A severe genotype with favourable outcome in very long chain acyl-CoA dehydrogenase deficiency (original) (raw)
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Very long-chain acyl CoA dehydrogenase deficiency which was accepted as infanticide
Forensic Science International, 2011
A one-month-old female patient was referred to our clinic for having three siblings who had died of an unknown cause in newborn period. Our patient was the second living child of her mother's five pregnancies. She was delivered by cesarean section at 39 weeks of gestational age. Birth weight of the patient was 2600 g. She was not breastfed. Formula feeding was used. Her parents were cousins. Parents' first and second children had died in 24 h, third one in 14 days suddenly after normal deliveries. The parents were investigated for infanticide. Hence, autopsy was performed in the last dead child, and showed inconclusive, nonspecific findings. The fourth child was healthy, male and 13 months old . The patient's physical examination was normal. The metabolic investigations showed that C14:1 (tetradecanoyl carnitine) was 1.72 mmol/L (normal range, 0-0.5 mmol/L), C14 (myristoyl carnitine) 1.11 mmol/L (normal range, 0-0.5 mmol/L), and C18:1 (oleyl carnitine) 4.21 mmol/L (normal range, 0-2.5 mmol/L) in plasma.
Journal of International Medical Research, 2018
The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods: Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cutoff values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results: In both patients, analysis of the organic acids in urine showed a possible b-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 þ 2T > C and c.527_533del). The results from a retrospective analysis of newborn screening cards clearly showed major elevations of MCAD-specific acylcarnitines in the patients.
Journal of Pediatric Nursing, 2013
A clinical case of very long chain fatty acid acyl-CoA dehydrogenase (VLCAD) deficiency with cardiac manifestation, is presented. A 2-day old newborn, delivered after a normal pregnancy, birth, and immediate post-natal period, was transported from an outside hospital (OSH) with episodic wide complex tachycardia. In this case, the newborn screen returned suggesting VLCAD deficiency, positively redirecting treatment. An overview of VLCAD, one category of inborn error of metabolism (IEM), is presented. Additionally, the importance of newborn screening, the role of genetic testing, and nursing implications to improve outcomes, will also be discussed. Published by Elsevier Inc.
The American Journal of Human Genetics, 1999
catalyzes the initial rate-limiting step in mitochondrial fatty acid b-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established.
Medium chain acyl-CoA dehydrogenase deficiency
Archives of Disease in Childhood, 1992
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.
Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency
Molecular Genetics and Metabolism, 2013
Background-Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is diagnosed in the US through newborn screening (NBS). NBS often unequivocally identifies affected individuals, but a growing number of variant patterns can represent mild disease or heterozygous carriers. Aims-To evaluate the validity of standard diagnostic procedures for VLCADD by using functional in vitro tools. Methods-We retrospectively investigated 13 patient samples referred to our laboratory because of a suspicion of VLCADD but with some uncertainty to the diagnosis. All 13 patients were suspected of having VLCADD either because of abnormal NBS or suggestive clinical findings. ACADVL genomic DNA sequencing data were available for twelve of them. Ten of the patients had an abnormal NBS suggestive of VLCADD, with three samples showing equivocal results. Three exhibited suggestive clinical findings and blood acylcarnitine profile (two of them had a normal NBS and the third one was unscreened). Assay of VLCAD activity and immunoblotting or immunohistologic staining for VLCAD were performed on fibroblasts. Prokaryotic mutagenesis and expression studies were performed for nine uncharacterized ACADVL missense mutations. Results-VLCAD activity was abnormal in fibroblast cells from 9 patients (8 identified through abnormal NBS, 1 through clinical symptoms). For these 9 patients, immunoblotting/staining showed variable presence of VLCAD; all but one had two mutated alleles. Two patients with equivocal NBS results (and a heterozygous genotype) and the two patients with normal NBS exhibited normal VLCAD activity and normal VLCAD protein on immunoblotting/staining thus ruling out VLCAD deficiency. Nine pathogenic missense mutations were characterized with prokaryotic expression studies and showed a decrease in enzyme activity and variable stability of VLCAD antigen.
The Journal of international medical research, 2018
Objective The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cut-off values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results In both patients, analysis of the organic acids in urine showed a possible β-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 + 2T > C and c.527_533del). The results from a retrospective analysis of newborn screen...