Clinical, Biochemical, and Genetic Heterogeneity in Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Maldegem, Bianca T. van; Durán, Marinus; Wanders, Ronald J. A.; Niezen-Koning, Klary E.; Hogeveen, Marije; IJlst, Lodewijk; Waterham, Hans R.; Wijburg, Frits A.

doi:10.1001/jama.296.8.943

Cited by 125 publications

(115 citation statements)

References 37 publications

(80 reference statements)

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“…This observation is likely to instigate consideration of its exclusion from newborn screening panels as was recently proposed for SCAD deficiency. 9 However, based on the frequent episodes of dehydration in one of our patients and on the clinical presentation observed in the first IBD-deficient patient described, it seems possible that this disorder carries a risk for clinically relevant symptoms. Thus, it is prudent to remain vigilant for such episodes in infants identified with IBD deficiency through newborn screening and to continue to follow them with care.…”

Section: Discussionmentioning

confidence: 85%

“…However, asymptomatic cases have also been described. 8,9 The biochemical phenotype of SCAD deficiency has been delineated through clinical testing and includes persistent ethylmalonic aciduria with or without the overexcretion of methylsuccinic acid and accumulation of butyrylcarnitine in plasma and blood. The molecular genetics of SCAD deficiency is complicated by two SCAD gene (ACADS) variants (511CϾT, 625GϾA) of questionable clinical importance.…”

mentioning

confidence: 99%

“…However, some individuals with both biochemical and molecular genetic evidence of SCAD deficiency have been reported to remain asymptomatic. 8,9 The variable expression of disease in both IBD and SCAD deficiency have led to the designation of these conditions as secondary targets in the newborn screening panel recently recommended by a working group of the American College of Medical Genetics contracted by the Human Resources and Services Administration of the U.S. Department of Health and Human Services. 15 This work group was charged to develop recommendations for which disorders should be included in every newborn screening program to overcome inequalities between the various state-mandated newborn screening panels.…”

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confidence: 99%

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Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Oglesbee¹,

Majumder

et al. 2007

Genetics in Medicine

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Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenasedeficient patients through newborn screening due to an elevation of C 4 -acylcarnitine in dried blood spots. Because C 4 -acylcarnitine represents both isobutyryl-and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C 4 -acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C 4 -acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase-and short-chain acyl-CoA dehydrogenase-deficient patients. Results: Quantification of C 4 -acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase-deficient from short-chain acyl-CoA dehydrogenase-deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase-deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age. Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C 4 -acylcarnitine identified through newborn screening. Genet Med 2007:9(2):108-116.

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Section: Discussionmentioning

confidence: 85%

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confidence: 99%

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confidence: 99%

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Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Oglesbee¹,

Majumder

et al. 2007

Genetics in Medicine

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“…In particular, NBS for CUD and SCADD is a matter of debate. Both these disorders have considerable variability in their incidence, heredity, clinical expression, symptoms, and the need for treatment [20][21][22]. An extraordinarily high screening incidence of these disorders has been found in our Roma group of newborns.…”

Section: Discussionmentioning

confidence: 99%

The First Results of Extended Newborn Screening in Slovakia—Differences between the Majority and the Roma Ethnic Group

Dluholucký

Knapková²

2017

IJNS

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Abstract:The authors present the first results of the National Extended Newborn Screening (ENS) in Slovakia in the majority (M) and the Roma (R) ethnic populations. A follow-up of ethnicity has been introduced in newborn screening for cystic fibrosis (NSCF) and afterwards to the entire ENS program comprising of 23 inborn errors of metabolism (IEM). In 2013-2015, a total of 165,648 newborns were investigated in ENS, 23,321 of them (14%) were the R ethnic group, a total of 313 positive cases were discovered (total ENS prevalence = 1:529, M = 1:758, R = 1:198). In the R ethnic group, there was a slightly higher prevalence of congenital hypothyroidism (CH), only one case of CF, and no cases of congenital adrenal hyperplasia (CAH) in the R ethnic group. The ENS prevalence of IEM detected by MS/MS was significantly higher in the R ethnic group than in M group (M = 1:1670 vs. R = 1:234, OR:7.13). Significant differences in the prevalence of individual types of IEM were also found. While PKU and other aminoaciduria and organic acidurias dominate in the M group, the fatty acid oxidation disorders (MCAD, SCAD) and carnitine defects (CUD) were more frequent in the R newborn group. Despite the preliminary nature of the results, an ethnic approach to ENS enables the recording of the ethnic differences in the screen prevalence of individual disorders, which would not be apparent without this approach.

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“…Short-chain acylCoA dehydrogenase (SCAD; OMIM [Online Mendelian Inheritance in Man; see http://www.ncbi.nlm.nih.gov/sites/ entrez?dbϭomim] 606885) is specific for acyl-CoAs four to six carbons in length (Naito et al, 1989). SCAD deficiency (SCADD, OMIM 201470) is a heterogeneous condition that has been associated with various clinical phenotypes ranging from fatal metabolic decompensation in infancy, developmental delay, hyper-and hypotonia, seizures, ketotic hypoglycemia, to late-onset progressive myopathy (Bhala et al, 1995;van Maldegem et al, 2006;Tein et al, 2008). Some individuals with biochemically apparent SCADD remain asymptomatic , making it impossible to differentiate diseased from nondiseased individuals (van Maldegem et al, 2006), and the most common presentation of SCADD is asymptomatic.…”

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confidence: 99%

Biochemical Correction of Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency After Portal Vein Injection of rAAV8-SCAD

et al. 2008

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Recombinant adeno-associated viral vectors pseudotyped with serotype 5 and 8 capsids (AAV5 and AAV8) have been shown to be efficient gene transfer reagents for the liver. We have produced AAV5 and AAV8 vectors that express mouse short-chain acyl-CoA dehydrogenase (mSCAD) cDNA under the transcriptional control of the cytomegalovirus-chicken ␤-actin hybrid promoter. We hypothesized that these vectors would produce sufficient hepatocyte transduction (after administration via the portal vein) and thus sufficient SCAD enzyme to correct the phenotype observed in the SCAD-deficient (BALB/cByJ) mouse, which includes elevated blood butyrylcarnitine and hepatic steatosis. Ten weeks after portal vein injection into 8-week-old mice, AAV8-treated livers contained acyl-CoA dehydrogenase activity (14.3 mU/mg) toward butyryl-CoA, compared with 7.6 mU/mg in mice that received phosphate-buffered saline. Immunohistochemistry showed expression of mSCAD within rAAV8-mSCAD-transduced hepatocytes, as seen by light microscopy. A significant reduction of circulating butyrylcarnitine was seen in AAV5-mSCAD-and AAV8-mSCAD-injected mice. Magnetic resonance spectroscopy of fasted mice demonstrated a significant reduction in relative lipid content within the livers of AAV8-mSCAD-treated mice. These results demonstrate biochemical correction of SCAD deficiency after AAV8-mediated SCAD gene delivery. 579

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Clinical, Biochemical, and Genetic Heterogeneity in Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Cited by 125 publications

References 37 publications

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

The First Results of Extended Newborn Screening in Slovakia—Differences between the Majority and the Roma Ethnic Group

Biochemical Correction of Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency After Portal Vein Injection of rAAV8-SCAD

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