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/FOD families, please email Deb. 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 ketones does not eliminate the diagnosis of MCAD; 29% of the patients in whom MCAD deficiency was subsequently diagnosed had ketones 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