title: Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.
abstract: Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n = 218) or presymptomatically by neonatal screening (n = 23), high-risk screening (n = 24), or macrocephaly (n = 14). Most symptomatic patients (n = 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with L-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.
authors.affiliation: Department of General Pediatric, University of Children's Hospital Heidelberg, D-69120 Heidelberg, Germany. Stefan.Koelker@med.uni-heidelberg.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.forename: Sven F
authors.initials: SF
authors.lastname: Garbade
authors.forename: Cheryl R
authors.initials: CR
authors.lastname: Greenberg
authors.forename: James V
authors.initials: JV
authors.lastname: Leonard
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saudubray
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: H Serap
authors.initials: HS
authors.lastname: Kalkanoglu
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lund
authors.forename: Begoña
authors.initials: B
authors.lastname: Merinero
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Mónica
authors.initials: M
authors.lastname: Troncoso
authors.forename: Monique
authors.initials: M
authors.lastname: Williams
authors.forename: John H
authors.initials: JH
authors.lastname: Walter
authors.forename: Jaume
authors.initials: J
authors.lastname: Campistol
authors.forename: Milagros
authors.initials: M
authors.lastname: Martí-Herrero
authors.forename: Melissa
authors.initials: M
authors.lastname: Caswill
authors.forename: Alberto B
authors.initials: AB
authors.lastname: Burlina
authors.forename: Florian
authors.initials: F
authors.lastname: Lagler
authors.forename: Esther M
authors.initials: EM
authors.lastname: Maier
authors.forename: Bernd
authors.initials: B
authors.lastname: Schwahn
authors.forename: Aysegul
authors.initials: A
authors.lastname: Tokatli
authors.forename: Ali
authors.initials: A
authors.lastname: Dursun
authors.forename: Turgay
authors.initials: T
authors.lastname: Coskun
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Chalmers
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Ernst
authors.initials: E
authors.lastname: Christensen
authors.forename: Peter
authors.initials: P
authors.lastname: Burgard
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
mesh_terms: D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000178:diet therapy / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D002648:Child; D005260:Female; D005838:Genotype; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D015997:Neonatal Screening; D010641:Phenotype; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D050770:Glutaryl-CoA Dehydrogenase