Download 6 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Medium-Chain Acyl-Coenzyme A
Dehydrogenase Deficiency
Synonym: MCAD Deficiency
Summary
Disease characteristics
•
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes
involved in mitochondrial fatty acid β-oxidation, which fuels hepatic ketogenesis, a
major source of energy once hepatic glycogen stores become depleted during
prolonged fasting and periods of higher energy demands.
•
In a typical clinical scenario, a previously healthy child with MCAD deficiency presents
with hypoketotic hypoglycemia, vomiting, and lethargy triggered by a common illness.
•
Seizures may occur.
•
Hepatomegaly and liver disease are often present during an acute episode, which can
quickly progress to coma and death.
•
Children are normal at birth and – if not identified through newborn screening –
typically present between ages three and 24 months; later presentation, even into
adulthood, is possible.
•
The prognosis is excellent once the diagnosis is established and frequent feedings are
instituted to avoid any prolonged period of fasting.
Metabolic defect in MCAD
Diagnosis/testing
•
Diagnosis requires the integrated interpretation of multiple analyses, including
consideration of the clinical status of the affected individual (i.e., acutely symptomatic
vs asymptomatic) at the time of sample collection. Initial testing should include the
following analyses and their proper interpretation:
– Plasma acylcarnitines
– Urine organic acids
– Urine acylglycines
•
The biochemical diagnosis of MCAD deficiency can be confirmed by:
– Determination of fatty acid β-oxidation in fibroblasts;
– Measurement of MCAD enzyme activity in fibroblasts or other tissues;
– Molecular genetic testing of ACADM.
•
The latter two tests can be used for prenatal diagnosis. Based on newborn screening results, approximately 50% of
individuals are homozygous for the common mutation p.Lys304Glu, and approximately 40% are heterozygous for
p.Lys304Glu and one of more than 90 rarer alleles.
Management
•
Treatment of manifestations: Most important is giving L-Carnitine and simple
carbohydrates by mouth (e.g., glucose tablets, or sweetened, non-diet beverages) or
IV if needed to reverse catabolism and sustain anabolism.
•
Prevention of primary manifestations: Oral L-Carnitine. The mainstay is avoidance of
fasting: infants require frequent feedings; toddlers could be placed on a relatively lowfat diet (e.g., <30% of total energy from fat) and could receive 2 g/kg of uncooked
cornstarch at bedtime to ensure sufficient glucose overnight.
•
Prevention of secondary complications: Weight control measures including proper
nutrition and exercise.
•
Agents/circumstances to avoid: Hypoglycemia (e.g., from excessive fasting); infant
formulas that contain medium-chain triglycerides as the primary source of fat.
•
Evaluation of relatives at risk: Evaluate plasma acylcarnitine concentration and urine
acylglycine in sibs and parents to permit early diagnosis and treatment of previously
asymptomatic at-risk family members.
Genetic counseling
•
MCAD deficiency is inherited in an autosomal recessive manner.
•
At conception, the sibs of an affected individual are at a 25% risk of being affected, a
50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not
carriers.
•
The risk of being affected could be 50% if one of the parents is also affected.
Because asymptomatic parents and sibs may have MCAD deficiency, biochemical
evaluation and/or molecular genetic testing should be offered to both parents and all
sibs.
•
Because of the high carrier frequency for the p.Lys304Glu mutation in individuals of
northern European origin, carrier testing should be offered to reproductive partners of
individuals with MCAD deficiency.
•
Prenatal testing for pregnancies at 25% or higher risk is possible by biochemical
methods or, if both parental mutations are known, by molecular genetic testing.
Diagnosis
Clinical Diagnosis (I)
•
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of
fatty acid oxidation. Fatty acid oxidation fuels hepatic ketogenesis, a major source of
energy for peripheral tissues once glycogen stores become depleted during prolonged
fasting and periods of higher energy demands.
•
In a typical clinical scenario, a previously healthy individual with MCAD deficiency
presents with:
– Hypoketotic hypoglycemia, lethargy, seizures, and coma triggered by a common
illness
– Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of
Reye syndrome, which is characterized by acute noninflammatory encephalopathy
with hyperammonemia, liver dysfunction, and fatty infiltration of the liver)
– Sudden and unexplained death
Clinical Diagnosis (II)
•
The first acute episode usually occurs before age two years, but affected individuals
may present at any age including adulthood.
•
Rapid clinical deterioration that is disproportionate in the setting of a common and
generally benign infection should raise the suspicion of MCAD deficiency or other fatty
acid β-oxidation disorders and should prompt administration of intravenous glucose
and L-Carnitine, and the collection of urine and blood samples for metabolic testing.
Testing (I)
•
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes
involved in the pathway of mitochondrial fatty acid β-oxidation (FAO).
•
This pathway consists of four sequential reactions catalyzed first by a set of
membrane-bound enzymes and then by a different set of matrix-soluble enzymes,
producing at the end of each cycle a molecule of acetyl-CoA and a molecule of acylCoA with two fewer carbons.
•
MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length
between four and 12 carbon atoms.
•
A defect of the MCAD enzyme leads to accumulation of medium-chain fatty acids,
which lead to the accumulation of glycine- and carnitine-esters and to dicarboxylic
acids.
•
These metabolites are detectable in body fluids (blood, urine, bile) by gas
chromatography-mass spectrometry (GC-MS) and tandem mass spectrometry
(MS/MS).
Testing (II)
•
Because of the nonspecific clinical presentation of MCAD deficiency, the differential
diagnosis from other FAO disorders is an increasingly complex process that can hardly
be achieved by a single test.
•
The diagnosis of MCAD deficiency therefore requires the integrated interpretation of
multiple analyses, including consideration of the clinical status of the affected
individual (acutely symptomatic vs asymptomatic) at the time of sample collection.
•
Initial testing should include the following analyses and their proper interpretation:
•
Plasma acylcarnitine analysis
•
Urine organic acid analysis
•
Urine acylglycine analysis
•
Analysis of fatty acid β-oxidation in cultured fibroblasts
•
Analysis of MCAD enzyme activity
Testing Strategy
•
To confirm/establish the diagnosis in a symptomatic child who present with acute liver
dysfunction associated with impaired vigilance, diagnostic laboratory tests be
performed on specimens collected early in the metabolic decompensation, including:
•
At least two of the three following screening methods:
•
–
Plasma acylcarnitine
–
Urine organic acids
–
Urine acylglycines
Confirmatory testing by:
–
Determination of fatty acid β-oxidation in fibroblasts;
–
Measurement of MCAD enzyme activity in fibroblasts or other tissues; and/or
–
Molecular genetic testing of ACADM.
• Molecular genetic testing. Perform targeted mutation analysis for the two most
common ACADM mutations:
•
If both are identified, the diagnosis is confirmed;
•
If neither or only one mutation is identified, perform sequence analysis.
Newborn screening
•
MCAD deficiency meets existing newborn screening criteria; several studies have
demonstrated that newborn screening for MCAD deficiency is cost-effective. Since the
early 1990s, tandem mass spectrometry (MS/MS) has been applied to the analysis of
newborn screening blood spots. Today, all US states and many countries have
adopted this technology and include MCAD deficiency in newborn screening
programs.
•
The specificity of MS/MS to identify MCAD deficiency appears to be 100%, with a few
false negative results having been reported as a result of inappropriate cut-off
selection
•
The positive predictive value (PPV) of acylcarnitine analysis to identify MCAD
deficiency varies significantly (8%-78%) among screening laboratories; nonetheless, it
is generally much higher than the PPV for the disorders screened by the traditional,
non-MS/MS methods (0.5%-6.0%). Of note, it is also possible to encounter newborns
with evidence of carnitine deficiency born to an affected, but previously undiagnosed,
mother with MCAD deficiency.
Clinical Description
Natural History
Fatty acid oxidation fuels hepatic ketogenesis, a major
source of energy for peripheral tissues once glycogen
stores become depleted during prolonged fasting and
periods of higher energy demands.
Clinical Description
Natural history
•
Fatty acid oxidation fuels hepatic ketogenesis, a major source of energy for peripheral
tissues once glycogen stores become depleted during prolonged fasting and periods
of higher energy demands.
Classic MCAD deficiency (I)
•
Individuals with MCAD deficiency appear normal at birth and usually present between
ages three and 24 months, although presentation in adulthood is also possible.
•
Affected individuals tend to present in response to either prolonged fasting (e.g.,
weaning the infant from nighttime feedings) or intercurrent and common infections
(e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause
loss of appetite and increased energy requirements when fever is present.
•
Such instances of metabolic stress lead to vomiting and lethargy, which may quickly
progress to coma and death.
•
The episodes may also begin with or be accompanied by seizures.
•
Sudden and unexplained death is often the first manifestation of MCAD deficiency.
•
If the diagnosis of MCAD has not been previously established, at least 18% of affected
individuals die during their first metabolic crisis.
Classic MCAD deficiency (II)
•
Hepatomegaly is usually present during acute decompensation, which is also
characterized by hypoketotic (not necessarily nonketotic) hypoglycemia, increased
anion gap, hyperuricemia, elevated liver transaminases, and mild hyperammonemia.
•
Individuals with classic MCAD deficiency are at risk of losing developmental
milestones and acquiring aphasia and attention deficit disorder, which are thought to
be secondary to brain injury occurring during the acute metabolic event. Chronic
muscle weakness is observed in 18% of individuals who experience several episodes
of metabolic decompensation.
•
McCandless reported that all of 41 newborns with MCAD deficiency identified by
newborn screening in North Carolina since 1997 were developing normally.
•
None experienced hypoglycemic episodes, but some required precautionary
hospitalization during intercurrent illnesses.
Classic MCAD deficiency (III)
•
Although the prognosis is excellent once the diagnosis is established, unexpected
death during the first metabolic decompensation is common and may occur as late as
adulthood (e.g., during metabolic stress precipitated by surgery).
•
Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys,
and heart.
•
In a long-term study of individuals with MCAD deficiency who were diagnosed prior to
newborn screening, many tended to complain about fatigue, muscle pain, and reduced
exercise tolerance; however, no physical correlate, in particular no cardiac
involvement, was identified.
•
Maternal pregnancy complications such as HELLP syndrome (hemolysis, elevated
liver enzymes, low platelets) and acute fatty liver of pregnancy (AFLP) may be more
frequent (as for other fatty acid β-oxidation disorders) when the fetus has MCAD
deficiency.
"Mild" MCAD deficiency
•
The expansion of newborn screening programs using MS/MS had led to the
identification of individuals with milder abnormalities in their acylcarnitine profiles.
•
Over a relatively short follow-up period, none of these individuals identified through
newborn screening had metabolic crises while being treated.
•
However, one person with a mild biochemical phenotype who was compound
heterozygous for the common p.Lys304Glu mutation and a new mutation (p.Gln24Glu)
developed hypoglycemia and became comatose during a second metabolic
decompensation.
•
Therefore, despite having higher residual MCAD enzymatic activity, such individuals
should be considered at risk of developing clinical manifestations and treatment should
be initiated.
•
To determine disease risk, detailed investigations, including carefully executed fasting
challenges as have been conducted for persons with "severe" mutations, should be
considered.
Genotype-Phenotype Correlations
•
Inclusion of MCAD deficiency in newborn screening programs has led to the
identification of individuals with less pronounced abnormalities in their acylcarnitine
profiles who are compound heterozygotes either for the common ACADM mutation
(p.Lys304Gly) and another mutation or for two non-p.Lys304Glu mutations.
•
One of these other mutations, p.Tyr42His, has an allele frequency of approximately
6% in MCAD-deficient newborns and is associated with some residual MCAD
enzymatic activity.
•
Because individuals with a “milder” biochemical phenotype can still develop lifethreatening symptoms and because intrafamilial differences in the phenotypic
expression of MCAD deficiency are commonly seen, a consistent genotype-phenotype
correlation does not exist.
•
It is reasonable to assume that environmental factors (e.g., diet, stress, intercurrent
illnesses) are critical in determining the natural history of this disorder.
Nomenclature
•
MCAD deficiency was first described in individuals presenting with a Reye-like
syndrome and urine organic acid analysis that revealed overexcretion of
medium-chain dicarboxylic acids and hexanoylglycine in the absence of
significant ketosis.
•
Accordingly, it is likely that prior to MCAD deficiency having been better
delineated, affected individuals were misdiagnosed as having Reye syndrome.
Prevalence
•
MCAD deficiency is prevalent in individuals of European (especially northern) descent.
•
The overall frequency of the disorder has been estimated to range between 1:4,900
and 1:17,000; variability is related to the ethnic background of the population studied.
•
The number of newborns detected with MCAD deficiency through newborn screening
programs exceeds that expected based on the population frequency of the common
985A>G mutation.
•
Based on newborn screening programs worldwide, the incidence of MCAD deficiency
has been defined in:
–
Northern Germany (1:4,900 newborns) /Southern Germany (1:8,500 newborns)
–
New South Wales, Australia (1:25,000 newborns)
–
USA (1:15,700 newborns)
–
Taiwan (~1:700,000 live births)
Differential Diagnosis (I)
•
MCAD belongs to the acyl-CoA dehydrogenase (ACAD) gene family, which also
includes three other dehydrogenases involved in the fatty acid oxidation pathway:
– short-chain acyl-CoA dehydrogenase (SCAD),
– long-chain acyl-CoA dehydrogenase (LCAD), and
– very long-chain acyl-CoA dehydrogenase (VLCAD).
•
Another gene, ACAD9, encodes a protein that has been reported to possibly play a
role in fatty acid oxidation and in stabilization of complex I of the respiratory chain.
•
Additional dehydrogenases with homology to MCAD are isovaleryl-CoA
dehydrogenase (encoded by IVD), 2-methyl branched-chain acyl-CoA
dehydrogenase (encoded by ACADSB), and isobutyryl-CoA dehydrogenase
(encoded by ACAD8).
Differential Diagnosis (II)
•
SCAD deficiency is a highly heterogeneous disorder with phenotypic manifestations
possibly modulated by two polymorphisms that are found in 7% to 14% of the general
population.
•
Although the presentation of VLCAD deficiency is in some cases similar to that of
MCAD deficiency, the majority of individuals with VLCAD present with
cardiomyopathy.
•
The first individual to be diagnosed with LCAD deficiency was recently described.
Contrary to manifestations in other ACAD deficiencies and expectations based on
LCAD-deficient mice, this individual presented with congenital surfactant deficiency
and hypothyroidism.
•
The phenotype of ACAD9 deficiency has not been fully delineated; however, recent
reports suggest involvement in the stabilization of the respiratory chain complex I in
persons with cardiomyopathy, encephalopathy, and lactic acidosis who have ACAD9
mutations.
Differential Diagnosis (III)
•
All causes of a Reye-like syndrome (i.e., acute noninflammatory encephalopathy
with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) need to be
considered, including other disorders of fatty acid β-oxidation, defects in
ketogenesis, urea cycle disorders, organic acidurias, respiratory chain defects, and
inborn errors of carbohydrate metabolism (e.g., hereditary fructose intolerance).
•
Although the same biochemical markers elevated in MCAD deficiency are also
elevated in glutaric acidemia type 2, the presence of several additional organic
acids (glutaric acid, 2-hydroxy glutaric acid, ethylmalonic acid), C4 and C5 carnitine,
and glycine esters, and the normal excretion of phenylpropionylglycine are
important discriminators.
Management
Evaluations Following Initial Diagnosis (I)
•
To establish the extent of disease in an asymptomatic individual diagnosed with
MCAD deficiency, the following evaluations are recommended:
• Plasma acylcarnitine analysis
• Plasma free and total carnitine measurement
• Urine acylglycine analysis
• Urine organic acid analysis
Evaluations Following Initial Diagnosis (II)
•
In a symptomatic individual the following additional laboratory studies should be
considered:
– Blood glucose concentration
– Blood gas analysis
– Ammonia
– Lactic acid
– CBC with differential
– Electrolytes
– Liver function tests
– Blood cultures (in case of fever)
•
Although development is typically normal for individuals treated prospectively, those
who experience metabolic decompensations requiring hospitalization often
demonstrate developmental and neurologic disabilities.
•
Neurodevelopmental assessments and intervention should therefore be considered for
such individuals.
Treatment of Manifestations
•
The most important aspect of treating symptomatic patients is reversal of catabolism
and sustained anabolism by provision of L-Carnitine and simple carbohydrates by
mouth (for example, glucose tablets, or sweetened, non-diet beverages) or IV LCarnitine and glucose if the patient is unable or unlikely to maintain or achieve
anabolism through oral intake of food and fluids.
•
All affected individuals should have a frequently updated "emergency" letter to be
given, if needed, to health care providers who may not be familiar with MCAD
deficiency.
•
This letter should include a detailed explanation of the management of acute metabolic
decompensation, emphasizing the importance of preventive measures (e.g.,
intravenous L-Carnitine and glucose regardless of "normal" laboratory results,
overnight in-hospital observation).
Prevention of Primary Manifestations
The mainstay in the treatment of MCAD deficiency is avoidance of fasting. Derks et al
[2007] studied the length of time that MCAD-deficient but asymptomatic individuals
should be able to fast. Based on their findings, they recommend maximum fasting times
of:
•
Up to eight hours in infants between ages six and 12 months
•
Up to ten hours during the second year of life
•
Up to 12 hours after age two years
To avoid excessive fasting:
•
Infants require frequent feedings.
•
Toddlers could receive 2 g/kg of uncooked cornstarch as a source of complex
carbohydrates at bedtime to ensure sufficient glucose supply overnight. A relatively
low-fat diet (e.g., <30% of total energy from fat) may be beneficial.
Prevention of Secondary Complications
•
Recent long-term outcome studies revealed that persons treated for MCAD deficiency
are prone to excessive weight gain [Derks et al 2006]. Accordingly, follow up should
include weight control measures such as regular education about proper nutrition and
allowed physical exercise.
Agents/Circumstances to Avoid
•
Hypoglycemia must be avoided by frequent feedings to avoid catabolism, if
necessary by intravenous administration of glucose.
•
Infant formulas containing medium-chain triglycerides as the primary source of fat
are contraindicated in MCAD deficiency
Evaluation of Relatives at Risk
• Sibs and parents should be tested by plasma acylcarnitine
and urine acylglycine analysis to allow early diagnosis and
treatment of those family members with MCAD deficiency
who have previously been asymptomatic.
• See Genetic Counseling for issues related to testing of atrisk relatives for genetic counseling purposes.
Demographics
•
MCAD deficiency is estimated to occur in approximately one out of every 13,000 to
20,000 live births.
•
This estimate is confounded to a certain degree by the fact that up to 25% of all
individuals affected with MCAD deficiency die the first time they exhibit any symptoms
of the disease.
•
Many of these children are often misdiagnosed with either sudden infant death
syndrome (SIDS) or Reye syndrome.
•
Unless an autopsy is performed, MCAD generally goes undetected in these
individuals; and, even then, unless the physician performing the autopsy is familiar
with MCAD deficiency, the cause of death may still be misreported.
Treatment and management
•
Because individuals affected with MCAD deficiency can still break down short chain
and long chain fatty acids at a normal rate and most have a diminished, but functional,
ability to break down medium chain fatty acids, a precipitating condition must be
present in order for symptoms of MCAD deficiency to develop.
•
The most common precipitators of MCAD deficiency symptoms are stress caused by
fasting or by infection.
•
At these times, the body requires a higher than normal breakdown of medium chain
fatty acids.
•
MCAD deficient individuals often cannot meet these increased metabolic demands
•
The main treatments for MCAD deficiency are designed to control or avoid
precipitating factors.
•
Persons affected with MCAD deficiency should never fast for more than 10 to 12
hours and they should strictly adhere to a low-fat diet.
•
Blood sugar monitoring should be undertaken to control episodes of hypoglycemia.
•
During acute episodes, it is usually necessary to administer glucose and supplement
the diet with carbohydrates and high calorie supplements.
•
Many individuals affected with MCAD deficiency benefit from daily doses of L-carnitine.
•
This vitamin is responsible for transporting long chain fatty acids across the inner
mitchondrial membrane.
•
Elevated levels of L-carnitine ensure that these individuals breakdown long chain fatty
acids in preference to medium chain fatty acids, which helps prevent acute
symptomatic episodes of MCAD deficiency.
•
Additionally, L-carnitine helps remove toxic wastes from the bloodstream to the urine,
so it is also pivotal in controlling hyperammonemia.
Carnitine
•
L-carnitine, which is synthesized endogenously, may become relatively depleted in
MCADD as it remains conjugated to the accumulated medium chain fatty acids and is
excreted as the acylcarnitine.
•
Recommended dosages for infants are 50-100 mg/kg.
•
The need for, and the amount of, supplemetation in children and adults is determined
by monitoring plasma free carnitine concentration according to the individual clinic's
protocols.
•
A plasma free carnitine in the 25-35 micromolar range is a usual goal.
•
IV carnitine: When oral intake of carnitine is decreased and/or carnitine requirements
increased due to catabolism, IV carnitine at a dose of 100mg/kg body weight may be
needed for the short term.
•
Because not all hospitals have IV carnitine available, it may be possible to continue
to give liquid carnitine orally since only small volumes are typically needed. Many
recommend doubling the oral carnitine dosage during illness.
Special Circumstances (I)
•
Surgery: Fasting before surgical procedures and during recovery puts an MCADD
individual at risk. Most agree that clear liquids can be given up to 4 hours before
surgery, but IV glucose should be started before the procedure and continued until the
patient can consume adequate oral intake and can maintain normoglycemia. Post surgical pain and nausea may affect appetite and intake.
•
Trauma: Trauma and injury increase caloric needs, but pain and possible alteration in
mental status may decrease intake. Careful monitoring is very important. IV glucose
should be used whenever there is any concern about catabolism.
•
Pregnancy and child birth in an MCADD female: During pregnancy, plasma free
carnitine levels will decline. Dosages of L-Carnitine 100mg/kg are recommended, but
free carnitine may still not reach pre-pregnancy levels. IV glucose should be started as
soon as labor begins and continued until the patient has adequate oral intake and can
maintain normoglycemia.
Special Circumstances (II)
•
Neonatal care for an MCADD sibling: Families, who already have a child/children with
MCADD, have a 25% risk of reccurence of MCADD with each pregnancy. If they do
not have prenatal diagnosis, it may take several days to have either screening or
diagnostic testing results available. It is important to monitor this at-risk infant closely.
If the mom wishes to breast feed, glucose water or small amounts of formula, given
after the newborn has been been put to the breast, can help prevent catabolism until
breast milk production is adequate.