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The following is a detailed summary by Deb Lee Gould
(in some places, word-for-word!) of an article printed in the March
1994 issue of the Journal of Pediatrics (pp. 405-415). It
was written by Drs. Kim Iafolla, Robert Thompson, and Charles Roe
of Duke University Medical Center (DUMC). It's entitled "Medium-chain
acyl-coenzyme A dehydrogenase deficiency: Clinical course in 120
affected children."
NOTE: If any of you have read other research
articles that may be of interest to MCAD families, please
feel free to let us know about them, or even write up your own summary
and send it to us. We're always interested to know what other
researchers are working on.
MCAD occurs in 1 of 23,000 live births, mostly in
white children of northern European ancestry (i.e., United Kingdom,
Germany, France). In the US and Great Britain it is suggested that
the carrier rate may be 1 in 68 for the most common genetic mutation
A985G.
The purpose of the study was to collect biochemical,
medical, psychodevelopmental, clinical, and family history information
from 120 MCAD patients (55 male, 65 female) who were referred to
DUMC for biochemical testing. The results would assist professionals
in counseling physicians and families regarding the mortality and
morbidity rates for MCAD deficiency.
Of the 120 subjects, 118 were white, 1 black, and
1 Native American; 112 from the US, 8 from United Kingdom, Canada,
Australia, or Ireland. 32% of the patients with symptoms either
had a sibling with MCAD or one that had died of SIDS. 15 symptom-
free patients were tested because a sibling had died of SIDS or
the sibling had MCAD. The MCAD diagnosis for 23 children came after
death. 19 of them had no previous illness and 4 were treated for
an episode of hypoglycemia. No child has died of a biochemically-
related illness after being diagnosed with MCAD.
Onset of symptoms ranged from 2 days to 6.5 years;
with 14 children diagnosed with MCAD at the onset of illness. Various
other diagnosis were given to 106 children such as Reye Syndrome
(25), idiopathic hypoglycemia (21), and SIDS (16).
95% of the patients required hospitalization or emergency
care upon illness. In all the MCAD patients, at first evaluation,
urine ketones were either "absent or had lower values than expected."
9 patients had elevated creatinine kinase values and 3 had increased
serum cortisol values. 85% of the children had symptoms of infection
(vomiting, diarrhea, or upper respiratory tract problem) at onset.
18 had ear infections and 6 had upper gastrointestinal tract bleeding
which developed during their illness. 5 of these 6 patients died.
Upon autopsy, it was determined that 4 had penetrating ulcers of
the upper GI tract.
Before diagnosis the average number of episodes (illness/hospitalization)
was 2. 42 patients had more than 1 episode before diagnosis. The
time to MCAD diagnosis after clinical onset ranged from 0 - 13.9
years, with an average of 1.8 years. Those unrecognized patients
who died, died within 2 months - 3 years of initial manifestations.
12 died at less than 2 years of age; 11 attributed to SIDS and 1
attributed to Reye Syndrome. 2 older children died from gastrointestinal
hemorrhage and from adrenal insufficiency.
After diagnosis, all 97 of the surviving MCAD patients
had medical or dietary interventions. All were asked to avoid fasting.
74% received supplemental L-carnitine; 2 were given glycine and
1 riboflavin; and 63% had a lowfat diet.
Of the 70 (62 living) siblings tested, 23 had MCAD,
26 were carriers, and 21 were normal. Of the 97 survivors, 71% had
no clinical episode after diagnosis and starting treatment. However,
29% had between 1 and 14 (average 3) episodes. The type of treatment
and number of subsequent episodes had no correlation.
Some of the medical complaints by the survivors included:
hypoglycemia, muscle weakness (16%), seizure disorder (14%), failure
to thrive (10%), and cerebral palsy (9%). There was a strong correlation
between "seizures at clinical onset and development of subsequent
seizure disorder or cerebral palsy." Development of muscle weakness
strongly correlated with the time between onset and diagnosis. Those
with muscle weakness were older at diagnosis (>3 years of age),
had more episodes (4.3 vs. 1.7), and had more hospitalizations (3.6
vs. 1.5) before diagnosis. There was an increased risk of chronic
muscle weakness with a delay in diagnosis of only 1 month after
clinical onset.
Psychodevelopmental information on 73 patients revealed
that 44 were judged to be "normal" and 29 had abnormal screening
results. All were thought to have had normal development before
the clinical onset of MCAD. 12 patients had global developmental
disability without behavioral disabilities; 7 had isolated behavioral
abnormalities; and 4 had both developmental and behavioral disabilities.
16 had speech disabilities. There was a high correlation
between development of speech problems and clinical onset between
12 and 18 months of age, which included encephalopathy or seizures.
There also was a strong association between female gender and the
development of attention deficit disorder (ADD). 8 children (1 male,
7 female) had ADD. ADD patients more likely had seizures, encephalopathy,
and hyperammonemia at the time of onset; had more illness episodes
before and after diagnosis; and were older at diagnosis than patients
without ADD. "No patient in whom MCAD was diagnosed before the onset
of symptoms had ADD."
The data from the study on ethnicity was consistent
with other reports. MCAD was concluded to be a disease of white
persons of northern European ancestry. 2 non-white MCAD families
may have had unrecognized European ancestors.
In this study, 1 in 5 children died during a clinical
episode; thus the incidence of sudden death appeared to be higher
in MCAD patients. After diagnosis there were no deaths from MCAD,
even with several episodes.
5 of the children that died may still be alive if
their siblings, who died of SIDS, were tested for an inborn error
of metabolism. The study's authors recommend that "inborn errors
of metabolism should be included in the differential diagnosis of
the cause of sudden death in infancy and childhood." Evaluation
for hypoglycemia and inborn errors may have also saved 4 children
who died after recurrent hypoglycemic episodes. It was noted that
"the presence of keytones does not eliminate the diagnosis of MCAD;
29% of the patients in whom MCAD deficiency was subsequently diagnosed
had keytones in their urine at time of onset."
The study suggested that MCAD children may be at a
higher risk of death from profound hypoglycemia because they may
not have appropriate endocrine counterregulatory mechanisms. These
abnormal counterregulatory responses to hypoglycemia may develop
even after 1 episode and during chronic hypoglycemia, the sensitivity
to these mechanisms decreases.
Some of the upper GI tract ulceration and gastritis
noted in some of the patients may be due to hypoglycemia counterregulatory
mechanisms. When there is profound hypoglycemia, there is an increase
in cortisol and gastric acid secretion; thus "stress" ulcers may
develop and cause life threatening hemorrhage. GI hemorrhage in
4 of the study's patients may have contributed to their deaths.
In MCAD patients, an exaggerated endocrine response to hypoglycemia
may place patients at a "higher risk of cortisol- induced ulcerations
and therefore, of GI bleeding periods of profound hypoglycemia.
In most children, especially small ones, an intercurrent
illness may have led to decreased oral intake, which hastened hypoglycemia.
The fasting may be the initiating factor, rather than the underlying
infection.
As for the chronic muscle weakness, there is a correlation
between that and multiple episodes before diagnosis. It is suggested
that early diagnosis and treatment may prevent that.
It was hypothesized that abnormal metabolites may
affect the brain and cause various learning disorders. In this study,
one-third of the children older than 2, had developmental disorders.
Speech disorders were especially noted. There was a strong correlation
with seizures or encephalopathy at clinical onset, suggesting a
brain injury and not a developmental disorder. Acquired aphasia
(sudden loss of normal speech) is suggested since appropriate speech
development was reported until onset of episode and then followed
by the return of speech ability after years of therapy.
Another strong relationship was found between ADD
and brain injury. Impulsivity, distractibility, short attention
span, and sometimes hypersensitivity, are characteristics of ADD.
In this study, the incidence of ADD was almost twice that expected
on the basis of frequencies in the general population. Again, early
diagnosis and treatment may prevent these complications.
This study has shown that unrecognized MCAD patients
are at high risk for sudden death and that survivors of severe clinical
episodes may be at high risk for developmental disabilities. Thus,
because of MCAD satisfies the criteria for newborn screening, it
should be part of the newborn screening battery that is already
in place nationally.
Source: Dr. Kim Iafolla, Shady Grove Adventist
Hospital, Rockville, MD; Dr. Robert Thompson, Duke University Medical
Center, Durham, NC; Dr. Charles Roe, Institute of Metabolic Disease,
Dallas, TX
Reprinted from the MCAD Communication Network,
Volume 5, Issue 5, January, 1995
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