A severe genotype with favourable outcome in very long chain acyl-CoA dehydrogenase deficiency.

A patient with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is reported. He had a severe neonatal presentation and cardiomyopathy. He was found to be homozygous for a severe mutation with no residual enzyme activity. Tandem mass spectrometry on dried blood spots revealed increased long chain acylcarnitines. VLCAD enzyme activity was severely decreased to 2% of control levels. Dietary management consisted of skimmed milk supplemented with medium chain triglycerides and L-carnitine. Outcome was good and there was no acute recurrence.     

A severe genotype with favourable outcome in very long chain acyl-CoA dehydrogenase deficiency

A patient with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is reported. He had a severe neonatal presentation and cardiomyopathy. He was found to be homozygous for a severe mutation with no residual enzyme activity. Tandem mass spectrometry on dried blood spots revealed increased long chain acylcarnitines. VLCAD enzyme activity was severely decreased to 2% of control levels. Dietary management consisted of skimmed milk supplemented with medium chain triglycerides and L-carnitine. Outcome was good and there was no acute recurrence.     

Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency

Background

Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase (VLCAD), and which can present as cardiomyopathy in neonates, as hypoketotic hypoglycemia in infancy, and as myopathy in late-onset patients. Although many ACADVL mutations have been described, no prevalent mutations in the ACADVL gene have been associated with VLCADD. Herein, we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD.

Methods

Seven Chinese patients, from newborn to 17 years old, were included in this study. Tandem mass spectrometry was performed to screen for VLCAD deficiency. All exons and flanking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing. Online analysis tools were used to predict the impact of novel mutations.

Results

All cases had elevated serum levels of tetradecanoylcarnitine (C14:1) which is the characteristic biomarker for VLCADD. The phenotype of VLCADD is heterogeneous. Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth. Three patients showed hepatomegaly and hypoglycemia in infancy. The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis. Three of the patients died at the age of 6–8 months. Eleven different mutations in the ACADVL gene in the 7 patients were identified, including seven reported mutations (p.S22X, p.W427X, p.A213T, p.G222R, p.R450H, c.296-297delCA, c.1605+1G>T) and four novel mutations (p.S72F, p.Q100X, p.M437T, p.D466Y). The p.R450H and p.D466Y (14.28%, 2/14 alleles) mutations were identified in two alleles respectively.

Conclusions

The clinical manifestations were heterog-eneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients. R450H may be a relatively common mutation in Asian populations. The genotype and phenotype had a certain correlation in our patients.     

Medium chain acyl-CoA dehydrogenase deficiency.

From 65 reported cases of medium chain acyl-CoA dehydrogenase deficiency, we found an average presenting age of 13.5 months and a mean age at death of 18.5 months. One quarter of patients died of a Reye-like syndrome and/or sudden infant death. In half the cases there had been at least one sibling death. Asymptomatic cases were not uncommon (12% of cases). The crises were generally induced by a prolonged fast and after a viral prodromal phase in three quarters of cases. The crises consisted of somnolence progressing to lethargy which could lead to coma. Vomiting was frequent (60% of cases). Seizures, which were found in 29% of cases, represented a bad prognosis. The physical examinations revealed frequently a variable and regressive anicteric hepatomegaly. Blood and urine analysis revealed in most instances hypoglycaemia (96% of cases) with hypoketonuria and sometimes metabolic acidosis. Hepatic and muscular cytolytic enzymes were frequently raised, as were plasma ammonia, urea, and uric acid. Plasma total or free carnitine concentrations, especially non-fasting, were diminished in most cases. Plasma saturated medium chain fatty acids and particularly unsaturated cis-4-decenoate were on the other hand raised during the crises or during fasting. Urinary organic acid analysis revealed a characteristic profile of medium chain aciduria: C6-C10 dicarboxylic acids, hydroxy acids, glycine conjugates, and carnitine conjugates. Oral loading tests with carnitine or phenylpropionate allow a precise diagnosis. The diagnosis is confirmed by specific assays in various tissues. Avoidance of prolonged fasting seems to be the mainstay of treatment.     

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: A severe fatty acid oxidation disorder

3-Hydroxyacyl-CoA dehydrogenase deficiency is a newly recognised fatty acid oxidation disorder with a usually fatal outcome. We present a further patient who presented with hypoketotic hypoglycaemia, hepatopathy, secondary carnitine deficiency and increased plasma long-chain acylcarnitines. 3-Hydroxydicarboxylic aciduria was present and the diagnosis confirmed in cultured skin fibroblasts. Our patient is compared with those reported in the literature with respect to clinical symptoms, differential diagnosis and possible therapeutic regimens.     

极长链酰基辅酶A脱氢酶缺乏症研究进展

极长链酰基辅酶A脱氢酶缺乏症是一种较罕见的脂肪酸代谢障碍疾病,根据起病年龄和临床表现分为三型：心肌病型、肝型、肌病型。心肌病型病情重,病死率高。临床诊断可通过血串联质谱(MS/MS)检测血肉豆蔻烯酰基肉碱(C14:1)水平进行,进一步确诊可通过基因诊断、酶学分析及脂肪酸氧化流量分析。治疗上主要包括避免空腹,减少长链脂肪酸的摄入,补充中链甘油三酯等。     

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.     

Outcome of medium chain acyl-CoA dehydrogenase deficiency after diagnosis.

BACKGROUND: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inborn error of fatty acid metabolism. Undiagnosed, it has a mortality rate of 20-25%. Neonatal screening for the disorder is now possible but it is not known whether this would alter the prognosis. OBJECTIVE: To investigate the outcome of MCAD deficiency after the diagnosis has been established. METHOD: All patients with a proved diagnosis of MCAD deficiency attending one centre in a four year period were reviewed. RESULTS: Forty one patients were identified. Follow up was for a median of 6.7 years (range, 9 months to 14 years). Nearly half of the patients were admitted to hospital with symptoms characteristic of MCAD deficiency before the correct diagnosis was made. After diagnosis, two patients were admitted to hospital with severe encephalopathy but there were no additional deaths or appreciable morbidity. There was a high incidence (about one fifth) of previous sibling deaths among the cohort. CONCLUSIONS: Undiagnosed, MCAD deficiency results in considerable mortality and morbidity. However, current management improves outcome, supporting the view that the disorder should be included in newborn screening programmes.     

Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement

OBJECTIVE: To determine the spectrum of presentation, including both clinical and biochemical abnormalities, and the clinical course in a cohort of patients with complete mitochondrial trifunctional protein (MTP) deficiency, a rare inborn error of mitochondrial fatty acid oxidation. STUDY DESIGN: A questionnaire was sent to the referring physicians from 25 unselected MTP-deficient patients. RESULTS: Twenty-one patients could be included. Questionnaires about four patients were not returned. Nine (43%) patients presented with rapidly progressive clinical deterioration; six (67%) of them had hypoketotic hypoglycemia. The remaining 12 patients presented with a much more insidious disease with nonspecific chronic symptoms, including hypotonia (100%), cardiomyopathy (73%), failure to thrive, or peripheral neuropathy. Ten patients (48%) presented in the neonatal period. Mortality was high (76%), mostly attributable to cardiac involvement. Two patients who were diagnosed prenatally died despite treatment. CONCLUSION: Complete MTP deficiency often presents with nonspecific symptomatology, which makes clinical recognition difficult. Hypotonia and cardiomyopathy are common presenting features, and the differential diagnosis of an infant with these signs should include MTP deficiency. In spite of early diagnosis and treatment, only a few patients with this condition have survived.     

Retrospective diagnosis of medium chain acyl-CoA dehydrogenase deficiency

Abstract A male infant is reported who died suddenly and who at post-mortem had pathological evidence suggestive of a genetic defect of fatty acid β-oxidation. A specific diagnosis could not be made enzymatically because of unavailability of suitable tissue for assay. The diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency was made by specific mutation analysis using the polymerase chain reaction and DNA extracted from the newborn screening card of this infant. This powerful new molecular diagnostic technique should prove to be of use in similar circumstances.     

Carrier detection in X-linked adrenoleukodystrophy by determination of very long chain fatty acid levels and by linkage analysis

Diagnosis of X-linked adrenoleukodystrophy is based upon demonstration of high levels of very long chain fatty acids. More recently, in addition to biochemical analysis, closely linked DNA probe St14 has been used for prenatal diagnosis in informative families. Identification of heterozygotes is particularly important, both in order to specifically address only carrier females to prenatal diagnosis, and because appropriate dietary therapy is now available to treat those heterozygotes presenting with neurological symptoms. We report two pedigrees in which carrier detection was performed by a combination of biochemical and molecular genetic analysis. Such approach should allow extremely high accuracy in carrier detection.     

Outcome of medium chain acyl-CoA dehydrogenase deficiency after diagnosis

BACKGROUND—Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inborn error of fatty acid metabolism. Undiagnosed, it has a mortality rate of 20-25%. Neonatal screening for the disorder is now possible but it is not known whether this would alter the prognosis.OBJECTIVE—To investigate the outcome of MCAD deficiency after the diagnosis has been established.METHOD—All patients with a proved diagnosis of MCAD deficiency attending one centre in a four year period were reviewed.RESULTS—Forty one patients were identified. Follow up was for a median of 6.7 years (range, 9 months to 14 years). Nearly half of the patients were admitted to hospital with symptoms characteristic of MCAD deficiency before the correct diagnosis was made. After diagnosis, two patients were admitted to hospital with severe encephalopathy but there were no additional deaths or appreciable morbidity. There was a high incidence (about one fifth) of previous sibling deaths among the cohort.CONCLUSIONS—Undiagnosed, MCAD deficiency results in considerable mortality and morbidity. However, current management improves outcome, supporting the view that the disorder should be included in newborn screening programmes.     

Adrenoleukodystrophy: impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts, and amniocytes

We compared the formation of 14CO2 from [I-14C]fatty acids in homogenates of cultured skin fibroblasts and white blood cells from 25 patients with adrenoleukodystrophy (ALD) and from 24 controls. The ALD group included 16 boys with childhood ALD, five men with adrenomyeloneuropathy (AMN), and two boys and two girls with neonatal ALD. The substrates were unbranched saturated fatty acids ranging in chain length from 16-26 carbons. From C24:0, the radioactive CO2 production by homogenates of ALD fibroblasts and white blood cells was 17% and 37% of control, respectively, and from C26:0 it was 17% of control in ALD fibroblasts. The CO2 evolution from palmitate (C16:0) in the ALD was identical to the control group; for C18:0, the value for ALD cells was 76% of control, and fatty acids with chain lengths between C18:0 and C24:0 gave intermediate results. Results for childhood ALD patients were similar to those for the AMN patients. More limited studies with cultured amniocytes of fetuses with childhood ALD gave results similar to those obtained with cultured skin fibroblasts, and results with neonatal ALD patients appeared to be the same as for childhood ALD and AMN. Studies of three women who were carriers for childhood ALD gave values intermediate between ALD and control. The total C26:0 levels in ALD cultured skin fibroblasts and white blood cells were 4-6 times that of control; the total C24:0 levels were increased 10-30%, whereas the C22:0 levels were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phenotyping a new mitochondrial fatty acid oxidation deficient mouse model

Tijdschrift voor Kindergeneeskunde -     

Prospective surveillance study of medium chain acyl-CoA dehydrogenase deficiency in the UK

BACKGROUND: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a common disorder of fatty acid oxidation in north west Europe. It is very variable in its clinical consequences and is believed to be considerably underdiagnosed. OBJECTIVE: To investigate the diagnosis and outcome of MCAD deficiency in the UK. METHOD: A prospective surveillance study through the British Paediatric Surveillance Unit. RESULTS: Of 62 affected individuals identified, 57 were from England, giving an incidence of 4.5 cases/100,000 births. Forty six cases presented with an acute illness (10 of whom died), 13 cases were identified because of family history, and three for other reasons. Six of the survivors were neurologically impaired. CONCLUSIONS: Despite increased clinical awareness, the mortality and morbidity from MCAD deficiency remain high. The frequency and severity of the disease support the case for the introduction of universal neonatal screening in England and Scotland.     

Medium chain acyl-CoA dehydrogenase deficiency. Apropos of a case with demonstration of this enzyme deficiency

The medium chain acyl-CoA deshydrogenase defect: a new inherited metabolic disorder. This enzymatic defect blocks the catabolism of non esterified fatty acids during fasting. Thus, this disease is revealed by a coma due to hypoglycemia in a young child; the presence of dicarboxylic aciduria in such a situation is the main evidence for this diagnosis. Finally, the enzymatic studies performed on skin fibroblasts show a defect in medium chain acyl-CoA deshydrogenase. When a child is investigated away from a coma episode, the ketotic diet induces dicarboxylic aciduria but must be performed in an intensive care unit for its dangers.     

早产儿长链多价不饱和脂肪酸水平及相关因素研究

目的 探讨早产儿出生时长链多价不饱和脂肪酸（ＬＣＰ）水平及其相关因素。方法 用毛细管气相色谱法测定２８例早产儿脐静脉血（简称脐血）及其母亲静脉血血浆和红细胞膜ＬＣＰ水平,同时测定早产儿出生时体重、身长、头围。２０例健康足月儿作为对照组。结果（１）母血亚油酸（ＬＡ）、亚麻酸高于脐血,差异有显著意义;脐血花生四烯酸（ＡＡ）、廿二碳六烯酸（ＤＨＡ）高于母血;脐血（ＬＡ）、亚麻酸高于脐血,差异有显著意义;