Acyl-CoA Dehydrogenase Deficiency: Varieties With Neurological Involvement

The special importance of acyl-CoA dehydrogenase deficiency is the possibility it offers for successful treatment. In view of this, the characteristics of the different varieties will first of all be described, and references given so that additional information can be obtained if needed.
Different varieties and their symptomatology
Acyl-CoA dehydrogenase deficiency can occur in various autosomal recessive forms: short-chain, medium-chain, and very-long-chain. Short-chain acyl-CoA dehydrogenase is an enzyme involved in mitochondrial short-chain fatty acid oxidation, and its deficiency can cause hypotonia, developmental delay, seizures, microcephaly, lethargy, scoliosis, and also hypoglycaemia, vomiting, poor feeding, and failure to thrive. In fact, there seem to be several types of presentation: individuals with episodic hypoglycaemia and ketosis, those with developmental delay and hypotonia, and those with atypical features. The latter include those showing hepatic dysfunction and recurrent attacks of vomiting, for example, as Seidel and colleagues1 reported of a boy who experienced vomiting attacks once or twice a year although growth and development were normal. In this case the condition was considered to result from unusual mutations. In a study by Bhala and coworkers2 it was stressed that all the individuals described had neurological abnormalities but none had episodes of hypoglycaemia. However, homozygosity for an inactivating short-chain acyl-CoA dehydrogenase mutation does not necessarily result in disease, although the reasons for this are unclear.3 It is possible that the hypoglycaemia, occurring under the stress of fasting, may be partly due to lack of reducing equivalents from the oxidation of short- chain fatty acids due to a short-chain acyl-CoA deficiency.4 Yet the correlation between short-chain acyl-CoA dehydrogenase mutations and clinical phenotypes is not clear, although all of them are missense mutations identified in the exons of the gene. Two mutations have been described in exons 5 and 6 of the short-chain acyl-CoA dehydrogenase gene and their relative frequencies have been estimated in different ethnic populations.5
There is also a short/branched-chain acyl-CoA dehydrogenase deficiency. It is an autosomal recessive condition causing a disorder of L-isoleucine metabolism, and very few families have been described so far. The presentation can be in the neonatal period with poor feeding, lethargy, hypothermia, hypoglycaemia, and metabolic acidosis. One child reported by Matern et al.6 developed athetoid cerebral palsy and another showed severe motor developmental delay, the mother in one family was affected but was asymptomatic.
Medium-chain acyl-CoA dehydrogenase deficiency, an autosomal recessive disorder of fatty acid oxidation, has an incidence in the UK between one in 9000 and one in 22 000, with the common A985G mutation. Fasting or illness can lead to hypoglycaemic encephalopathy, with a risk of sudden death or permanent neurological damage. Kairomkanda and coworkers7 have reported such an encephalopathy in a child following a perforated duodenal ulcer. Symptoms usually develop in early childhood, but can occur in the neonatal period, usually when breast fed.8 However, in spite of the often grave prognosis, more benign clinical phenotypes can occur.9 The incidence of the condition in some areas of the UK can be as low as 1 in 10 000, but Seddon and colleagues10 stress that this can vary from region to region.
Very-long-chain acyl-CoA dehydrogenase deficiency catalyzes the first step in the long-chain oxidation of fatty acids. It is a heterogeneous disease. It can present as an early onset cardiomyopathy and hepatopathy which can be massive,11 and can sometimes cause sudden and unexpected death.12,13 There is also a hepatic phenotype with recurrent hypoketotic hypoglycaemia usually in infancy, and a late onset mild myopathic form with episodes of muscle weakness, myalgia, and myoglobinuria. Parina and colleagues14 considered that the condition should be included in the differential diagnosis of acute cardiomyopathy at any age. The arrhythmias and conduction defects that can occur may be due to the accumulation of intermediary metabolites of fatty acids.15 The incidence of these deficits is unknown, although over a hundred patients have been described. This milder form is linked to missense mutations. The condition may be more common than thought and affected patients are at risk. An undiagnosed child, for example, died at the age of 5 years after perioperative fasting and sedation,16 and Hamano and colleagues17 reported a patient, who since the age of 18 years, had experienced recurrent episodes of exercise-induced limb muscle pain and weakness, accompanied by dark-coloured urine due to rhabdomyolysis. They stress the need to consider this diagnosis in individuals with such a history, and there is no doubt that they can be confused with other conditions like McArdle disease,18 and carnitine palmitoyl transferase II which is another &#946,- oxidation defect. Straussberg and Strauss19 reported a normal mutation in three siblings who presented with rhabdomyolysis and myoglobinuria, which altered alanine to threonine and most probably caused the changes in enzyme function and the clinical features, favouring a genotype-phenotype correlation. The 14-year-old girl with this condition, described by Fukao and colleagues,20 manifested recurrent myalgia with elevated serum creatine kinase after moderate exercise. She had never had hypoglycaemic attacks, and there was no enlargement of the heart or liver. Her symptoms were due to temperature-sensitive mild mutations from both her parents, and residual acyl-CoA dehydrogenase activity was reduced or absent at slightly raised temperatures. Similar findings were reported by Takusa and coworkers21 who also classified the disorder into three types: a severe childhood form with early onset, a high mortality, and a high incidence of cardiomyopathy, a milder childhood form with a later onset presenting with hypoketotic hypoglycaemia, low mortality, and a rare cardiomyopathy, and an adult form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria usually triggered by exercise or fasting. However, a myopathic form can also occur in early infancy.22
A number of children with multiple acyl-CoA dehyctrogenase deficiency have been reported. It is a heterogeneous genetic defect of the electron transfer flavoprotein causing dysfunction of dehydrogenases linked to flavine adenine dinucleotide and is, therefore, an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism.23 The clinical presentations are variable. Neonates sometimes die in infancy with malformations and severe metabolic decompensation, and infants and children present with metabolic decompensation, hepatic dysfunction, myopathy, and cardiomyopathy. Olsen and colleagues24 have divided the condition into three clinical types: a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies, and a late onset form due to different mutations. A prenatal diagnosis is possible by analysis of the acylcarnitine profile in the amniotic fluid consistent with this type of dehydrogenase deficiency, and by mutational analysis of the involved gene, but the significance of a raised maternal serum alpha-fetoprotein is not definitely proven. Also a sonogram may show growth delay, cystic renal disease, and oligohydramnios.25
Metabolic disorders in different types of acyl-CoA dehydrogenase deficiency
Short-chain acyl-CoA dehydrogenase is the first enzyme of the &#946,-oxidation of short-chain fatty acids. Deficiency of the enzyme causes a high excretion of ethylmalonic acid and methylsuccinate, and sometimes the presence of n-butyrylcarnitine in the urine. The excretion of ethylmalonate can be increased after a medium-chain triglyceride load,26 and on plasma acylcarnitine analysis there can be an increase of C^sub 4^-carnitine. Also there was low activity of the enzyme in fibroblasts,3 which can be measured with the electron-transfer flavoprotein-linked assay.2
In 2-methylbutyryl-CoA dehydrogenase deficiency, or short/ branched-chain acyl-CoA dehydrogenase deficiency, there is a defect in the third step of the metabolic pathway of the branched-chain amino acid L-isoleucine.27 This results in an abnormally elevated concentration of 2-methylbutyrylcarnitine, indicative of a defect in L-isoleucine metabolism in one patient, and in another mutation there was an increased urinary excretion of ethylmalonic acid suggesting a degradation defect of short-chain fatty acids, and an increase of n-butyrylcarnitine in freshly collected serum.1 In another mutation 2-methylbutyrylglycinuria has been found, indicating a defect in both isoleucine and valine metabolism.28
Medium-chain acyl-CoA dehydrogenase deficiency is a disorder of fatty acid oxidation which leads to the accumulation of octanoylcarnitine in the blood of affected patients, and this can be confirmed by the analysis of the concentration of acylcarnitines in neonatal blood spots by tandem mass spectrometry.29,30 The high octanoylcarnitine persists in individuals who survive. The urine of those diagnosed in this way showed detectable suberylglycine, phenylpropionylglicine, and hexonylglycine.7
In the case of very-long-chain acyl-CoA dehydrogenase deficiency the levels of muscle-origin enzymes including creatine kinase and aldolase are mildly elevated, but the ischaemic forearm exercise test shows normal levels of lactate and pyruvate. Total carnitine and acyl-carnitine levels can be low in the serum, but tandem mass spectrometry on dried blood spots, and in serum, can identify elevated levels of tetradecenoic acid. Also, the activity of palmitoyl-CoA in lymphocytes is deficient.17
In individuals with multiple acyl-CoA dehydrogenase deficiency, abnormal excretion of organic acids are found, hence, the alternative names of glutaric aciduria type II and ethylmalonic adipic aciduria.


There seems to be no doubt that screening by tandem mass spectrometry can save lives in these potentially fatal conditions.31 Pourfarzam and colleagues7 screened infants for medium-chain acyl- CoA dehydrogenase deficiency and analyzed the concentrations of acylcarnitines in stored neonatal blood spots, and reviewed patients with high octanoylcarnitine concentrations at the age of 7 to 8 years. As a result of these studies it was considered that neonatal screening was justified in view of the high morbidity and mortality of the condition. This involves a heel-prick filter paper sample from the neonate so that it can be done when testing for other metabolic disorders. Without this it has been estimated that there is a mortality of around 25% in diagnosed cases presenting clinically,32 but accurate information on the prevalence of the various types of deficiency is not available.
Similar screening methods have been used to diagnose asymptomatic neonates with very-long-chain acyl-CoA dehydrogenase deficiency when a mild elevation of acylcarnitines are found.16 However, Carpenter and colleagues33 warn that such screening, although effective in preventing morbidity and mortality, must be accompanied by effective management and counselling, acknowledging that not all identified infants are at risk.
When unexpected death occurs in infancy it is possible to screen for fatty acid oxidation disorders post-mortem by the analysis of Guthrie cards with tandem mass spectrometry.34


The first episode may be misdiagnosed as sudden infant death syndrome or as an encephalopathy such as Reye’s syndrome. In addition, some individuals can present with specific learning difficulties or other unlikely symptoms in later childhood.35 An early warning of metabolic imbalance can be an elevation of creatine kinase and uric acid levels due to breakdown of tissue before onset of some acute episode.36
The diagnosis may well be made by screening methods in infancy, and the same techniques can be used on those suspected to have such deficiencies, and there can be no doubt that acylcarnitine analysis in blood and urine is the method of choice. Also, as shown by Young and colleagues,37 profiling methods can be used to separate different varieties of short-chain acyl-CoA dehydrogenase deficiencies. They used cultured fibroblasts from classical and variant forms, and the accumulations of butyrylcarnitine were analyzed by mass spectrometry. It was found that a moderate reduction of the enzyme activity was associated with variants of the condition due to genetic causes.
Apart from the introduction of correct management, diagnosis is important for future pregnancies and preimplantation diagnosis which is now available.35 However, as stated, diagnosis is not always easy, as clinical presentation can vary and metabolites may not be consistently excreted. Repeated examination of urine and plasma specimens maybe needed,2 and especially if there has been no neonatal screening, a high level of suspicion must be maintained. In view of the many mutations discovered in the last few years, molecular diagnosis may become increasingly important in the future.


Prevention of hypoglycaemia and the brain damage that results from this can be assured by the avoidance of fasting by adequate glucose or carbohydrate intake, and dietary treatment with protein restriction.37 Possible treatment with carnitine supplementation has been recommended.35 However, there is a certain lack of evidence on the effectiveness of various treatments that have been tried. Solis and Singh38 have reviewed these, including frequency of meals, the administration of cornstarch and carnitine, and various formulas containing a high percentage of medium-chain triglyceride oil and essential fats, as well as vitamins and minerals. In the case of very-long-chain fatty acid oxidation defects it has been suggested that the replacing of dietary medium-even-chain fatty acids by medium-odd-chain fatty acids would restore energy production and improve cardiac and skeletal muscle function. This was tried in three patients with definite improvement.39
Individuals, severely affected by multiple acyl-CoA dehydrogenase deficiency, can be responsive to riboflavine, and those with cerebral and cardiac complications have been treated with a low fat diet, avoidance of fasting, and with D,L-3-hydroxybutyrate, but the response may be poor.


The justification for drawing attention to these unusual conditions is the poor prognosis and the possibilities for treatment. For example, Wilson and colleagues41 investigated the outcome of children with medium-chain acyl-CoA dehydrogenase deficiency. They followed up 41 individuals and found that nearly half of them were admitted to hospital with characteristic symptoms before an accurate diagnosis was made. After the diagnosis was established, and the correct management was started, all patients progressed satisfactorily with no additional deaths or appreciable morbidity, except for two who were admitted to hospital with severe encephalopathy.


The importance of early diagnosis of these conditions is the possibility that they can be prevented by a regular intake of carbohydrate. There seems to be no doubt that a case can be made for neonatal screening of disorders due to acyl-CoA dedrogenase deficiencies. Then, if a diagnosis is made this can lead to a reduction in parental stress, planned management, such as special diets, and biochemical monitoring, medication, and special services.35
In the future the rapid development of mutation detection systems, such as chip technologies, may make profile analysis feasible, and so make the specific diagnosis of these fatty acid oxidation defects easier than by the traditional enzymatic assays.42 A most useful review of the mitochondrial fatty acid oxidation deficiencies due to defects in enzymes of fatty acid &#946,- oxidation and transport proteins has been given by Gregersen and colleagues,42 and they conclude that the genetic defect in most individuals with short-chain acyl-CoA dehydrogenase deficiency is not due to rare inactivating sequence variations but rather to the presence of one or two susceptibility gene variations.