Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study.
BACKGROUND
Since the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant ACADM (gene encoding MCAD enzyme) genotypes that have never been identified in clinically ascertained patients. It could be hypothesised that residual MCAD enzyme activity can contribute in risk stratification of subjects with variant ACADM genotypes.


METHODS
We performed a retrospective cohort study of all patients identified upon population NBS for MCAD deficiency in the Netherlands between 2007-2010. Clinical, molecular, and enzymatic data were integrated.


RESULTS
Eighty-four patients from 76 families were identified. Twenty-two percent of the subjects had a variant ACADM genotype. In patients with classical ACADM genotypes, residual MCAD enzyme activity was significantly lower (median 0%, range 0-8%) when compared to subjects with variant ACADM genotypes (range 0-63%; 4 cases with 0%, remainder 20-63%). Patients with (fatal) neonatal presentations before diagnosis displayed residual MCAD enzyme activities <1%. After diagnosis and initiation of treatment, residual MCAD enzyme activities <10% were associated with an increased risk of hypoglycaemia and carnitine supplementation. The prevalence of MCAD deficiency upon screening was 1/8,750 (95% CI 1/7,210-1/11,130).


CONCLUSIONS
Determination of residual MCAD enzyme activity improves our understanding of variant ACADM genotypes and may contribute to risk stratification. Subjects with variant ACADM genotypes and residual MCAD enzyme activities <10% should be considered to have the same risks as patients with classical ACADM genotypes. Parental instructions and an emergency regimen will remain principles of the treatment in any type of MCAD deficiency, as the effect of intercurrent illness on residual MCAD enzyme activity remains uncertain. There are, however, arguments in favour of abandoning the general advice to avoid prolonged fasting in subjects with variant ACADM genotypes and >10% residual MCAD enzyme activity.
Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Centre of Groningen, PO Box 30 001, CA84, 9700 RB, Groningen, The Netherlands. n.touw@umcg.nl
Catharina M L
CM
Touw
G Peter A
GP
Smit
Maaike
M
de Vries
Johannis B C
JB
de Klerk
Annet M
AM
Bosch
Gepke
G
Visser
Margot F
MF
Mulder
M Estela
ME
Rubio-Gozalbo
Bert
B
Elvers
Klary E
KE
Niezen-Koning
Ronald J A
RJ
Wanders
Hans R
HR
Waterham
Dirk-Jan
DJ
Reijngoud
Terry G J
TG
Derks
D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology*; D015997:Neonatal Screening; D010641:Phenotype; D012189:Retrospective Studies; D012307:Risk Factors
D042964:Acyl-CoA Dehydrogenase