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Spectrum of Medium-Chain Acyl-CoA Dehydrogenase Deficiency Detected by Newborn Screening

^a Department of Pediatrics, New England Newborn Screening Program, University of Massachusetts Medical School, Jamaica Plain, Massachusetts
^b Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
^c Department of Pediatrics, Children's Hospital Boston, Boston, Massachusetts
^d Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts

	ABSTRACT

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OBJECTIVE. Our goal was to describe the clinical spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by routine newborn screening and assess factors associated with elevations of octanoylcarnitine in newborns and characteristics associated with adverse clinical consequences of medium-chain acyl-CoA dehydrogenase deficiency.

METHODS. The first 47 medium-chain acyl-CoA dehydrogenase deficiency cases detected by the New England Newborn Screening Program were classified according to initial and follow-up octanoylcarnitine values, octanoylcarnitine-decanoylcarnitine ratios, medium-chain acyl-CoA dehydrogenase genotype, follow-up biochemical parameters, and feeding by breast milk or formula.

RESULTS. All 20 patients who were homozygous for 985AG had high initial octanoylcarnitine values (7.0–36.8 µM) and octanoylcarnitine-decanoylcarnitine ratios (7.0–14.5), whereas the 27 patients with 0 to 1 copy of 985AG exhibited a wide range of octanoylcarnitine values (0.5–28.6 µM) and octanoylcarnitine-decanoylcarnitine ratios (0.8–12.7). Initial newborn octanoylcarnitine values decreased by days 5 to 8, but the octanoylcarnitine-decanoylcarnitine ratio generally remained stable. Among 985AG homozygotes, breastfed newborns had higher initial octanoylcarnitine values than newborns who received formula. Adverse events occurred in 5 children, 4 985AG homozygotes and 1 compound heterozygote with a very high initial octanoylcarnitine: 2 survived severe neonatal hypoglycemia, 1 survived a severe hypoglycemic episode at 15 months of age, and 2 died as a result of medium-chain acyl-CoA dehydrogenase deficiency at ages 11 and 33 months.

CONCLUSION. Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency has detected cases with a wide range of genotypes and biochemical abnormalities. Although most children do well, adverse outcomes have not been entirely avoided. Assessment of potential risk and determination of appropriate treatment remain a challenge.

Key Words: newborn screening • metabolic disorders • fatty acid oxidation defects

Abbreviations: MCAD—medium-chain acyl-CoA dehydrogenase • C8—octanoylcarnitine • PCR—polymerase chain reaction • C10—decanoylcarnitine

Medium-chain acyl-CoA DEHYDROGENASE (MCAD) deficiency is the most common fatty acid oxidation disorder, occurring in 1:15000 births.¹ The MCAD protein is an enzyme that catalyzes the breakdown of fatty acids for energy production during periods of prolonged fasting or physiologic stress. Children with MCAD deficiency are unable to use medium-chain fatty acids for energy, resulting in severe hypoglycemia precipitated by seemingly mild illnesses. Patients typically present clinically between 3 and 15 months of age and can sustain permanent neurologic sequelae as a result of metabolic decompensation before diagnosis. Preventive measures, including avoidance of fasting and aggressive intervention during minor illnesses, have been shown to reduce morbidity and mortality.^2–4

Newborn screening for MCAD deficiency has been implemented in many regions. The metabolic marker for MCAD deficiency, octanoylcarnitine (C8) can be detected with a high degree of sensitivity in newborns by tandem mass spectrometry.^5,6 Historically, cohorts with clinically detected MCAD deficiency consisted primarily of homozygotes for the common severe mutation 985AG, whereas cohorts detected by newborn screening have had a lower proportion of 985AG homozygotes and more compound heterozygotes with 1 or 2 rare mutations.²⁷ The risk for clinical disease in infants with newly described mutations is largely unknown. In this study, we summarize results of our first 6 years of neonatal screening for MCAD deficiency and the spectrum of cases identified in a population-based screening program, coupled with comprehensive follow-up.

	METHODS

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The population comprises birth cohorts from 4 New England states that were screened for MCAD deficiency through January 31, 2006. Screening for MCAD deficiency began February 1, 1999, for infants who were born in Massachusetts. Screening began in Maine on September 1, 1999, in Rhode Island on July 1, 2002, and in Vermont on November 1, 2003. The 713522 infants with satisfactory specimens tested between February 1, 1999, and January 31, 2006, were included in this report. Initial dried blood spot specimens were usually collected from all newborns between 24 and 72 hours of age. Repeat blood specimens were obtained when an initial specimen showed an abnormality and routinely at 2, 6, and 10 weeks of age in very low birth weight infants (<1500 g).

Blood spots were extracted into methanol solution that contained deuterium-labeled internal standards and derivatized to butyl esters before analysis. Acylcarnitines and amino acids were analyzed with multiple reaction monitoring as previously described.⁶ Blood spots with C8 concentrations of >0.5 µM prompted an analysis for the 985AG mutation by using polymerase chain reaction (PCR) methods previously described⁶ and more recently by using Tag-It Mutation Detection Assay for use with the Luminex 100 xMAP System. Specimens that were found by PCR to be homozygous for 985 AG did not undergo gene sequencing. Direct DNA sequencing of specimens that were not homozygous for 985AG was performed in the laboratory of Dr Strauss by the dideoxy-chain termination method in an automated Applied Biosystems DNA sequencer of amplified DNA from all 12 exons.

Infants with an initial C8 value of 0.8 µM were referred directly to a metabolic specialist for immediate evaluation. When the C8 value was between 0.5 and 0.79 µM ("indeterminate"), a repeat specimen was requested. Additional evaluation by a metabolic specialist was recommended when at least 1 copy of the 985AG mutation was present or when the C8 value in a subsequent specimen remained >0.5 µM. Parents of all referred infants were advised to maintain frequent feedings and seek medical attention for any signs of illness until metabolic evaluation for MCAD deficiency could be completed. The diagnosis of MCAD deficiency was made by pediatric metabolic specialists and clinical geneticists, using a combination of biochemical and genetic tests, including plasma acylcarnitines, urine organic acids, and DNA sequencing.

Clinical and developmental follow-up information was collected by a faxed survey of primary pediatricians and/or metabolic specialists. Statistical differences between the C8 values of breastfed and formula-fed infants were computed by using the Wilcoxon rank-sum test (SAS 8.2 [SAS Institute, Cary, NC]).

	RESULTS

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Screening Outcomes
Among the 713522 infants screened, 113 initial specimens (collected at 1–5 days of age; median: 2 days) had a C8 result of >0.5 µM. The 47 infants who had a diagnosis of MCAD deficiency all had C8 elevations detected in the initial specimen. An additional 98 infants had transient elevations of C8 that had not been present in the initial specimen and were detected incidentally in a repeat specimen. Most of these infants were preterm, receiving parenteral nutrition or dietary supplements, and had multiple amino acid and/or acylcarnitine elevations in addition to C8. A telephone survey of regional metabolic specialists revealed no additional cases of MCAD deficiency that had presented clinically. The overall incidence of MCAD deficiency was 1:15200.

The median C8 value in our population was 0.1 µM. Elevations in C8 values ranged from the cutoff value of 0.5 µM to a high of 36.8 µM. Newborns with higher initial C8 values were more likely to receive a diagnosis of MCAD deficiency and were also more likely to be homozygous for the common 985AG mutation. Among the 33 infants with initial C8 value of >5.0 µM, 100% had MCAD deficiency and 70% (20 of 33) were 985AG homozygotes. Among 24 infants with moderate initial C8 values between 0.8 and 4.9 µM, 46% (11 of 24) had a diagnosis of MCAD deficiency, but none was a 985AG homozygote. The remaining 13 included 6 carriers of 985AG and 6 infants who were found to have other abnormalities of fatty acid oxidation not consistent with MCAD deficiency. Among 56 infants with an indeterminate initial C8 value (0.5 and 0.79 µM), only 4% (3 of 56) were classified as MCAD deficiency cases, 66% (37 of 56) were 985AG carriers, and 16 were neither.

Diagnosis of MCAD Deficiency
The 47 cases of MCAD deficiency were diagnosed by pediatric metabolic specialists, using a combination of genetic and biochemical tests. All patients were tested by PCR for presence of the common severe mutation 985AG. Twenty (43%) patients found to have 2 copies, 22 (47%) had 1 copy, and 5 (11%) had no copies of the 985AG mutation. Of the 22 patients with a single copy of 985AG, 17 were found to have a second variant by sequencing of the MCAD gene, 1 infant's sequence did not reveal a second mutation, and parents of the remaining 4 infants declined having DNA sequencing performed. In each of the 5 cases in which no copies of 985AG were detected by PCR, DNA sequencing revealed 2 variants in the MCAD gene.

MCAD deficiency cases were further characterized by grouping according to genotype and severity of biochemical test results. Group 1 consisted of 985AG homozygotes, and group 2 consisted of compound heterozygotes, with 1 or no copies of 985AG. All group 1 patients had clearly elevated C8 levels and/or urinary hexanoylglycine. Group 2 patients were subdivided into those with elevated plasma C8 levels and/or elevated urinary hexanoylglycine (group 2a) and patients with normal or borderline results (group 2b.) The 5 patients without a genetic diagnosis (4 whose parents declined sequencing and 1 for whom sequencing failed to detect a second mutation) were in group 2a. The initial and follow-up acylcarnitine profiles of cases and carriers are summarized in Table 1. Although the medians for C8 and C8-decanoylcarnitine (C10) ratios were higher for group 1 than group 2a, there was considerable overlap. There was also overlap between the profiles of group 2b cases and MCAD carriers. The highest C8 values were seen in initial specimens, usually taken at 24 to 72 hours of age. Repeat specimens taken on days 5 to 13 (median: 7 days) showed moderate to dramatic decreases in C8 value. The median C8 decrease between the initial and repeat specimen was 17.0 µM for group 1, 6.9 µM for group 2a, and 0.5 µM for group 2b. Follow-up C8 values for all group 1 cases remained elevated (>0.8 µM), whereas 30% of group 2a cases and all of group 2b cases had a follow-up C8 value that fell to the normal or indeterminate range (0.5–0.79 µM) by days 5 to 13.

View larger version (10K): [in this window] [in a new window]   FIGURE 1 C8/C10 ratio versus newborn C8 level.

Genotypes of Compound Heterozygote Cases
The MCAD genotypes of 20 unrelated compound heterozygote infants identified in our cohort are listed in Table 2. The variants all were missense mutations resulting in single amino acid changes. The first 13 infants were in group 2a. Infant 1 died at 11 months of age (details are provided in "Clinical Follow-up" below). None of the others have experienced clinical problems associated with MCAD deficiency.

Clinical Follow-up
Two infants were symptomatic in the newborn period. Both were homozygous for 985AG, term, and initially breastfed. The first infant developed lethargy and hypothermia at 36 hours and had a brief cardiac arrest the next day. The initial C8 value obtained after resuscitation was 33.4 µM, followed by a repeat of 1.3 µM at 7 days. The second infant developed lethargy, hypothermia, and hypoglycemia at 53 hours of age with mild laboratory evidence of hepatic and renal dysfunction and did well after intravenous fluids were started. His initial C8 level was 15.6 µM at 1 day of age (before symptoms), 34.4 µM at 3 days, and 3.0 µM at 8 days. These infants are now 1 and 2 years of age and have not experienced additional episodes of symptomatic hypoglycemia.

The 47 patients in our cohort are now 1 to 7 years of age. Two have died as a result of complications of MCAD deficiency. The first infant, a 985AG homozygote, had no perinatal complications and was seen by a metabolic specialist for follow-up and education several times during the first year of life. At 33 months, after 1 day of vomiting and diarrhea at home, she became lethargic and was taken by ambulance to the hospital, where she died in the emergency department. The second infant, a compound heterozygote (Table 2, infant 1) was evaluated by a metabolic specialist soon after birth; the family declined additional visits to the metabolic clinic and chose to follow up with their primary pediatrician. At 11 months of age, the infant had several episodes of vomiting. After a telephone call to the pediatrician's office, he was given a snack and put to bed. The next morning, he was unresponsive and could not be resuscitated. One infant experienced a severe hypoglycemic episode after 1 day of diarrhea at 15 months of age. He was unresponsive on arrival to the emergency department but responded quickly to treatment and fully recovered. He has had no additional episodes of hypoglycemia and is now 4 years of age with normal development. Three other children have experienced borderline hypoglycemia with glucose in the 50s to 60s during acute illnesses. All 4 are homozygous for 985AG.

Developmental follow-up information (age range: 7 months to 6 years) is available on 32 of the 36 children born before 2005. One 2-year-old who had neonatal hypoglycemia has a mild expressive speech delay that is improving with therapy. The remaining 31 children all are developmentally normal.

	DISCUSSION

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As newborn screening programs gain experience with screening for MCAD deficiency, issues continue to arise with case definition, diagnosis, and treatment. Our findings confirm reports of other newborn screening programs that detected a smaller proportion of 985AG homozygotes among screened patients than among clinical cohorts and noted that cases detected by screening have a wider range of biochemical abnormalities.^4,8,9 985AG homozygotes comprised 43% (20 of 47) of our cohort but accounted for 80% (4 of 5) of the patients who manifested severe clinical symptoms. Newborn screening is likely to be detecting some individuals who would otherwise remain asymptomatic.

Timing of the newborn screening sample is a critical element in detection of many of the fatty acid oxidation disorders, including MCAD deficiency. C8 levels peak on days 2 to 3 of life and fall rapidly over subsequent days. As has been shown with long-chain fatty acid oxidation disorders, full evaluation for MCAD deficiency should be completed even when subsequent C8 values normalize.¹⁰ Genotyping should be considered for all patients with borderline C8 values.

No infant with a normal initial C8 value followed by an elevation in a repeat specimen has received a diagnosis of MCAD deficiency. Most of these repeats were obtained as part of routine screening in NICUs to detect delayed thyrotropin rises in preterm infants. All were tested for 985AG, and none was found to be a carrier during the study period. In addition to experiencing metabolic stress associated with prematurity, many of these infants were receiving nutritional supplements that contained medium-chain triglycerides, which can be associated with elevated plasma C8 levels.¹¹

Whether an infant initially receives breast milk or formula can affect the level of the initial C8. Although the number of formula-fed infants in our cohort was small, none of the formula-fed group 1 infants had an initial C8 of >10, whereas 80% of the breastfed infants, including the 2 with neonatal symptoms, attained C8 values of >10. Newborns who receive formula may be less likely to experience the period of relative fasting associated with initiation of breastfeeding. Breastfed infants may be more likely to experience neonatal symptoms,^12,13 and appropriate treatment may be delayed if symptoms begin before newborn screening results are available.

The C8/C10 ratio correlates with newborn C8 elevations taken at 2 to 3 days of life and remains elevated in cases with MCAD deficiency, even after the initial C8 level has fallen. This relative stability may have utility in the diagnosis of older children who did not have a newborn specimen taken during the first few days of life, some of whom will have C8 levels close to or in the reference range. The C8/C10 ratio may also be a useful parameter in the assessment of patients who have novel MCAD genotypes,^5,14,15 All 985AG homozygotes in our cohort as well as other published studies have had C8/C10 ratios > 5,^8,14,15 whereas patients with the genotype 985AG/199TC, which has not been described among clinical cases, have generally had C8/C10 ratios of <5.^8,14,16 Among the 5 clinically symptomatic patients in our cohort, 4 were 985AG homozygotes. The remaining infant, who died at 11 months of age, had the highest C8/C10 ratio among the 27 compound heterozygotes. These observations suggest that a higher C8/C10 ratio may be associated with greater clinical risk, although there are no data at this time on which to base a limit below which there would be no risk.

Our program uses a relatively low C8 cutoff (0.5 µM) to maximize sensitivity while relying on follow-up testing by metabolic specialists to determine the diagnosis. This C8 cutoff value also detects a number of 985AG carriers, who have elevated C8 values compared with the general population.^17,18 Some programs use a higher C8 cutoff and incorporate a C8/C10 ratio in their screening algorithm to increase specificity.^4,8,19 Depending on the cutoff values used, some or all of our group 2b cases may not have been identified, whereas programs that use a lower C8 cutoff, 0.3 µM⁵ or 0.32 µM,²⁰ may detect cases missed by our cutoff. The challenge remains in determining appropriate screening cutoff values; some overlap with 985AG carriers may be inevitable. Although our specialists consider that the risk for metabolic decompensation may be low in these infants, they are being treated until more data become available.

Twelve of our patients had previously identified MCAD mutations.^{4,6,16,21–23} At least 3 of these, 799GA,²² 617GT,²¹ and 250 CT⁴ (in patients 2, 4, and 6, respectively), are known to cause clinical disease. The commonly occurring MCAD allele 199TC, which has a carrier frequency of 1 in 500,¹⁶ occurred in 2 patients in our cohort. Three unrelated newborns in our cohort had the same MCAD genotype, 985AG/127GA, previously thought to be rare. The first infant had a mildly elevated C8 level at birth (1.8 µM), and 2 other infants, as well as the younger brother of the first patient, had initial C8 values only in the indeterminate range (0.5–0.6 µM). The C8/C10 ratios ranged from 0.8 to 1.1. Each had normal plasma acylglycine levels, and 1 had trace urinary hexanoylglycine level. This genotype has also been detected in a newborn in Australia, but their criteria for MCAD deficiency were not fully met because the C8/C10 ratio was <1 and hexanoylglycine level was only marginally and intermittently increased.⁴

Our cohort also included 8 children with 11 novel alleles in the MCAD gene. Six are compound heterozygotes with 985AG, and the remaining 3 children have 2 novel sequences each. Although 1 child has died, the rest remain free of symptoms. Assessment of the clinical risk associated with newly identified mutations in the MCAD gene is especially difficult, because even some children with known severe mutations have remained asymptomatic.^1,24 Because the potential risk associated with these newly identified variants is unknown, infants require complete evaluation and follow-up, even when the biochemical abnormalities seem minimal. Fibroblast studies may be helpful in evaluating enzyme activity in vitro but do not take into account the effect of physiologic stressors such as fever,²⁵ and parents may consider tissue sampling to be overly invasive, preferring instead to follow the treatment protocol presumptively. Fasting studies for older children or measurement of glucose and urinary metabolites during acute illnesses may also be useful in risk assessment. Although treatment for MCAD deficiency is relatively noninvasive, parental anxiety and risk for obesity remain significant concerns.²⁶

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Although newborn screening has proved effective in the presymptomatic diagnosis of MCAD deficiency, severe metabolic crisis and death have not been entirely avoided. Future efforts should include regular assessment of parent understanding, reinforcement of parent education throughout early childhood, and close coordination between metabolic specialist and primary care provider. Long-term outcome remains dependent on constant monitoring for early signs of illness and rapid medical intervention to prevent complications.

	ACKNOWLEDGMENTS

 
This study was funded in part by Health Resources and Services Administration grants 1H46MC00198 and U22MC03959.

This study would not have been possible without the collaboration of the Massachusetts Department of Health, the Maine Department of Health and Human Services, the Rhode Island Department of Health, and the Vermont Department of Health. We thank Drs Stephen Amato, Mary Ampola, Thomas Brewster, Laurie Demmer, Cheryl Garganta, Beverly Hay, Mark Korson, Harvey Levy, Catherine Nowak, Chanika Phornphutkul, and Wendy Smith for providing clinical information and insight. We are indebted to Joyce Bailey, Ann Delaney, and Rosalie Hermos in the follow-up program; Donna Johnson and the metabolic laboratory; and Dr Marvin Mitchell for helpful discussion.

	FOOTNOTES

 
Accepted Oct 12, 2007.

Address correspondence to Ho-Wen Hsu, MD, New England Newborn Screening Program, University of Massachusetts Medical School, 305 South St, Jamaica Plain, MA 02130. E-mail: ho-wen.hsu{at}umassmed.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

What's Known on This Subject MCAD deficiency is a common metabolic disorder that can be readily identified in newborns by using tandem mass spectrometry.

 

What This Study Adds In spite of early diagnosis, severe complications have not been entirely avoided, emphasizing the need for careful monitoring of patients through infancy and eary childhood.

 

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Hsu, H.-W. Articles by Eaton, R. B. PubMed PubMed Citation Articles by Hsu, H.-W. Articles by Eaton, R. B. Related Collections Premature & Newborn

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