Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening.
Since the addition of tandem mass spectrometry (MS/MS) to the North Carolina Newborn Screening Program, 20 infants with two consecutive elevated 3-hydroxyisovalerylcarnitine (C5OH) levels have been evaluated for evidence of inborn errors of metabolism associated with this metabolite. Ten of these 20 infants had significant concentrations of both 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in their urine, suggestive of 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency. Four of these 10 were infants whose abnormal metabolites were found to be of maternal origin. Of 8 patients with probable 3-MCC deficiency, 7 have been tested and found to have the enzyme deficiency confirmed in lymphoblasts or cultured fibroblasts; one of these 7 infants had only marginally decreased 3-MCC activity in lymphocytes but deficient 3-MCC in fibroblasts. We estimate the incidence of 3-MCC deficiency at 1:64000 live births in North Carolina. We conclude that MS/MS newborn screening will detect additional inborn errors of metabolism, such as 3-MCC deficiency, not traditionally associated with newborn screening. The evaluation of newborns with two abnormally elevated C5OH levels on MS/MS newborn screening should include, at least, urine organic acid analysis by capillary GC-MS and a plasma acylcarnitine profile by MS/MS. Long-term follow-up is needed to determine the outcome of presymptomatically diagnosed patients with 3-MCC deficiency by MS/MS newborn screening.
Koeberl
D D
DD
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. koebe001@mc.duke.edu
Millington
D S
DS
Smith
W E
WE
Weavil
S D
SD
Muenzer
J
J
McCandless
S E
SE
Kishnani
P S
PS
McDonald
M T
MT
Chaing
S
S
Boney
A
A
Moore
E
E
Frazier
D M
DM
D000143:Acids / Q000652:urine; D019735:Carbon-Carbon Ligases / Q000172:deficiency* / Q000235:genetics*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000652:urine; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007231:Infant, Newborn; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D013058:Mass Spectrometry; D008661:Metabolism, Inborn Errors / Q000453:epidemiology / Q000235:genetics*; D015997:Neonatal Screening; D009657:North Carolina / Q000453:epidemiology; D010865:Pilot Projects
D000143:Acids; C116917:acylcarnitine; D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase; D002331:Carnitine