Improving the outcome for fatty acid oxidation disorders.

Abstract

Fatty acids are an important fuel for most tissues, particularly heart and skeletal muscle. Fasting and illness increase the mobilization of fatty acids from adipose tissue and their subsequent oxidation by other tissues. During prolonged fasting, even the brain ceases to depend entirely on glucose, instead using ketone bodies, which are formed from fatty acids in the liver. Energy is derived from fatty acids by oxidation in mitochondria. A simplified summary of the pathway is shown in Figure 1; greater detail can be found elsewhere (1). Most naturally occurring fatty acids have a chain length of 16 to 18 carbon atoms. These long-chain fatty acids can only enter mitochondria when bound to carnitine. Within mitochondria, fatty acids undergo β-oxidation. This is a spiral pathway, with each turn of the spiral involving four steps (flavin adenine dinucleotide [FAD]-linked dehydrogenation, hydration, nicotinamide adenine dinucleotide [NAD]+-linked dehydrogenation, and thiolytic cleavage to release acetyl-coenzyme A [CoA]). The overall effect is to generate energy and to shorten the fatty acid by two carbon atoms. Each step is catalyzed by two or more enzymes of overlapping chain length specificities. The enzymes for long-chain substrates are bound to the inner mitochondrial membrane, whereas those for shorter substrates are found in the matrix. Three of the reactions for long-chain substrates are catalyzed by a trifunctional protein.FIG. 1.: A simplified summary of fatty acid oxidation. Long-chain substrates undergo repeated cycles of β-oxidation initially catalyzed by membrane-bound long-chain–specific enzymes and subsequently by medium-and/or short-chain–specific enzymes within the matrix. CPT carnitine palmitoyltransferase (types I and II); CAT, carnitine-acylcarnitine translocase; VLCAD, very-long-chain acyl-CoA dehydrogenase; TFP, trifunctional protein; AD, medium-and short-chain acyl-CoA dehydrogenases; EH, medium-and short-chain 2-enoyl-CoA hydratases; HAD, short-chain 3-hydroxyacyl-CoA dehydrogenase; OT, short-chain 3-oxoacyl-CoA thiolase.FATTY ACID OXIDATION DISORDERS Fatty acid oxidation defects are relatively common inherited metabolic diseases. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common, with a prevalence of approximately 1:15,000 in the United Kingdom (2). Most of these individuals are homozygous for a single mutation (985A→G) (3). A common mutation has also been identified in the α-subunit of the trifunctional protein (1528G→C) (4). This mutation lies in the domain with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity and deficiency of LCHAD is the main biochemical abnormality in patients who are homozygous for this mutation. Small studies in Finland (5) and the United States (6) have given carrier frequencies for the 1528G→C mutation of 1:240 and 1:180, respectively. Thus the homozygote frequencies are likely to be on the order of 1:230,000 and 1:120,000. The prevalence of other disorders is less well established. In all fatty acid oxidation disorders, fasting or illness can lead to acute encephalopathy, with a risk of permanent neurologic handicap or sudden death. These episodes can be prevented simply by avoiding fasting and maintaining a high carbohydrate intake during illness. Additional problems are often seen in defects of long-chain fatty acid oxidation (i.e., disorders of the carnitine pathway, very-long-chain acyl-CoA dehydrogenase or the trifunctional protein). Cardiomyopathy is common, but, if detected early, it often responds to a diet low in long-chain fat. Thus, there can be little doubt that early diagnosis improves the prognosis for fatty acid oxidation defects. INVESTIGATION The investigation of fatty acid oxidation defects has been revolutionized by the development of tandem mass spectrometry (7). This technique can analyze acylcarnitine species in blood spots and can establish the diagnosis in the majority of fatty acid oxidation disorders. In the future, many countries will probably introduce neonatal screening for MCAD deficiency and perhaps also for other β-oxidation defects. How can we achieve early diagnosis before the introduction of screening? The article by Skladal et al. in this issue highlights the importance of investigating all patients with a relevant family history or clinical features. Two patients are reported, in both of whom the diagnosis could have been reached earlier. In one patient, the delay had no serious long-term consequences, but the death of the other child might have been prevented by appropriate treatment. On the basis of these cases and our experience, we suggest that acylcarnitine analysis should be undertaken on blood spots from all patients with relevant clinical features—effectively, a policy of selective screening for high-risk patients until routine neonatal screening is introduced. The main indications for blood spot acylcarnitine analysis are summarized in Table 1. Hypoglycemic encephalopathy is the most common presentation of fatty acid oxidation defects, and we therefore recommend acylcarnitine analysis in all cases of unexplained hypoglycemia or encephalopathy, even if it is mild. This will have the added benefit of detecting most organic acidemias. Other important presentations of long-chain fatty acid oxidation defects include cardiomyopathy, usually in infancy, and recurrent rhabdomyolysis in older children or adults.TABLE 1: Indications for analysis of acylcarnitine species in blood spotsThe family history may also suggest the possibility of a fatty acid oxidation disorder. Sudden death in early childhood with hepatic or cardiac steatosis strongly suggests a fatty acid oxidation disorder (8). A diagnosis can usually be established using blood spots obtained at autopsy and, if the results are equivocal, it is often possible to retrieve and analyze residual neonatal specimens from the screening laboratory. If specimens from a deceased child are unavailable, acylcarnitine analysis should be undertaken on siblings soon after birth. This would have established the diagnosis promptly in the first patient reported by Skladal et al. and might well have improved the outcome. Finally, we recommend blood spot acylcarnitine analysis in all infants born after a pregnancy complicated by acute fatty liver of pregnancy (AFLP) or the form of pre-eclampsia characterized by hypertension, elevated liver enzymes, and low platelets (HELLP syndrome). In the second pedigree reported by Skladal et al., this would have established the diagnosis soon after the birth of the first child. The association between fetal LCHAD deficiency and maternal complications was first reported in 1993 (9). Acute fatty liver of pregnancy or HELLP syndrome occurred in four of six pregnancies in which the fetus had LCHAD deficiency but in none of the five pregnancies in which the fetus was unaffected. Subsequent studies have confirmed the association (6,10). Initially, it seemed that AFLP and HELLP syndrome might be associated specifically with the 1528G→C mutation (6), but these complications have also occurred in pregnancies in which the fetus had other defects of the trifunctional protein (11). Indeed, the complications may not even be specific to this enzyme. Acute fatty liver of pregnancy has recently been reported in association with fetal carnitine palmitoyltransferase (CPT) I deficiency (12). The pathogenesis remains poorly understood. Presumably, metabolites from the fetus cross the placenta and have a toxic effect on the liver of the mother, who herself has lower than normal LCHAD activity. Metabolic changes associated with normal pregnancy may exacerbate the problem (13). The HELLP syndrome occurs in approximately 1% of pregnancies, and only a very small proportion of the fetuses have a fatty acid oxidation defect. Nevertheless, it seems reasonable to undertake blood spot acylcarnitine analysis on these infants, because the test is relatively inexpensive. Urinary organic acid analysis is not a satisfactory alternative under these circumstances (14). TREATMENT How effective is our treatment of fatty acid oxidation defects, once they have been diagnosed? The prognosis in MCAD deficiency is excellent with very simple treatment: avoidance of prolonged fasting and use of an emergency regimen during illness (15). Similar measures can prevent episodes of encephalopathy in long-chain fatty acid oxidation disorders. Treatment of cardiomyopathy in these patients is more difficult, but if they can be supported through the initial episode, cardiac function generally improves and often returns to normal (16). Frequent feeding and a diet very low in long-chain fatty acids both seem to be important (17). There is little evidence about the optimal feeding frequency or fat intake; these probably vary depending on the severity of the defect. Most of our patients with cardiomyopathy receive continuous overnight feedings, a strict diet (less than 6 g long-chain fat per day for the first 3 years), and a milk substitute in which long-chain fat is almost entirely replaced by medium-chain triglyceride. Carnitine is life-saving in primary carnitine deficiency, but its role in other disorders remains controversial (18). In summary, there is a high mortality during the initial illness in infants with long-chain fatty acid oxidation defects but chances of survival are markedly improved by early diagnosis. Subsequently, short-term outcomes are generally good with the measures we have outlined (19). Unfortunately, current treatment strategies are less good at preventing the long-term complications of long-chain defects. Muscle problems are common (20). Use of an emergency regimen during intercurrent illness reduces the risk of acute renal failure due to severe rhabdomyolysis, but many children continue to have weakness with marked increases in serum creatine kinase during infections. Exercise is the usual precipitant for rhabdomyolysis in older subjects, such as those with partial CPT II deficiency. These patients should avoid endurance sports and may be helped by consuming carbohydrate before exercise. Unfortunately, despite these measures and adherence to a strict low-fat diet, some patients develop chronic weakness, with high serum creatine kinase levels, for which we currently have no reliable treatment (21). Patients with defects of the trifunctional protein have two additional long-term complications. In most, a progressive pigmentary retinopathy develops, but the age of onset is variable, and patients with mild defects may be spared (22). Initially, the fundal changes may be asymptomatic, but, subsequently, color vision, dark adaptation, and acuity deteriorate (23). Peripheral neuropathy is the other long-term complication in these patients. Again, it has a variable age of onset and may become debilitating (22,24). The pathogenesis of the retinopathy and neuropathy are unknown. Deficiency of docosahexaenoic acid (DHA) has also been proposed, and there have been anecdotal reports that DHA supplements can lead to improvement in both retinal function (25) and nerve conduction (24). It is certainly essential that patients on very low-fat diets receive supplements of essential fatty acids, because DHA deficiency will develop otherwise. There is, however, little evidence that defects of the trifunctional protein cause DHA deficiency. We have found normal plasma and erythrocyte membrane DHA levels in virtually all our LCHAD-deficient patients and have not found any correlation between the levels and long-term complications (Lund et al., unpublished observations, 2000). In conclusion, early diagnosis is crucial in fatty acid oxidation defects. Until neonatal screening is introduced, clinicians should have a low threshold for investigating patients. The initial investigation should generally be analysis of blood spot acylcarnitines by tandem mass spectrometry. In MCAD deficiency, treatment is simple, and, once the diagnosis is established, the prognosis is excellent. In defects of long-chain fatty acid oxidation, management remains less satisfactory. There is still a high mortality during the initial illness, and, although dietary treatment can achieve a good short term outcome, long-term complications remain a problem.