Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes

Jeannette C. Bleeker; Irene L. Kok; Sacha Ferdinandusse; W. Ludo van der Pol; Inge Cuppen; Annet M. Bosch; Mirjam Langeveld; Terry G. J. Derks; Monique Williams; Maaike de Vries; Margot F. Mulder; Estela R. Gozalbo; Monique G. M. de Sain-van der Velden; Alexander J. Rennings; Peter J. C. I. Schielen; Eugenie Dekkers; Riekelt H. Houtkooper; Hans R. Waterham; Mia L. Pras-Raves; Ronald J. A. Wanders; Peter M. van Hasselt; Marja Schoenmakers; Frits A. Wijburg; Gepke Visser

doi:10.1002/jimd.12075

Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes

Jeannette C. Bleeker^*, Irene L. Kok, Sacha Ferdinandusse, W. Ludo van der Pol, Inge Cuppen, Annet M. Bosch, Mirjam Langeveld, Terry G. J. Derks, Monique Williams, Maaike de Vries, Margot F. Mulder, Estela R. Gozalbo, Monique G. M. de Sain-van der Velden, Alexander J. Rennings, Peter J. C. I. Schielen, Eugenie Dekkers, Riekelt H. Houtkooper, Hans R. Waterham, Mia L. Pras-Raves, Ronald J. A. WandersPeter M. van Hasselt, Marja Schoenmakers, Frits A. Wijburg, Gepke Visser^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Most infants with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) identified by newborn screening (NBS) are asymptomatic at the time of diagnosis and remain asymptomatic. If this outcome is due to prompt diagnosis and initiation of therapy, or because of identification of individuals with biochemical abnormalities who will never develop symptoms, is unclear. Therefore, a 10-year longitudinal national cohort study of genetically confirmed VLCADD patients born before and after introduction of NBS was conducted. Main outcome measures were clinical outcome parameters, acyl-CoA dehydrogenase very long chain gene analysis, VLCAD activity, and overall capacity of long-chain fatty acid oxidation (LC-FAO flux) in lymphocytes and cultured skin fibroblasts. Median VLCAD activity in lymphocytes of 54 patients, 21 diagnosed pre-NBS and 33 by NBS was, respectively, 5.4% (95% confidence interval [CI]: 4.0-8.3) and 12.6% (95% CI: 10.7-17.7; P10% 7 out of 12 diagnosed pre-NBS vs none by NBS experienced hypoglycemic events. NBS has a clear beneficial effect on the prevention of hypoglycemic events in patients with some residual enzyme activity, but does not prevent hypoglycemia nor cardiac complications in patients with very low residual enzyme activity. The effect of NBS on prevalence and prevention of myopathy-related complications remains unclear.

Original language	English
Pages (from-to)	414-423
Number of pages	10
Journal	Journal of Inherited Metabolic Disease
Volume	42
Issue number	3
DOIs	https://doi.org/10.1002/jimd.12075
Publication status	Published - May 2019

Keywords

cardiomyopathy
fatty acid oxidation
hypoglycemia
myopathy
newborn screening
very-long-chain acyl-CoA dehydrogenase deficiency
ACID BETA-OXIDATION
BIOLOGICAL FEATURES
FOLLOW-UP
DEFECTS
DISORDERS
MUTATIONS
DIAGNOSIS
PHENOTYPE
SYMPTOMS
GENOTYPE

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Bleeker, J. C., Kok, I. L., Ferdinandusse, S., van der Pol, W. L., Cuppen, I., Bosch, A. M., Langeveld, M., Derks, T. G. J., Williams, M., de Vries, M., Mulder, M. F., Gozalbo, E. R., de Sain-van der Velden, M. G. M., Rennings, A. J., Schielen, P. J. C. I., Dekkers, E., Houtkooper, R. H., Waterham, H. R., Pras-Raves, M. L., ... Visser, G. (2019). Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes. Journal of Inherited Metabolic Disease, 42(3), 414-423. https://doi.org/10.1002/jimd.12075

@article{896fece8548a4b2cb31d16e801a32b0a,

title = "Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes",

abstract = "Most infants with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) identified by newborn screening (NBS) are asymptomatic at the time of diagnosis and remain asymptomatic. If this outcome is due to prompt diagnosis and initiation of therapy, or because of identification of individuals with biochemical abnormalities who will never develop symptoms, is unclear. Therefore, a 10-year longitudinal national cohort study of genetically confirmed VLCADD patients born before and after introduction of NBS was conducted. Main outcome measures were clinical outcome parameters, acyl-CoA dehydrogenase very long chain gene analysis, VLCAD activity, and overall capacity of long-chain fatty acid oxidation (LC-FAO flux) in lymphocytes and cultured skin fibroblasts. Median VLCAD activity in lymphocytes of 54 patients, 21 diagnosed pre-NBS and 33 by NBS was, respectively, 5.4% (95% confidence interval [CI]: 4.0-8.3) and 12.6% (95% CI: 10.7-17.7; P10% 7 out of 12 diagnosed pre-NBS vs none by NBS experienced hypoglycemic events. NBS has a clear beneficial effect on the prevention of hypoglycemic events in patients with some residual enzyme activity, but does not prevent hypoglycemia nor cardiac complications in patients with very low residual enzyme activity. The effect of NBS on prevalence and prevention of myopathy-related complications remains unclear.",

keywords = "cardiomyopathy, fatty acid oxidation, hypoglycemia, myopathy, newborn screening, very-long-chain acyl-CoA dehydrogenase deficiency, ACID BETA-OXIDATION, BIOLOGICAL FEATURES, FOLLOW-UP, DEFECTS, DISORDERS, MUTATIONS, DIAGNOSIS, PHENOTYPE, SYMPTOMS, GENOTYPE",

author = "Bleeker, {Jeannette C.} and Kok, {Irene L.} and Sacha Ferdinandusse and {van der Pol}, {W. Ludo} and Inge Cuppen and Bosch, {Annet M.} and Mirjam Langeveld and Derks, {Terry G. J.} and Monique Williams and {de Vries}, Maaike and Mulder, {Margot F.} and Gozalbo, {Estela R.} and {de Sain-van der Velden}, {Monique G. M.} and Rennings, {Alexander J.} and Schielen, {Peter J. C. I.} and Eugenie Dekkers and Houtkooper, {Riekelt H.} and Waterham, {Hans R.} and Pras-Raves, {Mia L.} and Wanders, {Ronald J. A.} and {van Hasselt}, {Peter M.} and Marja Schoenmakers and Wijburg, {Frits A.} and Gepke Visser",

note = "Funding Information: First, we would like to thank all the patients and their families for participating in our study. Second, we would like to thank Jos Ruiter for his help with enzymatic analyses and Astrid Verhoef, Sanna Kulik, Ellen Blok and Debbie Spiekman for their help in coordinating clinical evaluation in the Dutch Fatty Acid Oxidation Expertise Center. This work was supported by grants from ZonMW and Metakids. Publisher Copyright: {\textcopyright} 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM",

year = "2019",

month = may,

doi = "10.1002/jimd.12075",

language = "English",

volume = "42",

pages = "414--423",

journal = "Journal of Inherited Metabolic Disease",

issn = "0141-8955",

publisher = "Wiley",

number = "3",

}

Bleeker, JC, Kok, IL, Ferdinandusse, S, van der Pol, WL, Cuppen, I, Bosch, AM, Langeveld, M, Derks, TGJ, Williams, M, de Vries, M, Mulder, MF, Gozalbo, ER, de Sain-van der Velden, MGM, Rennings, AJ, Schielen, PJCI, Dekkers, E, Houtkooper, RH, Waterham, HR, Pras-Raves, ML, Wanders, RJA, van Hasselt, PM, Schoenmakers, M, Wijburg, FA & Visser, G 2019, 'Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes', Journal of Inherited Metabolic Disease, vol. 42, no. 3, pp. 414-423. https://doi.org/10.1002/jimd.12075

TY - JOUR

T1 - Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes

AU - Bleeker, Jeannette C.

AU - Kok, Irene L.

AU - Ferdinandusse, Sacha

AU - van der Pol, W. Ludo

AU - Cuppen, Inge

AU - Bosch, Annet M.

AU - Langeveld, Mirjam

AU - Derks, Terry G. J.

AU - Williams, Monique

AU - de Vries, Maaike

AU - Mulder, Margot F.

AU - Gozalbo, Estela R.

AU - de Sain-van der Velden, Monique G. M.

AU - Rennings, Alexander J.

AU - Schielen, Peter J. C. I.

AU - Dekkers, Eugenie

AU - Houtkooper, Riekelt H.

AU - Waterham, Hans R.

AU - Pras-Raves, Mia L.

AU - Wanders, Ronald J. A.

AU - van Hasselt, Peter M.

AU - Schoenmakers, Marja

AU - Wijburg, Frits A.

AU - Visser, Gepke

N1 - Funding Information: First, we would like to thank all the patients and their families for participating in our study. Second, we would like to thank Jos Ruiter for his help with enzymatic analyses and Astrid Verhoef, Sanna Kulik, Ellen Blok and Debbie Spiekman for their help in coordinating clinical evaluation in the Dutch Fatty Acid Oxidation Expertise Center. This work was supported by grants from ZonMW and Metakids. Publisher Copyright: © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM

PY - 2019/5

Y1 - 2019/5

N2 - Most infants with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) identified by newborn screening (NBS) are asymptomatic at the time of diagnosis and remain asymptomatic. If this outcome is due to prompt diagnosis and initiation of therapy, or because of identification of individuals with biochemical abnormalities who will never develop symptoms, is unclear. Therefore, a 10-year longitudinal national cohort study of genetically confirmed VLCADD patients born before and after introduction of NBS was conducted. Main outcome measures were clinical outcome parameters, acyl-CoA dehydrogenase very long chain gene analysis, VLCAD activity, and overall capacity of long-chain fatty acid oxidation (LC-FAO flux) in lymphocytes and cultured skin fibroblasts. Median VLCAD activity in lymphocytes of 54 patients, 21 diagnosed pre-NBS and 33 by NBS was, respectively, 5.4% (95% confidence interval [CI]: 4.0-8.3) and 12.6% (95% CI: 10.7-17.7; P10% 7 out of 12 diagnosed pre-NBS vs none by NBS experienced hypoglycemic events. NBS has a clear beneficial effect on the prevention of hypoglycemic events in patients with some residual enzyme activity, but does not prevent hypoglycemia nor cardiac complications in patients with very low residual enzyme activity. The effect of NBS on prevalence and prevention of myopathy-related complications remains unclear.

AB - Most infants with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) identified by newborn screening (NBS) are asymptomatic at the time of diagnosis and remain asymptomatic. If this outcome is due to prompt diagnosis and initiation of therapy, or because of identification of individuals with biochemical abnormalities who will never develop symptoms, is unclear. Therefore, a 10-year longitudinal national cohort study of genetically confirmed VLCADD patients born before and after introduction of NBS was conducted. Main outcome measures were clinical outcome parameters, acyl-CoA dehydrogenase very long chain gene analysis, VLCAD activity, and overall capacity of long-chain fatty acid oxidation (LC-FAO flux) in lymphocytes and cultured skin fibroblasts. Median VLCAD activity in lymphocytes of 54 patients, 21 diagnosed pre-NBS and 33 by NBS was, respectively, 5.4% (95% confidence interval [CI]: 4.0-8.3) and 12.6% (95% CI: 10.7-17.7; P10% 7 out of 12 diagnosed pre-NBS vs none by NBS experienced hypoglycemic events. NBS has a clear beneficial effect on the prevention of hypoglycemic events in patients with some residual enzyme activity, but does not prevent hypoglycemia nor cardiac complications in patients with very low residual enzyme activity. The effect of NBS on prevalence and prevention of myopathy-related complications remains unclear.

KW - cardiomyopathy

KW - fatty acid oxidation

KW - hypoglycemia

KW - myopathy

KW - newborn screening

KW - very-long-chain acyl-CoA dehydrogenase deficiency

KW - ACID BETA-OXIDATION

KW - BIOLOGICAL FEATURES

KW - FOLLOW-UP

KW - DEFECTS

KW - DISORDERS

KW - MUTATIONS

KW - DIAGNOSIS

KW - PHENOTYPE

KW - SYMPTOMS

KW - GENOTYPE

U2 - 10.1002/jimd.12075

DO - 10.1002/jimd.12075

M3 - Article

SN - 0141-8955

VL - 42

SP - 414

EP - 423

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

IS - 3

ER -