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fact
sheet
MCAD Deficiency
Medium-chain acyl-CoA
dehydrogenase
Sophia Wang,
PhD
print version
HuGE Review
Published May, 2000
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MCAD Gene |
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The
gene for medium-chain acyl-CoA dehydrogenase (MCAD) is located |
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at
chromosome
1p31. MCAD is an enzyme responsible for the metabolism of medium chain
fatty acids. |
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Gene Variants |
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Twenty-six MCAD gene variants
have been reported. One of these gene variants, the K304E MCAD mutation,
accounts for the majority of MCAD mutations identified to date. MCAD is an
autosomal recessive disorder; therefore, individuals who are homozygous or
compound heterozygous for an MCAD mutation may have abnormal protein
product and subsequent inefficient enzymatic activity to metabolize
medium-chain fatty acids. MCAD deficiency is therefore an inherited error
of fatty acid metabolism.
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Prevalence
of K304E |
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K304E is reportedly found in 90%
of all retrospectively identified MCAD deficient patients’ alleles; 81%
of all MCAD deficient patients are homozygous, and 18% of MCAD deficient
patients are compound heterozygous for K304E. Caucasians of Northern
European descent exhibit the highest frequency of MCAD deficient
genotypes. The carrier frequency of K304E among this group is estimated to
be 1:40-100 and the homozygote frequency is 1:6,500-20,000.
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Clinical
manifestation
of MCAD Deficiency |
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In
general, MCAD-deficient patients are at risk for a combination of the
following outcomes: hypoglycemia, vomiting, lethargy, encephalopathy,
respiratory arrest, hepatomegaly, seizures, apnea, cardiac arrest, coma,
and sudden death. Long-term outcomes may include developmental and
behavioral disability, chronic muscle weakness, failure to thrive,
cerebral palsy, and attention deficit disorder (ADD). However, differences
in clinical disease specific to allelic variants (e.g.,
genotypic-phenotypic correlations) have not been documented.
The penetrance of MCAD genotypes is also
unknown; there appears to be a number of asymptomatic MCAD- deficient
individuals and some uncertainty as to who will manifest symptoms and who
will remain asymptomatic.
A precipitating
factor is needed for clinical symptoms to present. It is
often in times of metabolic stress induced by fasting or infection, when
the demands on fatty acid oxidation are particularly high, that an
MCAD-deficient patient may present with symptoms. Factors that may
contribute to presentation and/or increased severity of clinical outcomes
include prolonged fasting, infections or recent immunization, age, and
family history of Sudden Infant Death Syndrome (SIDS) or MCAD deficiency.
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K304E and SIDS |
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A
recent review of the literature evaluating the relationship between the main
MCAD allelic variant, K304E, with sudden infant death syndrome (SIDS), defined
as the sudden and unexplained death of an infant in the first year of life,
indicates that while people homozygous for K304E may have an increased risk for
SIDS, the K304E MCAD allelic variant accounts for less than 0.1% of SIDS’
cases in the U.S., Europe, and Australia. The study did not find that infants
heterozygous for K304E were at an increased risk for SIDS.
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Laboratory tests for
detecting MCAD mutations
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MCAD
mutations can be identified through DNA-based tests using polymerase chain
reaction (PCR) and therefore can be detected in newborns by DNA analysis from
newborn blood spots. When identification of the K304E is used for diagnostic
purposes, detection of homozygosity confirms diagnosis of MCAD deficiency;
those heterozygote for K304E will need confirmation of a second MCAD allelic
variant. Since 81% of MCAD-deficient individuals are homozygous for K304E and
18% are heterozygous for K304E, approximately 1% of MCAD-deficient patients will
remain undetected if diagnosis is based on K304E DNA analysis. Mass screening
for MCAD deficiency, however, is generally conducted with the detection of
abnormal metabolites in urine or blood by tandem mass spectrometry (MS/MS).
Typically, MS/MS is used as an initial screening modality followed by
confirmation of MCAD deficiency with urine organic acid profile or DNA mutation
analysis.
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Current status of testing
for MCAD
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Testing for MCAD
deficiency is currently conducted on the basis of the detecting abnormal
metabolites (via tandem mass spectrometry) in newborns. North Carolina and
Massachusetts currently test for MCAD deficiency as part of their newborn
screening programs. California will soon offer optional testing for MCAD
deficiency, and Wisconsin will begin conducting testing for MCAD deficiency on a
pilot basis. In addition, Neo Gen Screening (Pittsburgh, PA, 15220) offers
voluntary MCAD-deficiency testing to newborns born at birthing centers in the
Northeast; 75% of Pennsylvania’s newborns receive this test in addition to the
testing provided by the Pennsylvania State Screening Program. From
a recent TMS survey, there are currently eleven states with tandem MS/MS
in use, either by private or state laboratories. At least seven of these
states test for MCAD deficiency, either on a pilot, voluntary, or
mandatory basis. In Europe, the
Institute of Child Health in London is planning a population-based pilot study
of MS/MS screening on newborns, which includes screening for MCAD deficiency.
Identification of MCAD mutations is offered by laboratories but is more
typically used to confirm diagnoses.
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References |
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Pollitt
RJ, Leonard JV. Prospective surveillance study of medium chain acyl-CoA
dehydrogenase deficiency in the UK. Arch Dis Child 1998;79:116-19.
Roe
C, Coates P. Mitochondrial Fatty Acid Oxidation Disorders. Chap 45 in:
Scriver C, Beaudet A, Sly W, Valle D, editors. The Metabolic Basis of Inherited
Disease. New York: McGraw Hill, 1994:1501-33.
Wang S,
Fernhoff P, Hannon H, Khoury M. Medium chain acyl Co-A dehydrogenase
(MCAD) deficiency human genome epidemiology (HuGE) review. Genetics in
Medicine. 1999;1(7):332-339.
Wang
S, Khoury M. Epidemiologic assessment between the G985A MCAD allelic
variant and sudden infant death syndrome (SIDS). Pediatrics 2000 May; 105:
1175-76.
Ziadeh
R, Hoffman E, Finegold D, et al. Medium chain acyl-CoA dehydrogenase
deficiency in Pennsylvania: neonatal screening shows high incidence and
unexpected mutation frequencies. Pediatr Res 1995;37(5):675-78.
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Web sites |
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National
Organization for Rare Disorders, Inc.
Fatty
Acid Oxidation Disorder Network (mcad3)
Fatty
Acid Oxidation Disorder Network (mcad2)
UC San Diego MCAD
presentation
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Related
Slide Set |
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Slide Set on MCAD deficiency from
the workshop
"Enhancing
the Implementation of Tandem Mass Spectrometry in Newborn Screening Programs."
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