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PEDIATRICS Vol. 109 No. 1 January 2002, pp. 99-104

Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: Clinical Presentation and Follow-Up of 50 Patients

Margarethe E. J. den Boer, MD*,, Ronald J. A. Wanders, PhD*,{ddagger}, Andrew A. M. Morris, MD, PhD§, Lodewijk IJlst{ddagger}, Hugo S. A. Heymans, MD, PhD* and Frits A. Wijburg, MD, PhD*

* Department of Pediatrics Academic Medical Center, University of Amsterdam, the Netherlands
{ddagger} Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, the Netherlands
§ Department of Department of Child Health, University of Newcastle Upon Tyne, United Kingdom

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objectives. To assess the mode of presentation, biochemical abnormalities, clinical course, and effects of therapy in patients of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

Background. LCHAD deficiency is a rare, autosomal recessive inborn error of fatty acid oxidation. Although case reports and small series of patients have been published, these may not give a true picture of the clinical and biochemical spectrum associated with this disorder. To improve the early recognition and management of this potentially lethal disorder, we have reviewed a large cohort of LCHAD-deficient patients.

Methods. A questionnaire was sent to the referring physicians of 61 unselected patients with LCHAD deficiency diagnosed in our center. The standardized questionnaire requested information about the clinical signs and symptoms at presentation, the clinical history, family history, pregnancy, biochemical parameters at presentation, treatment, and clinical outcome.

Results. Questionnaires on 50 patients (82%) were returned and included in this study. The mean age of clinical presentation was 5.8 months (range: 1 day-26 months). Seven (15%) of the patients presented in the neonatal period. Thirty-nine patients (78%) presented with hypoketotic hypoglycemia, the classical features of a fatty acid oxidation disorder. Eleven patients (22%) presented with chronic problems, consisting of failure to thrive, feeding difficulties, cholestatic liver disease, and/or hypotonia. In retrospect, most (82%) of the patients presenting with an acute metabolic derangement also suffered from a combination of chronic nonspecific symptoms before the metabolic crises. Mortality in this series was high (38%), all dying before or within 3 months after diagnosis. Morbidity in the surviving patients is also high, with recurrent metabolic crises and muscle problems despite therapy.

Conclusions. LCHAD deficiency often presents with a combination of chronic nonspecific symptoms. Early diagnosis is difficult in the absence of the classical metabolic derangement. Survival can be improved by prompt diagnosis, but morbidity remains alarmingly high despite current therapeutic regimes.

Key Words: fatty acid oxidation • long-chain 3-hydroxyacyl-CoA dehydrogenase • hypoglycemia • cardiomyopathy

Abbreviations: LCHAD, long-chain 3-hydroxylacyl-CoA dehydrogenase • MTP, mitochondrial trifunctional protein • MCAD, medium-chain acyl-CoA dehydrogenase • VLCAD, very long-chain acyl-CoA dehydrogenase • CPT, carnitine palmitoyl-CoA transferase • HELLP, hemolysis, elevated liver enzymes, and low platelets • AFLP, acute fatty liver of pregnancy • MCT, medium-chain triglycerides • ATP, adenosine triphosphate • SCAD, short-chain acyl-CoA dehydrogenase • CK, creatine kinase • DHA, docosahexanoic acid


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) catalyzes the third step of the mitochondrial oxidation of long-chain fatty acids, converting long-chain 3-hydroxyacyl-CoA esters into the corresponding 3-ketoacyl-CoA esters. The LCHAD enzyme is part of the mitochondrial trifuntional protein (MTP), which also harbors long-chain enoyl-CoA hydratase and the long-chain thiolase activity.

Since the first description of LCHAD deficiency in 1990,1 a number of case reports have highlighted individual clinical and biochemical features of the disorder. From these reports, the most prominent finding at presentation seems to be hypoketotic hypoglycemia, as in the commonest fatty acid oxidation disorder, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.2 Additional features reported in LCHAD deficiency include cardiomyopathy, severe liver disease with cholestasis, and recurrent muscle cramps with raised serum creatine kinase levels. These features also occur in other long-chain fatty acid oxidation disorders (such as very long-chain acyl-CoA dehydrogenase [VLCAD] and carnitine palmitoyl-CoA transferase II [CPT-II] deficiency) but not in MCAD deficiency. Finally, a number of LCHAD-deficient patients develop pigmentary retinopathy and peripheral neuropathy, long-term complications that are not seen in any of the other mitochondrial fatty acid oxidation disorders.

Diagnosis of LCHAD deficiency is suggested by demonstrating increased secretion of 3-hydroxy-dicarboxylic acids in urine by gas chromatography-mass spectrometry, or by demonstrating accumulation of 3-hydroxyacyl-carnitines as measured by tandem-mass-spectrometry in plasma.3 Confirmation of the diagnosis is possible by measuring LCHAD activity in lymphocytes, fibroblasts, muscle or liver biopsies,1,4 and by mutational analysis. A common mutation has been identified in the {alpha}-subunit of the trifunctional protein, in the domain with LCHAD activity. In the majority of LCHAD-deficient patients, at least 1 allele carries this point mutation (1528 G>C).5

Case reports and small series of patients often do not give a balanced view of the clinical and biochemical spectrum associated with inborn errors of metabolism. To provide clinical data on a large, unselected, affected population to allow appreciation of the clinical spectrum, we reviewed 50 patients by sending questionnaires to the relevant metabolic pediatricians.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
For the last decade, the metabolic center at the Academic Medical Center of the University of Amsterdam has been a referral center for the diagnosis of LCHAD deficiency. The diagnosis has been established in 80 patients from all over Europe by enzyme analysis in lymphocytes, fibroblasts, or liver tissue1,4 and/or by demonstrating homozygosity for the common LCHAD mutation (1528G>C) by using previously described methods.5,6 A standardized questionnaire was sent to the referring specialists of 61 patients for whom the referring physician was known. For the other 19 patients, the name of the referring physician was unknown to our laboratory, and thus a questionnaire could not be sent. Patients with MTP deficiency were excluded from this survey.

The questionnaire requested patient initials, sex, date of birth, and clinical and biochemical parameters at time of diagnosis and during follow-up, clinical history before diagnosis, family history, pregnancy, neonatal period, and current treatment. All data were analyzed anonymously, and can not be reduced to the individual patient. Frequencies and frequency distributions were calculated using the SPSS software program (SPSS Inc, Chicago, IL). Statistical analysis included the Fisher exact test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Patients
Fifty questionnaires (82%) out of the 61 were completed by 26 referring specialists.

The 50 patients originated from 45 unrelated families. Five families had 2 affected siblings. Twenty-three patients were male, 27 were female. Most patients (47) were of European origin, the other 3 coming from the United States, Australia, and Israel. Only 8 of the 50 patients have been published previously.7–13

Diagnosis
All patients were proven to be LCHAD-deficient, either by enzymatic analysis (38/50, 76%) and/or by mutation analysis (49 out of 50 patients). Mutation analysis demonstrated the presence of the common 1528G>C mutation in 84 out of the 98 alleles tested (allele frequency 86%). Thirty-six patients were homozygous and 12 were heterozygous for this mutation. One patient was found to be homozygous for the 583G>D mutation. All heterozygous 1528G>C and the homozygous 583G>D were enzymatically proven to be LCHAD-deficient.

Pregnancies
For 47 of the 50 patients, data on the pregnancies were available. Seven (15%) of the pregnancies were complicated by HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Two pregnancies (4%) were complicated by AFLP (acute fatty liver of pregnancy).

Clinical Presentation
The age of onset of clinical symptoms ranged from 1 day to 26 months, with a mean of 5.8 months (Fig 1). Seven (15%) of the patients presented within the neonatal period (0–4 weeks of age).



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  		Fig 1. Age at first presentation in months.

 
Thirty-nine patients (78%) presented with an acute metabolic derangement with hypoketotic hypoglycemia. Clinical signs and symptoms at acute presentation are given in Table 1.


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  		TABLE 1. Signs and Symptoms in 39 LCHAD-Deficient Patients Presenting With Acute Metabolic Derangement

 
The other 11 patients (22%) presented with a more chronic disorder, consisting of liver disease, failure to thrive, feeding difficulties, and/or hypotonia (Table 2). These children did not suffer any acute metabolic derangement with hypoglycemia before diagnosis.


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  		TABLE 2. Signs and Symptoms Before and at Diagnosis in All 50 LCHAD-Deficient Patients

 
Careful analysis of the clinical history of those patients presenting with an acute hypoglycemic episode revealed that 32 (82%) of the 39 patients already had nonspecific problems, probably related to LCHAD deficiency, before the hypoglycemic attack. These problems are comparable to those observed in the 11 patients who presented with chronic symptoms (Table 2).

Laboratory Abnormalities at Presentation
Besides hypoglycemia, patients with an acute presentation showed a number of other laboratory abnormalities. These are summarized in Table 3.


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  		TABLE 3. Laboratory Values in 39 LCHAD-Deficient Patients Presenting With Acute Metabolic Derangement

 
Clinical Outcome
Nineteen (38%) of the 50 patients were already deceased at the time of the study. Mortality in patients presenting with acute hypoglycemia (15/39, 38%) did not differ significantly from that in patients presenting with chronic nonspecific symptoms (4/11, 36%). Fourteen patients died before the diagnosis of LCHAD deficiency was made. The other 5 children died within the first 3 months after diagnosis, 1 attributable to sudden infant death, 1 attributable to hepatic failure, and 3 attributable to cardiomyopathy. The latter 4 patients had all presented with acute hypoglycemia but severe liver disease/cardiomyopathy were already present at this time.

Follow-up for the 31 surviving patients (62%) ranged from 0.5 to 11 years with a median follow-up of 3.4 years. Of these 31 patients, 29 (94%) were reported to be generally "in good clinical condition". However, morbidity in this group is still high, with recurrent metabolic crises and other clinical problems (Table 4). The metabolic crises were reported to be less severe than the initial acute metabolic derangement. No patient died during follow-up.


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  		TABLE 4. Signs and Symptoms During Follow-Up in 31 Surviving LCHAD-Deficient Patients

 
Treatment
All surviving patients (31) are treated with a low-fat, high-carbohydrate diet. Twenty-three patients receive a medium-chain triglycerides (MCT)-enriched diet, and 12 are being treated with L-carnitine (50–100 mg per kg bodyweight per day). No statistically significant difference in morbidity, as defined as the presence of recurrent metabolic attacks and/or muscle cramps, could be detected between the patients receiving and those not receiving L-carnitine supplements (Fisher exact test: P < .01).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Our study is the first to report the presentation and outcome in a large, unselected group of LCHAD-deficient patients. The clinical picture revealed differs in several respects from the pattern emerging from the previous literature. Published reports suggest that most patients present with hypoketotic hypoglycemia and a Reye-like illness after a period of prolonged fasting often during a mild illness.14–16 Only a few isolated patients with a more chronic presentation have been described.7–9,17–21 In our series of 50 patients, 11 patients (22%) presented with a variety of chronic problems, such as cholestatic liver disease, failure to thrive, cardiomyopathy, muscular hypotonia, and feeding difficulties. Careful analysis of the clinical history of those patients presenting with acute hypoglycemia revealed that 32 (82%) of the 39 patients already had a combination of nonspecific symptoms probably related to LCHAD deficiency before the hypoglycemic episode. In total, therefore, 43 (86%) of our 50 patients initially had chronic rather than acute problems. Unfortunately, because the chronic symptoms tend to be nonspecific, their significance is easily missed. These symptoms are also observed in other long-chain fatty acid oxidation disorders, such as VLCAD and CPT-II deficiency.22,23 Hypotonia, liver disease, cardiomyopathy, and other chronic problems are probably caused by an accumulation of long-chain acyl-CoA esters, which have, for example, been shown to be toxic to cardiomyocytes in vitro.24 Furthermore, because they are relatively poorly excreted in urine, they accumulate even in the absence of an acute metabolic crises.

Neonatal symptoms are increasingly recognized in fatty acid oxidation disorders. Previous studies have shown a high incidence of neonatal symptoms in MCAD and VLCAD deficiencies.25–28

Fifteen percent of patients with LCHAD deficiency in our study presented in the neonatal period. Few patients with MCAD deficiency present between the neonatal period and the age of 6 months, the median age of presentation being 12 months in this condition.25–27 In contrast, the median age of presentation in our patients was 5.8 months. In this respect, as in many others, LCHAD deficiency resembles VLCAD deficiency more closely than MCAD deficiency.

Mortality in LCHAD deficiency is high. In our series, 38% of the patients died before or within 3 months after diagnosis. Although this mortality rate is lower than has been reported previously,7,14 it is still much higher than the mortality in MCAD deficiency (range: 16%–19%).26,27 The young age at presentation and the high mortality rate in LCHAD deficiency may be explained by 2 mechanisms. First, toxicity from long-chain acyl-CoA esters may contribute to the increased mortality by causing cardiac rhythm disturbances and cardiomyopathy. Second, the block in long-chain fatty acid oxidation results in an almost complete inability to synthesize ketone bodies and/or adenosine triphosphate (ATP) from long-chain fatty acids, the most abundant energy store in man. In MCAD deficiency, there is no production of toxic long-chain acyl-CoA esters and it is still possible to oxidize long-chain fatty acids to medium-chain fatty acids, resulting in significant production of ketone bodies and ATP.

Our study reveals a high incidence of lactic acidemia during metabolic decompensation attributable to LCHAD deficiency (Table 3). This has been reported previously in a number of case histories.10,11,14,15,18,29–32 The cause of the lactic acidosis in LCHAD deficiency is unclear, but it can probably be attributed to the toxicity of long-chain acyl-CoA esters. Long-chain acyl-CoA esters inhibit the mitochondrial ATP/adenosine diphosphate carrier33,34 and the dicarboxylate carrier35,36 in vitro. Inhibition of these carriers will increase the intramitochondrial and via the malate-aspartate shuttle the cytoplasmatic NADH/NAD+ ratio, leading to lactic acidosis with an increased lactate to pyruvate ratio. A second potential mechanism would involve direct inhibition of mitochondrial oxidative phosphorylation by 3-hydroxypalmitoyl-CoA.37 Again, this would be expected to cause lactic acidosis with an increased lactate to pyruvate ratio. Finally, long-chain acyl-carnitines may inhibit the pyruvate dehydrogenase complex38 and this should, however, cause lactic acidaemia with a normal lactate to pyruvate ratio. It is, therefore, difficult to predict the lactate to pyruvate ratio in LCHAD deficiency. The ratio was increased in 6 of the 10 patients with a high lactate concentration in our series, and it was normal in the remaining 4 patients.

It is now well-established that LCHAD deficiency in a fetus predisposes the mother to the gestational complications, HELLP syndrome, and AFLP.15,30,39–46 The frequency of these complications is, however, unclear. Ibdah et al44 reported 12 cases of AFLP and 3 of HELLP syndrome in a series of 19 pregnancies in which the fetus had LCHAD deficiency. In contrast, Tyni et al46 found only 1 case of AFLP and 3 of HELLP syndrome in a series of 29 affected pregnancies, although they also found an increased frequency of intrahepatic cholestasis, preeclampsia, and pregnancy-induced hypertension. The frequencies of AFLP and HELLP syndrome in our series were closer to those reported by Tyni et al. Of the 47 pregnancies for which we have data, 7 were complicated by HELLP syndrome and 2 by AFLP. This is still much higher than the prevalence in the normal population. The most likely cause is the production of toxic long-chain acyl-CoA esters by the feto-placental unit, probably in combination with the obligatory heterozygous state of the mother. However, the fact that, at least in animal studies, the unborn fetus predominantly depends on carbohydrate degradation for energy supply,47,48 with low oxidation rates for fatty acids,49 makes a substantial production of long-chain acyl-CoA esters by the fetus unlikely. Other factors may therefore be involved in the pathogenesis of HELLP and AFLP. HELLP syndrome and AFLP have also been reported in association with fetal MTP deficiency,50,51 CPT-1 deficiency,52 MCAD deficiency,53 and a short-chain acyl-CoA dehydrogenase (SCAD) variant.54 The latter 2 case reports may, however, be chance associations, because this SCAD variant is common (6% of the normal population) and MCAD deficiency is sufficiently common for us to know that gestational complications in this disorder are very rare.

Despite dietary treatment consisting of avoidance of prolonged fasting and a carbohydrate-rich, fat- restricted diet, morbidity in the surviving patients with LCHAD deficiency is remarkably high, with recurrent episodes of metabolic decompensation in 26% of the patients and recurrent muscle pains with raised creatine kinase (CK) levels in 32%. This might be because of the production of long-chain acyl-CoA esters, which can continue despite treatment, as has been shown by Gillingham et al.15 Differences in outcome, however, can be attributable to different dietary regimens, because Gillingham et al15 also demonstrated that changing the composition of the diet results in changes in the concentration of long-chain acyl-CoA esters. Because we have no details on the exact dietary management of the patients in this study, we can not exclude beneficial influences of a low-fat, carbohydrate-rich, MCT-enriched diet in the treatment of LCHAD deficiency.

There is much debate about the use of L-carnitine in patients with LCHAD deficiency. There have been several anecdotal reports suggesting that carnitine supplements may improve the clinical outcome in LCHAD-deficient patients. Conversely, by promoting the formation of long-chain acyl-CoA esters, L-carnitine may be harmful: there are reports suggesting that patients on L-carnitine therapy do worse than those without L-carnitine supplementation.11,14,55 Almost half the patients in our study were receiving L-carnitine supplements but we were unable to demonstrate any significant effect on the frequency of metabolic decompensation or muscle cramps. Although this conclusion is based on retrospective data, we do not think there is sufficient evidence to support the routine use of L-carnitine in LCHAD-deficient patients.

Retinopathy with progressive visual impairment, a serious long-term complication in LCHAD deficiency, was found in 9 (29%) of the 31 patients examined in our study. This is lower than the frequency reported by Tyni et al,56 who found retinal changes in >50% of their patients. The most likely explanation for this discrepancy is the relatively short period of follow-up for some of our patients. This may also explain the relatively low incidence of peripheral neuropathy in our series. The causes of the retinopathy and peripheral neuropathy in LCHAD deficiency are unknown. Low plasma concentrations of docosahexanoic acid (DHA) have been found in a few LCHAD-deficient patients and, after DHA supplementation, improvement has been reported in vision and nerve conduction.15,17 Low levels of DHA may, however, have been caused by dietary deficiency of essential fatty acids, especially {alpha}-linoleic acid, rather than LCHAD deficiency itself.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Our study demonstrates that early recognition and treatment are critical in LCHAD deficiency, because mortality is low after diagnosis is made before acute decompensation and before irreversible organic failure has occurred. It is, therefore, important to recognize that this disorder can present with chronic, nonspecific problems, such as failure to thrive, liver dysfunction, and hypotonia, as well as cardiomyopathy. Early detection will greatly benefit from newborn-screening programs for fatty acid oxidation disorders, including LCHAD deficiency. The long-term morbidity, however, can only be improved by multicenter studies to evaluate the effects of different therapeutic regimes, such as MCT, L-carnitine, and DHA supplementation.


   ACKNOWLEDGMENTS
 
We thank all contributors for making this study possible: A. Bachy, Charleroi, Belgium; P. Clayton, London, United Kingdom; A. Das, Hamburg, Germany; H. Dominick, Ludwigshafen, Germany; O. Elpeleg, Jerusalem, Germany; J. Leonard, London, United Kingdom; M. Lindner, Ulm, Germany; H. Losty, Cardiff, United Kingdom; B. Merinero, Madrid, Spain; S. Olpin, Sheffield, United Kingdom; M. Pohorencka, Warchaw, Poland; B. Poll-The, Utrecht, the Netherlands; B. Rhead, Iowa City, United States; A. Ribes, Barcelona, Spain; T. Rootwelt, Oslo, Norway; J. Smeitink, Nijmegen, the Netherlands; C. Steen, Hamburg, Germany; F. Trefz, Reutlingen, Germany; M. Ugarte, Madrid, Spain; U. Wendel, Düsseldorf, Germany; B. Wilcken, Sydney, Australia; M. Mathieu, Amiens, France; J. Zeman, Prague, Czech Republic.


   FOOTNOTES
 
Received for publication Jan 9, 2001; Accepted Jul 5, 2001.

Address correspondence to Frits A. Wijburg, Department of Pediatrics (Room G8-205), Academic Medical Center, University of Amsterdam, Box 22660, NL-1100 DD Amsterdam, the Netherlands. E-mail: f.a.wijburg{at}amc.uva.nl


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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