Clinical manifestations and management of fatty acid oxidation disorders

The two primary categories for cardiac presentations stemming from FAOD are cardiomyopathies and cardiac arrhythmias. In patients with FAOD, cardiac conditions often appear during the neonatal period or in early childhood. When neonates experience acute periods of fasting (during weaning or from overnight feeds), their glycogen stores become depleted and they subsequently rely on fatty acid oxidation for energy, which triggers symptoms [ 35]. Some patients do manifest cardiac conditions later in life, although these events also typically occur under catabolic conditions, such as fasting, intense exercise, fever, or illness [ 9].

Patients with FAOD may develop dilated cardiomyopathy because they lack the enzymes required to break down fatty acids, which accumulate in the cytoplasm and lysosomes of cardiac tissue [ 40]. Subsequent misalignment of the cardiac myofibrils results in inefficient contraction of the heart, whereas toxic fatty acid accumulation in the cytoplasm and lysosomes of cardiac cells increases tissue size and inflammation. Hypertrophic cardiomyopathy occurs primarily due to insufficient energy availability in the heart tissue and subsequent inefficient contraction, thereby stimulating cardiac muscle hypertrophy [ 40, 55].

Cardiac arrhythmias in patients with FAOD stem from the inherent lack of energy production during those periods in which the body relies more heavily on fatty acid catabolism, such as the immediate postnatal period, or following intense exercise, fasting, or illness [ 6, 56]. The causes of these arrhythmias are often multifactorial, but they appear to primarily affect patients with LC-FAOD. Ventricular tachycardia can be caused by reduced single-channel conductance of inward-rectifier potassium channels, leading to automatic action potential discharges from resting and plateau potentials [ 57]. Conduction velocities are slowed by a decrease in the presence of excitatory sodium current, leading to re-entry arrhythmia [ 57]. Fatty acids that have not been esterified are able to directly activate the voltage-dependent calcium currents in cardiac myocytes, leading to cytotoxic calcium overload and subsequent arrhythmias due to oscillatory and nonoscillatory potentials [ 57, 58]. Finally, amphipathic metabolites impair gap-junction channels via disturbance of the cell membrane lipid-protein interface [ 57].

Cardiac involvement is common in patients with FAOD, and these defects are a suspected cause of sudden death in early childhood [ 59]. Cardiomyopathies, alongside cardiac arrhythmias, commonly present in the immediate postnatal period [ 22]. The most common form of cardiomyopathy associated with FAOD is dilated cardiomyopathy, which can be asymptomatic or present as congestive heart failure, depending on the extent of ventricular dysfunction. In contrast, hypertrophic cardiomyopathies are typically more serious, with a higher risk of death [ 22].

Cardiac arrhythmias commonly present in the immediate postnatal period, when the demand for fatty acid oxidation is highest and frequently results in sudden infant death syndrome [ 57]. Many neonates with undetected/undiagnosed FAOD succumb to acute cardiac arrhythmia before any intervention is possible. Therefore, acute arrhythmia stemming from FAOD should always be considered in cases of sudden infant death syndrome [ 57]. However, it is important to acknowledge that cardiac arrhythmias can present at any age [ 22].

For patients with cardiac symptoms stemming from FAOD, there are no approved targeted therapeutic options. Instead, current management options typically treat the presenting cardiac conditions (arrhythmia/cardiomyopathy). These currently available interventions include low-intensity aerobic exercise, β-blockers (secondary), calcium channel blockers (secondary), diuretics, vasoconstrictors, combination therapy (β-blockers or diuretics + anti-arrhythmic agents), and angiotensin-converting enzyme inhibitors [ 60]. In more highly symptomatic cases, or in those where damage from the disease has progressed, other interventions include inotropic therapy, respiratory ventilation, mechanical cardiac support, and heart transplant.

Poor cardiac function can lead to dizziness, diminished physical function, or anxiety over a potential cardiac event and may even require surgery or transplantation. Following the development of cardiomyopathy or arrhythmia, patients require additional lifestyle changes, including low-intensity aerobic exercise [ 60]. Patients with cardiomyopathy and arrhythmia, regardless of cause, have reported decreased physical and psychological well-being [ 61, 62].

Liver dysfunction secondary to FAOD typically occurs early in life and presents in varying degrees of severity, ranging from episodic hypoketotic hypoglycemia to mild liver dysfunction to severe liver disease or Reye-like syndrome [ 12, 41]. Presentation of hepatic manifestations also occurs during periods of crisis later in life [ 12].

One mechanism by which energy stores are replenished is the conversion of fatty acids to ketone bodies in the liver, which can then serve as an energy source for other tissues, including skeletal muscle, the heart, and the brain [ 5, 63]. When glucose stores are depleted, the body releases fatty acids from adipose tissue for energy. However, the inability of the liver to metabolize fatty acids results in steatosis, whereby fatty acids accumulate in the liver, and the subsequent decreased production of ketones [ 63].

From birth, overnight fasting promotes lipolysis and ketogenesis; however, in children with FAOD, impaired β-oxidation impacts ketone production and dependence on glycogen stores. The subsequent depletion of glycogen stores manifests as hypoketotic hypoglycemia in which children present with hypoglycemia without an accompanying increase in serum ketones, which is a key indicator in the evaluation of patients with hypoglycemia and suspected FAOD [ 64, 65].

In children, initial symptoms of hepatic-presenting FAOD are commonly classified as Reye-like, which includes hypoketotic hypoglycemia, hepatic encephalopathy, hepatomegaly, hyperammonemia, microvesicular steatosis of the liver and other tissues, or unexplained hepatic failure, although true hepatic failure is less common [ 23].

The inability to break down fatty acids released from adipose tissue to replenish energy stores leads to a hypoglycemic state [ 3]. A key distinguishing characteristic of the form of hypoglycemia experienced by patients with FAOD is a lack of serum ketone bodies [ 43, 64]. In neonates, the presentation of hypoketotic hypoglycemia secondary to FAOD can vary; however, it typically exhibits some signs of adrenergic stimulation and/or impairment of the central nervous system in the form of lethargy, seizures, apnea, or coma [ 11, 43, 44].

Acute episodes of hypoglycemia during overnight infant fasting, when FAOD are unsuspected, may present as sudden death [ 11, 64]. FAOD should be considered as an underlying factor in any infants who die by sudden infant death syndrome [ 66]. Many FAOD manifesting as hypoglycemia stem from defects in the MCADD pathway; however, if accompanied by the cardiac defects (as detailed above), then LC-FAOD should also be considered [ 64]. Symptoms of liver dysfunction can include jaundice, pale stools, enlarged liver, cholestasis (increased bilirubin and glutamyl transferase, slight elevation of transaminases, normal platelet function), and axial hypotonia [ 23].

Among patients who experience an acute hypoglycemic episode, adherence to a low blood glucose protocol may reverse the effects by restoring free glucose levels [ 11]. This may require intravenous glucose at 2 mL/kg in infants or up to 12–15 mg/kg/min in older children and adults. The main goal of long-term treatment of hypoketotic hypoglycemia secondary to FAOD is to stop the attempted catabolism of fatty acids.

Standard interventions for children with FAOD and hepatic crisis include avoidance of fatty acid oxidation inhibitors (e.g., valproic acid, nonsteroidal anti-inflammatory agents, and salicylates), non-use of intravenous lipid emulsions, and initiation of L-carnitine therapy (50 mg/kg/day via enteral or intravenous administration) [ 67]. Furthermore, symptoms may improve following the switch to a diet low in long-chain fatty acids, along with MCT supplementation [ 23]. Hepatic manifestations typically resolve within one month of returning to a strict nutritional plan, including minimal long-chain fats and supplementation with MCTs [ 23]. Surgical management should include the avoidance of agents such as propofol and lactate-containing fluids, which place stress on the mitochondria and encourage fatty acid utilization. These therapeutic approaches have led to some improvements in short-term outcomes, with some remaining risk of hypoglycemia and muscle symptoms may still occur; in the longer-term, risks still include non-hepatic consequences such as retinitis pigmentosa and neuropathy [ 23, 37].

Acute hypoglycemic episodes frequently result in hospitalization, and patients undergoing medical examinations or procedures that require extended fasting (>8 h) must be hospitalized before the procedure as a precautionary measure [ 35]. A further complication is the difficulty in avoiding hypoglycemia while traveling, particularly when crossing time zones, because meal times and food availability can be disrupted [ 68].

The impact of hypoketotic hypoglycemia on patient and caregiver QoL is similar for those with or without an FAOD as the primary cause. Acute episodes can result in patients experiencing mood swings (including irritability, stubbornness, and depression) with recurrent episodes causing feelings of powerlessness, anxiety, and depression in both patients and their families [ 68]. Children may also be admitted to the hospital (frequently for episodes without hypoglycemia, but with altered oral intake and behavior issues from illness). Such episodes place stress on the family units, especially if they occur during the first years of life.

Children and adolescents with hepatic steatosis have reported diminished QoL, including increased anxiety, depression, and low self-esteem [ 69]. Furthermore, hepatic encephalopathy has been associated with impairment in daily functioning, learning ability, sleep disturbances, and an increased risk of falls warranting hospitalization [ 70].

In contrast to the manifestations of FAOD that present in neonates, the skeletal myopathy symptoms of FAOD tend to usually appear in older individuals, from toddlers and older children through to adults, typically starting in puberty or adulthood. Toddlers may show early symptoms of muscle impairment during development of motor skills and walking [ 45]. Alternatively, symptoms can appear later in life following periods of endurance-type exercise, fasting, or physiologic stress (e.g., anesthesia, viral illness, emotional stress, cold exposure, sleep deprivation) [ 45].

Elevated plasma creatine kinase and myoglobin, for example following prolonged exercise, are indicative of rhabdomyolysis and suggestive of possible underlying FAOD [ 21]. Currently, the pathogenesis of rhabdomyolysis among individuals with FAOD is poorly understood [ 71]. However, it is known that rhabdomyolysis can be triggered by periods of fasting or exercise, resulting in deficient delivery of adenosine triphosphate to the muscle cells, which disrupts cellular integrity, ultimately leading to cellular disintegration [ 72]. In FAOD, depleted glycogen stores in conjunction with the inability to process fatty acids results in deficiency of adenosine triphosphate in muscle cells leading to rhabdomyolysis [ 45]. The consequent disintegration of striated muscle results in the release of sarcomere-specific constituents, such as myoglobin, into the extracellular fluid and circulation. Normally, myoglobin is loosely bound to plasma globulins and only small amounts reach the urine. However, when massive amounts of myoglobin are released, the binding capacity of the plasma protein is exceeded. Rhabdomyolysis may range from subclinical creatine kinase elevation through muscular weakness and myoglobinuria to medical emergency due to interstitial and muscle cell edema, contraction of intravascular volume, and pigment-induced acute renal failure [ 72]. Decreased muscle contraction leads to the muscle weakness and symptoms such as the disrupted gait commonly associated with FAOD [ 26]. There are no therapies to prevent the onset of rhabdomyolysis associated with FAOD, and patients with known FAOD are usually advised to avoid intense or prolonged exercise [ 71]. Patients without a diagnosis of FAOD who present with atypical rhabdomyolysis (i.e., muscular weakness and myoglobinuria are frequent, or cases where the preceding activities do not typically cause rhabdomyolysis in healthy individuals) should be tested for FAOD [ 72].

In children or toddlers, the symptoms of early muscular disease that appear include hypotonia, disrupted gait, and muscle weakness. As the disease progresses, progressive or episodic muscle weakness, muscle pain (myalgia), chronic fatigue, exercise intolerance, and rhabdomyolysis may occur [ 15, 26]. Patients with FAOD who present with rhabdomyolysis have reported generalized muscle pain in conjunction with dark urine, most commonly following periods of intense exercise [ 21].

The primary management of patients experiencing skeletal muscular manifestations of FAOD is avoidance of aggravating symptoms that trigger crises. This includes adherence to the usual nutritional guidelines and lifestyle changes, such as avoidance of excess activity [ 73]. The use of additional MCT oil supplementation, with appropriate dosage and timing in relation to activity, may allow patients to have an active, healthy lifestyle while encouraging the building of lean body mass [ 36]. Lean body mass may also be preserved by encouraging a diet higher in protein (25% total energy needs) than is typically recommended [ 74].

Muscular symptoms can significantly impact patients’ QoL and activities of daily living, with some patients reporting difficulty climbing stairs, walking, opening doors, or even supporting their own weight [ 26]. Such muscular symptoms can have a profound impact not only on children by hindering their ability to play or participate in sports, but also on adults who may find it difficult to engage in regular daily activities or lose weight. Because of muscle pain with exertion, many patients are sedentary, and exercise-induced rhabdomyolysis frequently leads to exercise avoidance. Evaluation of QoL in one clinical trial, using SF-36 v2 physical composite scores, highlighted the impact of limited physical activity because of myopathy [ 75]. Additionally, muscular symptoms in conjunction with the restricted diet and limited fasting can contribute to an increased risk of obesity [ 73].

Neuropsychological symptoms are typically more subtle than some of the more severe physical manifestations that are experienced by individuals with FAOD. Delays in neurological milestones emerge later in a child’s development (teens or into adulthood) [ 12, 49]. Various FAOD subtypes can often present similar symptoms, whereas others display a distinct genotype-phenotype correlation.

The underlying mechanisms associated with the development of neurological and neuropsychological disorders secondary to FAOD remain unclear. However, it is known that energy deficiencies, unmetabolized intermediates, and docosahexaenoic acid deficiencies can all hinder brain development and may lead to some or all of the cognitive damage associated with these observed outcomes [ 50]. Importantly, LC-FAOD can also be associated with low docosahexaenoic acid levels due to dietary over-restrictions. Avoidance of over-restriction and supplementation is advocated [ 48]. This is an area that has not been explored extensively.

Several studies have assessed the neuropsychological outcomes of patients diagnosed with FAOD of varying subtypes. Patients with MCADD and LC-FAOD have presented with signs and symptoms that raise concerns over their neurological development, such as speech deficits; motor, language, or learning issues; or requirement for early intervention services [ 49]. Additional studies have also reported autism spectrum disorders stemming from specific LC-FAOD. Furthermore, some patients with specific LC-FAOD present with intellectual disability [ 50].

There have been additional reports of episodes of chronic, progressive peripheral neuropathy in patients, which occur in those individuals afflicted specifically with LCHADD or TFPD [ 47, 48]. Of concern, these neuropathies are irreversible despite current treatment efforts [ 46]. For example, peripheral neuropathies cannot be corrected using high-caloric intake, and progressive and acute neurologic symptoms are not always associated with the more easily detectable hypoglycemia [ 12].

Neuropathy stemming from FAOD is irreversible and can be progressive; however, the pathophysiology of this manifestation is not well understood. Consequently, no specific management guidelines are available beyond lifestyle changes and the recommended long-chain triglyceride restrictions associated with other LC-FAOD [ 46]. While there are no specific guidelines for neuropathies stemming from FAOD, common treatments for peripheral neuropathy include physical and occupational therapies to manage pain and loss of function [ 76].

The onset of peripheral neuropathy can vary based on underlying FAOD; however, it persists as a progressive presentation of the disease. As the neuropathy progresses, it can require more frequent clinical monitoring, although its treatment can be difficult [ 17]. Moreover, since this manifestation is irreversible, it poses a lifelong impact on patient QoL [ 46].

Some patients with FAOD develop vision problems, which typically present later than other manifestations. Of those patients with vision loss, ~50% have evidence of retinal changes by age 2 years [ 51]. Notably, once these changes to the retina have started, the damage is progressive and irreversible despite current treatment efforts [ 46].

The pathophysiology of retinopathy secondary to FAOD has yet to be elucidated; however, several theories have been proposed. Findings from studies have indicated that the number of metabolic decompensations is positively correlated with vision loss in patients with FAOD [ 51], suggesting that elevated levels of metabolic by-products during these crises may cause the observed retinopathy. A different theory has implicated a mutant α-subunit of the TFP as the driver of retinal cell death, leading to vision loss [ 51]. A further putative mechanism underlying the development of retinopathy involves the elevated plasma levels of hydroxyacylcarnitines and hydroxy fatty acids reported during metabolic crises that may have a role in the destruction of retinal cells [ 51].

Chronic and progressing retinopathy stemming from FAOD has been reported to manifest in four stages [ 66]. Stage 1 is characterized by a normal retina with hypopigmented fundus, whereas Stage 2 features the appearance of pigment clumping in the fovea with progressive retinal dysfunction (age-appropriate vision is unaffected). In Stage 3, the central pigmentation disappears and chorioretinal atrophy leads to macular pallor (noticeable night and color vision loss occurs). Finally, Stage 4 involves the posterior pole of the eye being devoid of photoreceptors, and most central vision is lost. Overall, patients’ experience of retinopathy secondary to FAOD includes decreases in color vision, low-light vision, and vision in the center of the field of view [ 48].

It is known that adherence to an FAOD-specific nutrition plan reduces the levels of hydroxyacylcarnitines and hydroxy fatty acids and slows the progression of vision loss. Therefore, a strict diet combined with MCT supplementation is recommended to slow the progression of retinopathy. Although docosahexaenoic acid supplementation has not been shown to prevent the progression of retinal damage, visual acuity improvements have been noted. Supplementation of L-carnitine has not demonstrated any benefits in patients with retinopathy secondary to FAOD [ 48].

The aforementioned patient experience of retinopathy in terms of decreased color vision, low-light vision, and vision in the center of the field of view inevitably makes tasks such as reading and driving more difficult, particularly in low-light conditions [ 48]. The diminished QoL associated with vision loss secondary to general retinopathy, not necessarily associated with FAOD, has been attributed to several factors, such as reduced income and economic security, reduced social interaction and support, and a diminished sense of control over one’s life, including a greater reliance on others [ 77].