Deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHADD), also known as trifunctional protein deficiency, is a rare inborn error of fatty acid metabolism. It is an autosomal recessive disorder caused by mutations in the HADHA gene.

The first confirmed case of LCHADD was described in 1983 by Glasgow et al. [7]. Subsequently, a number of cases were described defining the key features of hypoketotic hypoglycemia and showing the wide variability in clinical presentation [16].

Cardiomyopathy, a frequent finding in fatty acid oxidation disorders [5, 11, 12, 18, 20], has been reported in all types, with the exception of medium chain CoA acyl dehydrogenase deficiency. Contemporary classification of cardiomyopathy includes three subtypes: dilated, hypertrophic, and restrictive. This classification schema does not account for etiology, but rather attempts to divide disorders of myocardium into similar pathophysiologic groups. Dilated cardiomyopathy (DCM) is characterized by an enlarged left ventricular cavity and impaired systolic function. Hypertrophic cardiomyopathy (HCM) is characterized by an increased left ventricular mass, small left ventricular cavity, and decreased diastolic ventricular function. Restrictive cardiomyopathies, the least common of the three groups, are characterized by normal ventricular mass and volume with diastolic dysfunction.

Cardiomyopathy in LCHADD can be HCM or, less frequently, DCM. The largest reported series of LCHADD patients was described by Den Boer et al. [5] in 2002. Information on 50 patients was compiled via survey data from primary care and specialty physicians. Of these 50 patients, 21 (42%) were said to have cardiomyopathy, although the type of cardiomyopathy was not reported.

Tyni et al. [20] reported the second largest series of patients in 1997. Of the 13 patients in this report, 12 had an undefined cardiomyopathy and 1 was not examined with echocardiography. The nature of the cardiomyopathy was not reported except that four patients required treatment for “heart failure.” It is interesting to note that one patient in this series was alive at the time of publication, and it was said her cardiomyopathy resolved completely with a low-fat and low-carbohydrate diet and carnitine supplementation.

A large series of 107 subjects with fatty acid oxidation defect, including 10 cases of LCHADD, was reported by Saudubray et al. [18]. Both DCM and HCM were noted in their LCHADD patients.

Scattered reports in the literature since 1989 describe 10 other patients with LCHADD and cardiomyopathy [1, 8, 11, 13, 15, 21]. Three of these patients had DCM, and three had HCM, but the cardiomyopathy of the remaining four patients was not defined. We report the acute decompensation of a 3-year-old girl who had LCHADD with rapidly developing DCM.

Case Report

A girl age 3 years and 7 months with a known diagnosis of LCHADD was admitted to the hospital with metabolic decompensation. Her original diagnosis was LCHADD, determined during the newborn period after a newborn screen suggested the diagnosis. She had been maintained on a low-fat diet that included the formula Portagen for additional medium chain fat as an energy source and provision of essential long-chain fats. She had experienced several previous admissions for mild decompensations with intercurrent illness, but had not had any complications related to her underlying metabolic disorder.

The girl was followed regularly by the cardiology, ophthalmology, and metabolic genetics clinics. Her previous developmental assessments, echocardiography evaluations, and eye examinations were normal. She was known to have a complex social situation and had not been receiving her metabolic formula (Portagen) or L-carnitine for at least 3 to 4 months before this admission.

Vomiting and diarrhea developed 2 weeks before the girl’s admission. During this time, she reported leg and foot pain, refusing to bear weight. She was admitted briefly to a local hospital for intravenous (IV) fluids and then discharged home when her oral intake improved. An outpatient evaluation 6 days before the admission showed normal vital signs and euglycemia. However, the girl’s serum creatine kinase level exceeded 70,000 U/l. An acylcarnitine profile demonstrated elevation of C14, C14.1, OH-16, and OH-C18.1 The free carnitine level was 28.2 umol/l (normal range, 6.344.6 umol/l), and the total carnitine was 62.1 umol/l (normal range, 11.4–59 umol/l). An echocardiogram demonstrated normal left ventricular function (fractional shortening of 32%) at that time (Fig. 1).

Fig. 1
figure 1

M-mode echocardiogram through the left ventricle at the level of the papillary muscles obtained 6 days before the patient’s admission. The fractional shortening is derived by the following equation: (LVEDD – LVESD)/LVEDD. The LVEDD was 3.4 cm and the LVESD was 2.3 cm, eliciting a shortening fraction of 32%. LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter

For the 6 days before the admission, attempts to contact the patients’ family for follow-up evaluation were unsuccessful. The girl presented to a local hospital emergency department 1 day before admission with worsening leg pain and emesis. She was transferred to Nationwide Children’s Hospital for inpatient management by the genetics service.

At admission, the patient was dehydrated. She received 20 ml/kg of normal saline, then was started on dextrose 10% in water containing IV fluids. A serum creatine kinase at that time was 22,000 U/l. She received intravenous L-carnitine due to initial carnitine deficiency. Because of persistent emesis, the child was unable to take her metabolic formula by mouth.

During 5 days of hospital care, the girl’s clinical condition did not improve. An S3 gallop was noted at auscultation of the chest. An echocardiogram showed a severe DCM (fractional shortening of 12%) just 11 days after her initial normal echocardiogram (Fig. 2).

Fig. 2
figure 2

M-mode evaluation through the left ventricle at the level of the papillary muscles obtained 11 days after the study represented in Fig. 1. During her metabolic crisis and decompensation, the patient experienced decreased cardiac function (LVEDD was 3.7 cm and LVESD was 3 cm, eliciting a shortening fraction of 19%). LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter

The patient was transferred immediately to the intensive care unit (ICU) because of evolving cardiogenic shock. Her L-carnitine IV was discontinued after her admission to the ICU. Medium-chain triglyceride oil was administered via a nasojejunal (NJ) tube once enteral feeds were tolerated. After 2 weeks in the ICU, the child died of cerebellar herniation related to cerebral edema. She had minimal recovery of her cardiac function during the course of her ICU stay.

Discussion

Long-chain 3-hydroxyacyl-CoA (LCHAD) is one of three enzymes comprising the trifunctional protein of the inner mitochondrial membrane, which is responsible for the beta oxidation of long-chain fatty acids. It converts the hydroxyl group on the fatty acid chain to a keto group. The other two enzymes comprising the complex are enoyl coenzyme A (CoA) hydratase and long-chain 3-ketoacyl CoA thiolase [13]. The trifunctional protein is active against long-chain fatty acyls (C12 to C16) [19].

The deficiency of long-chain 3-hydroxyacyl-CoA results in an inability to metabolize long-chain fatty acids via beta oxidation in the mitochondria. When long-chain 3-hydroxyacyl-CoA is deficient, a child is unable to tolerate fasting, especially when the body is stressed in times of illness. It is in this condition that the body enters a catabolic state, shifting from the use of carbohydrates for energy production to the metabolism of fatty stores.

Normally, as long-chain fatty acids are oxidized, one molecule of acetyl-CoA is produced at each step. This subsequently enters the tricarboxylic acid (TCA) cycle for further adenosine triphosphate (ATP) production. Ketones also are produced as a by-product of beta oxidation.

In contrast, patients with LCHADD cannot effectively beta-oxidize long fatty acids. Instead, partially oxidized fatty acid esters build up in the body tissues, particularly those with the highest energy demands such as skeletal muscle, cardiac muscle, liver, and the central nervous system. Affected patients also cannot produce ketones from fatty acid beta oxidation.

Patients with LCHADD in acute metabolic crisis typically present with severe hypoketotic hypoglycemia precipitated by a prolonged period of fasting, often associated with intercurrent illness. This hypoglycemia may be accompanied by lactic acidosis, lethargy, coma, hepatomegaly, cardiomyopathy with associated arrhythmias and conduction defects, or myopathy, resulting in profound weakness and hypotonia [2, 17]. Although hypoketotic hypoglycemia is the most common presentation, especially in infants, a child may not be hypoglycemic yet still be seriously ill. Some patients may present initially with myopathy alone (often in early childhood) associated with elevated creatine kinase and occasionally myoglobinuria, only to decompensate later with the development of cardiomyopathy, hypoketotic hypoglycemia, or both. Other children may present initially with peripheral sensorimotor polyneuropathy [16].

Hepatomegaly typically occurs due to accumulation of fatty acid esters, resulting in a fatty liver often accompanied by fibrosis. However, some infants and children can present with chronic or acute cholestasis, or even with liver failure and hepatic necrosis. The use of tandem mass spectrometry as part of newborn screening in most states has allowed detection of neonates with LCHADD and implementation of treatment before an acute metabolic decompensation event occurs.

Currently, according to the National Newborn Screening and Genetics Resource Center in the most recent National Newborn Screening Status Report (updated 22 July 2008), 47 states have universal screening for LCHAD deficiency. Two additional states have not yet implemented universal screening, whereas the remaining state offers the test selectively.

Chronic management of patients with LCHAD deficiency typically involves avoidance of fasting together, adoption of a low-fat, high-carbohydrate diet, and administration of medium-chain triglycerides to provide 10% to 20% of daily energy requirements. More recently, it was suggested that administration of a small amount of vegetable, flax, walnut, or canola oils that contain long-chain fatty acids is necessary to provide essential fatty acids [6, 17]. The total amount of long-chain fatty acid intake should comprise no more than 10% of the total daily energy requirements. Uncooked cornstarch administration also can be useful to prevent hypoglycemia.

The use of L-carnitine for acute treatment of LCHAD deficiency, in the absence of documented carnitine deficiency, remains controversial. Cardiac arrhythmias are a well-known presentation in LCHADD and other fatty acid oxidation disorders [2]. Concerns arose originally when several articles pointed out the occurrence of ventricular arrhythmias during acute decompensations in which carnitine was given [5, 10, 20]. These findings coupled with animal data demonstrating accumulation of potentially toxic long-chain fatty acylcarnitines in cardiac ischemia models [4] have led to suggestions for withholding carnitine as a treatment during acute decompensations.

Recent evidence in the VLCAD mouse does suggest that long-chain acylcarnitines accumulate during carnitine supplementation [14]. However, there also are several case reports documenting death from ventricular arrhythmia of patients not treated with carnitine [2, 10, 15, 20]. Carnitine is shown to be protective against arrhythmia in cardiac ischemia [3] and safe in the setting of cardiomyopathy due to fatty acid oxidation defects [9, 22, 23].

Treatment in an acute metabolic crisis involves the administration of dextrose-containing fluids (dextrose 10% or higher depending on the glucose level at presentation) at 1.5 to 2 times the maintenance IV fluid rate. Medium-chain triglyceride oil supplementation should be administered once the patient is able to tolerate enteral feeds. Intravenous L-carnitine is useful if total carnitine levels are deficient. Monitoring of liver function tests and creatine kinase levels is necessary because hepatic dysfunction and myopathy can accompany an acute metabolic crisis. If the creatine kinase is elevated, urine myoglobin should be measured to detect signs of rhabdomyolysis. Careful cardiac evaluation with echocardiogram and electrocardiogram are imperative because cardiomyopathy and associated arrhythmias also can evolve rapidly in cases of metabolic crisis. Based on the currently published information, both HCM and DCM may be seen in LCHADD.

We describe a patient with LCHADD who presented in metabolic crisis with normal cardiac function. As her condition deteriorated over 1½ weeks, she experienced a severe DCM. Her case is remarkable in part because of the speed with which the cardiomyopathy developed. It is interesting to note that the symptoms of low cardiac output (fatigue, hepatomegaly, vomiting, and diarrhea) closely overlap with the symptoms of metabolic crisis in patients with LCHADD. Considered together, these findings underscore the importance of heightened vigilance for cardiomyopathy in patients with disorders of fatty acid oxidation.