Short-Chain Acyl-CoA Dehydrogenase Deficiency Associated with Early Onset Severe Axonal Neuropathy

Kurian, MA; Hartley, Louise; Zolkipli, Zarazuela; Little, Mark A.; Costigan, Donal; Naughten, E. R.; Olpin, S. E.; Muntoni, Francesco; King, Mark D.

doi:10.1055/s-2004-830371

Cited by 15 publications

(17 citation statements)

References 22 publications

(38 reference statements)

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“…From a study of 31 Dutch patients with SCADD, van Maldegem and coworkers (2006) noted that SCADD was not clinically severe and that it was not possible to differentiate diseased from nondiseased individuals (van Maldegem et al, 2006). Atypical presentation has, however, been reported, including two infants with SCADD, one who displayed early-onset severe axonal neuropathy and another who presented with brain malformation and infantile spasms (Kurian et al, 2004;Mikati et al, 2007). SCADD is relatively rare compared with MCAD and VLCAD deficiencies (Liebig et al, 2006); however, SCAD gene replacement does act as a surrogate model for MCAD and VLCAD deficiencies, which are clinically relevant.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Thus, as much as 14% of the normal population is homozygous for one or compound heterozygous for both of the common ACADS gene variations. Seventy-Wve patients have so far been reported in the literature with evidence of impaired SCAD enzyme function, that is, elevated EMA in urine, increased butyrylcarnitine accumulation in blood or cultured Wbroblasts, and/or reduced SCAD enzyme activity in Wbroblast cultures or muscle tissue (Amendt et al 1987;Baerlocher et al 1997;Bhala et al 1995;Birkebaek et al 2002;Bok et al 2003;Coates et al 1988;Corydon et al 2001;Dawson et al 1995;Koeberl et al 2003;Kurian et al 2004;Matern et al 2001;Mikati et al 2007;Ribes et al 1998;Seidel et al 2003;Sewell et al 1993;Tein et al 1999;Turpin and Tobias 2005;van Maldegem et al 2006;Young et al 2003). Molecular genetic analysis demonstrated that most of these individuals (60 of 67 investigated) have a genotype deWned by the common variations alone or by one of the common variations in combination with a rare variation (Amendt et al 1987;Birkebaek et al 2002;Bok et al 2003;Corydon et al 2001;Gregersen et al 1998;Koeberl et al 2003;Kurian et al 2004;Matern et al 2001;Naito et al 1990;Seidel et al 2003;Tein et al 2007;van Maldegem et al 2006;Young et al 2003).…”

Section: Introductionmentioning

confidence: 97%

The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level

Pedersen

Kølvraa

Kølvraa³

et al. 2008

Hum Genet

101

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Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an inherited disorder of mitochondrial fatty acid oxidation associated with variations in the ACADS gene and variable clinical symptoms. In addition to rare ACADS inactivating variations, two common variations, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser), have been identified in patients, but these are also present in up to 14% of normal populations leading to questions of their clinical relevance. The common variant alleles encode proteins with nearly normal enzymatic activity at physiological conditions in vitro. SCAD enzyme function, however, is impaired at increased temperature and the tendency to misfold increases under conditions of cellular stress. The present study examines misfolding of variant SCAD proteins identified in patients with SCAD deficiency. Analysis of the ACADS gene in 114 patients revealed 29 variations, 26 missense, one start codon, and two stop codon variations. In vitro import studies of variant SCAD proteins in isolated mitochondria from SCAD deficient (SCAD-/-) mice demonstrated an increased tendency of the abnormal proteins to misfold and aggregate compared to the wild-type, a phenomenon that often leads to gain-of-function cellular phenotypes. However, no correlation was found between the clinical phenotype and the degree of SCAD dysfunction. We propose that SCAD deficiency should be considered as a disorder of protein folding that can lead to clinical disease in combination with other genetic and environmental factors.

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“…Till date, 25 patients have been identified and 50 reported worldwide based upon reduced or absent SCAD activity in vitro [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Genotype-phenotype correlations have been inconsistent [8,18].…”

Section: Discussionmentioning

confidence: 99%

A Rare Case of Short-Chain Acyl-COA Dehydrogenase Deficiency: The Apparent Rarity of the Disorder Results in Under Diagnosis

Reddy

Sujatha

2011

Ind J Clin Biochem

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Short-chain acyl-CoA dehydrogenase (ACAD) deficiency is an extremely rare inherited mitochondrial disorder of fat metabolism. This belongs to a group of diseases known as fatty acid oxidation disorders. Screening programmes have provided evidence that all the fatty acid oxidation disorders combined are among the most common inborn errors of metabolism. Mitochondrial beta oxidation of fatty acids is an essential energy producing pathway. It is a particularly important pathway during prolonged periods of starvation and during periods of reduced caloric intake due to gastrointestinal illness or increased energy expenditure during febrile illness. The most common presentation is an acute episode of life threatening coma and hypoglycemia induced by a period of fasting due to defective hepatic ketogenesis. Here, the case of a 4 month old female patient who had seizures since the third day of her birth and persistent hypoglycemia is described. She was born to parents of second degree consanguinity after 10 years of infertility treatment. There was history of delayed cry after birth. Metabolic screening for TSH, galactosemia, 17-OHP, G6PD, cystic fibrosis, biotinidase were normal. Tandem mass spectrometric (TMS) screening for blood amino acids, organic acids, fatty acids showed elevated butyryl carnitine (C4) as 3.40 lmol/L (normal \2.00 lmol/L), hexanoyl carnitine (C6) as 0.92 lmol/L (normal \0.72 lmol/L), C4/C3 as 2.93 lmol/L (normal \1.18 lmol/L). The child was started immediately on carnitor syrup (carnitine) 1/2 ml twice daily. Limitation of fasting stress and dietary fat was advised. Baby responded well by gaining weight and seizures were controlled. Until now, less than 25 patients have been reported worldwide. The limited number of patients diagnosed until now is due to the rarity of the disorder resulting in under diagnosis.

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Short-Chain Acyl-CoA Dehydrogenase Deficiency Associated with Early Onset Severe Axonal Neuropathy

Cited by 15 publications

References 22 publications

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

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

The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level

A Rare Case of Short-Chain Acyl-COA Dehydrogenase Deficiency: The Apparent Rarity of the Disorder Results in Under Diagnosis

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