An unusual presentation of medium-chain acyl coenzyme A dehydrogenase deficiency.

OBJECTIVE--To report an atypical presentation of medium-chain acyl Coenzyme A dehydrogenase deficiency in a 13-year-old girl with hyperammonemic encephalopathy and orotic aciduria meeting the accepted criteria for diagnosis of a female heterozygous for ornithine transcarbamylase deficiency. DESIGN--Case report and definitive biochemical testing. SETTING--Children's hospital and university laboratory. PARTICIPANT--One teenager. INTERVENTIONS--Diagnosis and treatment with carnitine. MEASUREMENTS/MAIN RESULTS--Assay ornithine transcarbamylase deficiency had normal results. The diagnosis was confirmed by DNA analysis, which revealed homozygosity for prevalent mutation (the adenine to guanine transition at position 985). CONCLUSIONS--Patients with a clinical diagnosis of Reye's syndrome have, in general, an inborn error of metabolism. Medium-chain acyl Coenzyme A dehydrogenase deficiency and other disorders of fatty acid oxidation may present long after infancy. They may mimic the presentation of defects in the urea cycle.     

Morbidity and mortality in medium chain acyl coenzyme A dehydrogenase deficiency.

Medium chain acyl coenzyme A dehydrogenase (MCAD) deficiency presents with episodic fasting, hypoketotic hypoglycaemia, and coma. It is known to be potentially lethal, but the outlook for survivors is thought to be good. We reassessed all patients with MCAD deficiency diagnosed in New South Wales (population six million) to explore long term morbidity and mortality. There were 16 probands and two siblings were confirmed and two presumed to be affected. Assuming an incidence of 1:20,000 births, these represented about 22% of the total number of expected cases. Five (25%) of the 20 patients died aged 3 days-30 months, all during the first episode of illness. Seven others had only one episode and one affected sibling was asymptomatic. Eight had had significant neonatal symptoms. Only two had a significant, serious life threatening episode after diagnosis. Of 15 survivors, one has severe handicap after a single severe episode, and four, aged 9-17 years, have mild intellectual handicap. Eight (including six aged less than 7 years), have apparently normal development. Two are lost to follow up. Our study of unselected patients with MCAD deficiency from a defined population shows not only a substantial risk of death, but also of long term morbidity.     

Long-chain acyl coenzyme A dehydrogenase deficiency: an inherited cause of nonketotic hypoglycemia

Three children from unrelated families presented in early childhood with hypoglycemia and cardiorespiratory arrests associated with fasting. Significant hepatomegaly, cardiomegaly, and hypotonia were present at the time of initial presentation. Ketones were not present in the urine at the time of hypoglycemia in any patient; however, dicarboxylic aciduria was documented in one patient at the time of the acute episode and in two patients during fasting studies. Total plasma carnitine concentration was low with an increased esterified carnitine fraction. These findings suggested a defect in mitochondrial fatty acid oxidation, and specific assays were performed for the acyl coenzyme A (CoA) dehydrogenases. These analyses showed that the activity of the long-chain acyl CoA dehydrogenase was less than 10% of control values in fibroblasts, leukocytes, and liver tissue. Activities of the medium-chain, short-chain, and isovaleryl CoA dehydrogenases were not different from control values. With cultured fibroblasts, CO2 evolution from long-chain fatty acids was significantly reduced, while CO2 evolution from medium-chain and short-chain fatty acids was comparable to control values--findings consistent with a defect early in the beta-oxidation sequence. Studies of acyl CoA dehydrogenase activities in fibroblasts and leukocytes from parents of the patients showed levels of long-chain acyl CoA dehydrogenase activity intermediate between affected and control values and indicated an autosomal recessive form of inheritance of this enzymatic defect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunochemical characterization of variant medium-chain acyl-CoA dehydrogenase in fibroblasts from patients with medium-chain acyl-CoA dehydrogenase deficiency.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a common autosomal recessive disorder of mitochondrial fatty acid oxidation characterized by episodes of hypoketotic hypoglycemia usually beginning in the first 2 y of life. We previously showed, in pulse labeling experiments, that the biosynthesis and immediate posttranslational processing of MCAD are normal in fibroblasts from patients with MCAD deficiency. Most patients studied to date are homozygous for a point mutation (A985-G) that results in the substitution of glutamate for lysine ar residue 304 of the mature MCAD subunit. We performed immunoblot analysis of fibroblast MCAD from a total of 34 patients with MCAD deficiency, including 31 homozygous for the A985-G mutation, using a rabbit anti-rat MCAD antibody that cross-reacted specifically with human MCAD, but not with the related enzymes, short-chain and long-chain acyl-CoA dehydrogenases. All patients with the A985-G mutation lacked detectable MCAD. Pulse-chase labeling of MCAD-deficient fibroblasts with 35S-methionine demonstrated that this variant MCAD was unstable compared to controls. Taken together, these data suggest that this mutation affects the stability of MCAD protein within the mitochondrial matrix.     

Hyperuricemia in medium-chain acyl-coenzyme A dehydrogenase deficiency.

Six infants and children with medium-chain acyl-coenzyme A dehydrogenase deficiency were found to have hyperuricemia during an acute episode. Hyperuricemia may be a clue to the diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency.     

The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome

OBJECTIVES: To describe the clinical presentation and long-term follow-up of a large cohort of patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. STUDY DESIGN: A nationwide, retrospective analysis of clinical presentation and follow-up in 155 Dutch patients with MCAD deficiency. RESULTS: Most patients presented between 3 months and 5.1 years of age; 13% had symptoms as neonates not exclusively related to breast-feeding. An acute presentation before the diagnosis was made resulted in a mortality of 22% (25/114), whereas 21% (19/89) developed disabilities after the diagnosis. On follow-up, a total of 44 patients reported fatigue (35%; 28/80), muscle pain (31%; 25/80), and/or reduced exercise tolerance (39%; 31/80). Cardiac evaluation in 11 adult patients revealed no abnormalities in cardiac function explaining these complaints. Children with MCAD deficiency readily become overweight. CONCLUSIONS: Mortality and morbidity were high in undiagnosed children with MCAD deficiency; establishment of the diagnosis significantly improves outcome. Strikingly, after the diagnosis and initiation of treatment, overweight and chronic complaints (fatigue, muscle pain, and reduced exercise tolerance) were prominent.     

Long-chain acyl-coenzyme A dehydrogenase deficiency: biochemical studies in fibroblasts from three patients

We studied fibroblasts from three patients with long-chain acyl-coenzyme A dehydrogenase (LCADH) deficiency; siblings H.C. and J.C. had milder clinical phenotypes than unrelated patient R-1. In H.C., J.C., and R-1 oxidation of [9,10(n)-3H]palmitate was 50, 48, and 28% of control, respectively, with R-1 having significantly less activity than H.C. and J.C. (p less than 0.05). Assays of mitochondrial short-chain and medium-chain acyl-coenzyme A dehydrogenases were normal in H.C. and J.C. However, mitochondrial LCADH activities in all three ranged from 17 to 21% of control. Flavin adenine dinucleotide addition increased LCADH activities in all three to 27-36% of control. In the presence of monospecific medium-chain acyl-coenzyme A dehydrogenase antiseria, LCADH activity decreased 17% in controls, and fell to less than or equal to 11% of control in J.C. and R-1. The heterogeneity observed in the [3H]palmitate oxidation studies was not explained by differences in LCADH activities under any assay condition.     

Diagnostic and therapeutic implications of medium-chain acylcarnitines in the medium-chain acyl-coA dehydrogenase deficiency

The medium-chain acyl-coA dehydrogenase deficiency is one of several metabolic disorders presenting clinically as Reye syndrome. Evidence is presented for a characteristic organic aciduria that distinguishes this disorder from Reye syndrome and other masqueraders characterized by dicarboxylic aciduria. The key metabolites, suberylglycine and hexanoylglycine, are excreted in high concentration only when the patients are acutely ill. More significantly, using novel techniques in mass spectrometry, the medium-chain defect is shown to be characterized by excretion of specific medium-chain acylcarnitines, mostly octanoylcarnitine, without significant excretion of a normal metabolite, acetylcarnitine, in four patients with documented enzyme deficiency. Similar studies on the urine of two patients reported with Reye-like syndromes of unidentified etiology have suggested the retrospective diagnosis of medium-chain acyl-coA dehydrogenase deficiency. Administration of L-carnitine to medium-chain acyl-coA dehydrogenase deficiency patients resulted in the enhanced excretion of medium-chain acylcarnitines. Octanoylcarnitine is prominent in the urine both prior to and following L-carnitine supplementation. The detection of this metabolite as liberated octanoic acid, following ion-exchange chromatographic purification and mild alkaline hydrolysis, provides a straightforward diagnostic procedure for recognition of this disorder without subjecting patients to the significant risk of fasting. In view of the carnitine deficiency and the demonstrated ability to excrete the toxic medium-chain acyl-coA compounds as acylcarnitines, a combined therapy of reduced dietary fat and L-carnitine supplementation (25 mg/kg/6 h) has been devised and applied with positive outcome in two new cases.     

Familial Reye-like syndrome: a presentation of medium-chain acyl-coenzyme A dehydrogenase deficiency

A 20-month-old girl with a family history of two siblings who died of an encephalopathy diagnosed as Reye syndrome presented to an emergency room in hypoglycemic coma and was found to have medium-chain acyl-coenzyme A dehydrogenase deficiency. The salient clinical and biochemical features of this newly described inborn error of fatty acid metabolism are described and contrasted to those of classical Reye syndrome. Important clues that should lead the clinician to suspect this disorder, methods of diagnosis, and appropriate acute and long-term therapy are also discussed.     

Biosynthesis of variant medium chain acyl-CoA dehydrogenase in cultured fibroblasts from patients with medium chain acyl-CoA dehydrogenase deficiency

We prepared monospecific antiserum in rabbits against medium chain acyl-CoA dehydrogenase (MCAD) purified from rat liver and studied the biosynthesis of MCAD in cultured skin fibroblasts from patients with MCAD deficiency using the antibody. Cells were incubated with [35S]methionine. The labeled MCAD was immunoprecipitated using the anti-rat MCAD antiserum and Staphylococcus aureus cells and then analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We first demonstrated that antirat MCAD antibody crossreacted specifically with human MCAD. In 13 MCAD-deficient cell lines tested, the residual MCAD activity ranged from 5-12% of the mean of normal controls, but the variant MCAD in all of these cells was indistinguishable from the normal human MCAD on the basis of molecular size, indicating that MCAD deficiency in all of these patients is most likely due to point mutation(s) in the MCAD gene.     

Immunochemical characterization of variant long-chain acyl-CoA dehydrogenase in cultured fibroblasts from nine patients with long-chain acyl-CoA dehydrogenase deficiency

Long-chain acyl-CoA dehydrogenase (LCAD) deficiency is a disorder of mitochondrial fatty acid oxidation that is characterized by hypoglycemia, muscle weakness, and hepato- and cardiomegaly. To characterize variant LCAD, we first carried out preliminary experiments using pure enzyme preparations. Despite the significant sequence similarity of LCAD to medium-chain acyl-CoA dehydrogenase, the antibody raised against rat LCAD was monospecific for human and rat LCAD and did not cross-react with either human or rat medium-chain acyl-CoA dehydrogenase. Immunoblot analysis of variant LCAD in cultured fibroblasts from nine patients with LCAD deficiency revealed a single LCAD band in all nine LCAD-deficient cell lines. Each variant LCAD was comparable in molecular size and quantity to normal LCAD, suggesting that the LCAD mutation in each of these cell lines is likely to be a point mutation that produces a stable variant LCAD. The uniform nature of variant LCAD suggests that only a single, or at most a few, prevalent point mutations may be found in the majority of LCAD-deficient patients. If this is the case, it should be possible to devise a molecular diagnostic method for LCAD deficiency.     

Delayed diagnosis of fatal medium-chain acyl-CoA dehydrogenase deficiency in a child

A 5-year-old white female presented with coma and died unexpectedly. She had a history of recurrent episodes of febrile illnesses associated with lethargy and coma. Postmortem investigation revealed a fatty liver, leading to a suspicion of inborn error of fatty acid oxidation. The diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was suggested by abnormal acylcarnitine profile with increased octanoylcarnitine in the blood, and confirmed by fatty acid oxidation studies and mutation analysis in skin fibroblast cultures. This case emphasizes the need to consider fatty acid oxidation disorders in all children who present with hypoglycemia with absent or mild ketones in the urine and high anion gap metabolic acidosis.     

Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency

A family is described in which the father and three (and probably all four) of his children had a decreased capacity for the oxidation of medium-chain fatty acids. One of the children suddenly died at the age of 16 months following an episode of a rapidly deteriorating Reye syndrome-like illness with hypoketotic hypoglycemia and dicarboxylic aciduria, but without any previous alarming symptoms. The eldest sibling had died at the age of 19 months under similar conditions. The other family members had always been healthy. On fasting, all affected family members accumulated in their plasma the medium-chain fatty acids octanoic, decanoic, and cis-4-decenoic acids. Their urinary organic acid excretion profile could be characterized as "dicarboxylic aciduria." A deficiency of medium-chain acyl-coenzyme A dehydrogenase was demonstrated in a postmortem liver sample of the index patient. Cultured fibroblasts from the father and the two healthy children had a decreased rate of [14C]octanoate oxidation. It is suggested that a deficiency of medium-chain acyl-coenzyme A dehydrogenase may lead to a life-threatening illness when other complicating factors such as diarrhea and vomiting result in an abnormal depletion of the body's glycogen stores. Careful monitoring of at-risk patients during a minor illness is necessary.     

Early diagnosis and treatment of neonatal medium-chain acyl-CoA dehydrogenase deficiency: Report of two siblings

Two siblings are reported who were syptomatic in the neonatal period. The first died suddenly at 4 days of age after regurgitating a meal. The postmortem examination showed steatosis of the liver, kidney and muscle. In the second, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was diagnosed at 3 days of age with muscular hypotonia, vomiting, hyperammonaemia and mild acidosis. Thus disorders of fatty acid oxidation should also be considered in newborns. The biochemical work up indicates that in neonates, analysis of serum medium-chain fatty acids and of acyl and free carnitine are more likely to lead to a diagnosis than determining dicarboxylic acids alone in urine. Long-term treatment was effective and monitored by the acyl/free carnitine ratio.An abstract relating the initial findings of this patient was published by Catzeflis C, Délèze G, Kuchler H, Spahr A, Schütz B, Bachmann C (1987) Helv Paediatr Acta 42:47     

A fatal neonatal case of medium-chain acyl-coenzyme A dehydrogenase deficiency with homozygous A-->G985 transition.

A term neonate became lethargic and hypotonic at 46 hours of age and died 10 hours later despite supportive therapy. Urinary organic acids indicated medium-chain acyl-coenzyme A dehydrogenase deficiency, and DNA studies confirmed this disorder. Neonatal symptoms in this enzyme deficiency have rarely been reported, and recent reviews have ignored or discounted this presentation.     

Multiple sulfatase deficiency (Mucosulfatidosis): Impaired degradation of labeled sulfated compounds in cultured skin fibroblasts in vivo

Skin fibroblasts from a Japanese patient with multiple sulfatase deficiency (MSD) (Mucosulfatidosis) were studied with regard to metabolism of various sulfated compounds in vivo. Several sulfatase activities (arylsulfatases A,B and C, cholesterol sulfatase, heparin N-sulfatase) were deficient in skin fibroblasts grown in F-10 CO₂ medium. The accumulation and degradation of ³⁵S-sulfatide, ³⁵S-mucopolysaccharides, ¹⁴C-cholesterol sulfate by MSD cells were also studied, comparing them to control, Hunter and metachromatic leukodystrophy cells. MSD fibroblasts accumulated and failed to degrade these compounds in vivo. Cholesterol sulfate was also incorporated into the control and pathological cells, and MSD cells were unable to hydrolyze cholesterol sulfate, though cholesterol sulfate is known to be hydrolyzed in the non-lysosomal subfraction. From these data it is clear that multiple enzyme deficiencies in MSD fibroblasts can be demonstrated in vivo.Supported by grants Nanbyo from a Ministry of Education, 1979