deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

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