Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State

Georgianne L. Arnold, Carlos A. Saavedra-Matiz, Patricia A. Galvin-Parton, Richard Erbe, Ellen DeVincentis, David Kronn, Shideh Mofidi, Melissa Wasserstein, Joan E. Pellegrino, Paul A. Levy, Darius Adams, Matthew Nichols, Michele Caggana

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Abstract

Introduction: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. Method: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. Results: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 μmol/L in the asymptomatic vs. 19.1 μmol/L in the symptomatic, p < 0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p < 0.012). Four infants had initial C8 level >30 μmol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. Discussion: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.

Original languageEnglish (US)
Pages (from-to)263-268
Number of pages6
JournalMolecular Genetics and Metabolism
Volume99
Issue number3
DOIs
StatePublished - Mar 1 2010

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Acyl-CoA Dehydrogenase
Genetic Association Studies
Screening
Newborn Infant
Lethargy
Mutation
Genotype
Hypoglycemia
Early Medical Intervention
Fasting
Metabolites
Reye Syndrome
Metabolism
Inborn Errors Metabolism
Aftercare
Aptitude
Sudden Infant Death
Brain
Nonsense Codon
Sequence Deletion

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Arnold, G. L., Saavedra-Matiz, C. A., Galvin-Parton, P. A., Erbe, R., DeVincentis, E., Kronn, D., ... Caggana, M. (2010). Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Molecular Genetics and Metabolism, 99(3), 263-268. https://doi.org/10.1016/j.ymgme.2009.10.188
Arnold, Georgianne L. ; Saavedra-Matiz, Carlos A. ; Galvin-Parton, Patricia A. ; Erbe, Richard ; DeVincentis, Ellen ; Kronn, David ; Mofidi, Shideh ; Wasserstein, Melissa ; Pellegrino, Joan E. ; Levy, Paul A. ; Adams, Darius ; Nichols, Matthew ; Caggana, Michele. / Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. In: Molecular Genetics and Metabolism. 2010 ; Vol. 99, No. 3. pp. 263-268.
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abstract = "Introduction: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. Method: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. Results: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 μmol/L in the asymptomatic vs. 19.1 μmol/L in the symptomatic, p < 0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p < 0.012). Four infants had initial C8 level >30 μmol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from {"}SIDS{"}, and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. Discussion: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.",
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Arnold, GL, Saavedra-Matiz, CA, Galvin-Parton, PA, Erbe, R, DeVincentis, E, Kronn, D, Mofidi, S, Wasserstein, M, Pellegrino, JE, Levy, PA, Adams, D, Nichols, M & Caggana, M 2010, 'Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State', Molecular Genetics and Metabolism, vol. 99, no. 3, pp. 263-268. https://doi.org/10.1016/j.ymgme.2009.10.188

Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. / Arnold, Georgianne L.; Saavedra-Matiz, Carlos A.; Galvin-Parton, Patricia A.; Erbe, Richard; DeVincentis, Ellen; Kronn, David; Mofidi, Shideh; Wasserstein, Melissa; Pellegrino, Joan E.; Levy, Paul A.; Adams, Darius; Nichols, Matthew; Caggana, Michele.

In: Molecular Genetics and Metabolism, Vol. 99, No. 3, 01.03.2010, p. 263-268.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State

AU - Arnold, Georgianne L.

AU - Saavedra-Matiz, Carlos A.

AU - Galvin-Parton, Patricia A.

AU - Erbe, Richard

AU - DeVincentis, Ellen

AU - Kronn, David

AU - Mofidi, Shideh

AU - Wasserstein, Melissa

AU - Pellegrino, Joan E.

AU - Levy, Paul A.

AU - Adams, Darius

AU - Nichols, Matthew

AU - Caggana, Michele

PY - 2010/3/1

Y1 - 2010/3/1

N2 - Introduction: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. Method: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. Results: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 μmol/L in the asymptomatic vs. 19.1 μmol/L in the symptomatic, p < 0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p < 0.012). Four infants had initial C8 level >30 μmol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. Discussion: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.

AB - Introduction: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. Method: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. Results: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 μmol/L in the asymptomatic vs. 19.1 μmol/L in the symptomatic, p < 0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p < 0.012). Four infants had initial C8 level >30 μmol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. Discussion: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.

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