title: Primary and maternal 3-methylcrotonyl-CoA carboxylase deficiency: insights from the Israel newborn screening program.
abstract: BACKGROUND
  3-Methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an inborn error of leucine catabolism. Tandem mass spectrometry newborn screening (NBS) programs worldwide confirmed 3MCCD to be the most common organic aciduria and a relatively benign disorder with favorable outcome. In addition, several asymptomatic 3MCCD mothers were initially identified following abnormal screening of their healthy babies and were appropriately termed maternal 3MCCD.
  
  
  METHODS
  This is a retrospective study that summarizes all the clinical, biochemical, and genetic data collected by questionnaires of all 3MCCD individuals that were identified by the extended Israeli NBS program since its introduction in 2009 including maternal 3MCCD cases.
  
  
  RESULTS
  A total of 36 3MCCD subjects were diagnosed within the 50-month study period; 16 were classified primary and 20 maternal cases. Four additional 3MCCD individuals were identified following sibling screening. All maternal 3MCCD cases were asymptomatic except for one mother who manifested childhood hypotonia. Most of the primary 3MCCD individuals were asymptomatic except for two whose condition was also complicated by severe prematurity. Initial dried blood spot (DBS) free carnitine was significantly lower in neonates born to 3MCCD mothers compared with newborns with primary 3MCCD (p = 0.0009). Most of the mutations identified in the MCCC1 and MCCC2 genes were missense, five of them were novel.
  
  
  CONCLUSIONS
  Maternal 3MCCD is more common than previously thought and its presence may be initially indicated by low DBS free carnitine levels. Our findings provide additional confirmation of the benign nature of 3MCCD and we suggest to exclude this disorder from NBS programs.
authors.affiliation: Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rips
authors.affiliation: National Newborn Screening Program, Israeli Ministry of Health, Tel HaShomer Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Almashanu
authors.affiliation: Rappaport School of Medicine, Technion, Haifa, Israel.|Metabolic Unit, Rambam Medical Center, Haifa, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Genetic Institute, Kaplan Medical Center, Rehovot, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Josephsberg
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Pediatric Neurology Unit, Metabolic-Neurogenetic Service, Wolfson Medical Center, Holon, Israel.
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.affiliation: Pediatric Neurology Unit, Metabolic-Neurogenetic Service, Wolfson Medical Center, Holon, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Zerem
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Unit, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Podeh
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Unit, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Department of Paediatrics, Ziv Medical Center and Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: Anthony
authors.initials: A
authors.lastname: Luder
authors.affiliation: Neonatal Intensive Care Unit, Soroka Medical Center, Beer Sheva, Israel.
authors.forename: Orna
authors.initials: O
authors.lastname: Staretz Chacham
authors.affiliation: Rappaport School of Medicine, Technion, Haifa, Israel. spiegelr@zahav.net.il.|Department of Pediatrics B, Emek Medical Center, Afula, 18101, Israel. spiegelr@zahav.net.il.
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
mesh_terms: D019735:Carbon-Carbon Ligases / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D002331:Carnitine / Q000097:blood; D002675:Child, Preschool; D005190:Family; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007557:Israel; D008297:Male; D009154:Mutation / Q000235:genetics; D015997:Neonatal Screening / Q000379:methods; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D053719:Tandem Mass Spectrometry / Q000379:methods; D056806:Urea Cycle Disorders, Inborn / Q000097:blood / Q000175:diagnosis* / Q000235:genetics
chemical_list: D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase; D002331:Carnitine