Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.
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.
Kölker
Stefan
S
Department of General Pediatric, University of Children's Hospital Heidelberg, D-69120 Heidelberg, Germany. Stefan.Koelker@med.uni-heidelberg.de
Garbade
Sven F
SF
Greenberg
Cheryl R
CR
Leonard
James V
JV
Saudubray
Jean-Marie
JM
Ribes
Antonia
A
Kalkanoglu
H Serap
HS
Lund
Allan M
AM
Merinero
Begoña
B
Wajner
Moacir
M
Troncoso
Mónica
M
Williams
Monique
M
Walter
John H
JH
Campistol
Jaume
J
Martí-Herrero
Milagros
M
Caswill
Melissa
M
Burlina
Alberto B
AB
Lagler
Florian
F
Maier
Esther M
EM
Schwahn
Bernd
B
Tokatli
Aysegul
A
Dursun
Ali
A
Coskun
Turgay
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Chalmers
Ronald A
RA
Koeller
David M
DM
Zschocke
Johannes
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Christensen
Ernst
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Burgard
Peter
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Hoffmann
Georg F
GF
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
D050770:Glutaryl-CoA Dehydrogenase