Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening.
Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, also known as 2-methylbutyryl-CoA dehydrogenase deficiency, is a recently described autosomal recessive disorder of isoleucine metabolism. Most patients reported thus far have originated from a founder mutation in the Hmong Chinese population. While the first reported patients had severe disease, most of the affected Hmong have remained asymptomatic. In this study, we describe 11 asymptomatic non-Hmong patients brought to medical attention by elevated C5-carnitine found by newborn screening and one discovered because of clinical symptoms. The diagnosis of SBCAD deficiency was determined by metabolite analysis of blood, urine, and fibroblast samples. PCR and bidirectional sequencing were performed on genomic DNA from five of the patients covering the entire SBCAD (ACADSB) gene sequence of 11 exons. Sequence analysis of genomic DNA from each patient identified variations in the SBCAD gene not previously reported. Escherichia coli expression studies revealed that the missense mutations identified lead to inactivation or instability of the mutant SBCAD enzymes. These findings confirm that SBCAD deficiency can be identified through newborn screening by acylcarnitine analysis. Our patients have been well without treatment and call for careful follow-up studies to learn the true clinical impact of this disorder.
Alfardan
Jaffar
J
King Fahad Specialist Hospital-Dammam, Saudi Arabia.
Mohsen
Al-Walid
AW
Copeland
Sara
S
Ellison
Jay
J
Keppen-Davis
Laura
L
Rohrbach
Marianne
M
Powell
Berkley R
BR
Gillis
Jane
J
Matern
Dietrich
D
Kant
Jeffrey
J
Vockley
Jerry
J
D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000201:enzymology* / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D019295:Computational Biology; D004252:DNA Mutational Analysis; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007231:Infant, Newborn; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D015997:Neonatal Screening; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D017433:Protein Structure, Secondary
D050505:Mutant Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C038808:2-methylacyl-CoA dehydrogenase