 |
|
The Otolaryngological Manifestations of Mitochondrial Disease and the Risk of Neurodegeneration With Infection
Joseph L. Edmonds, MD;
Daniel J. Kirse, MD;
Donald Kearns, MD;
Reena Deutsch, PhD;
Liesbeth Spruijt, MD;
Robert K. Naviaux, MD, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:355-362.
ABSTRACT
| |
Objective To report the nature and extent of hearing loss and other otolaryngological
problems in patients with mitochondrial disease, and to document the risk
of neurodegeneration with infection.
Design Medical chart review and telephone interview of 40 patients with documented
mitochondrial disease.
Setting An international referral center for the diagnosis and management of
mitochondrial disorders.
Patients We describe 40 patients with a definitive diagnosis of mitochondrial
disease. Thirty-three (82%) were younger than 15 years.
Results Hearing loss was the most common clinical finding associated with mitochondrial
disease. Twenty-eight (80%) of the 35 patients undergoing testing had hearing
loss or significant auditory dysfunction. In 20 (57%) of these, brainstem
conduction abnormalities were identified. Eight (30%) of the 27 patients had
an abnormal number of recurrent upper respiratory tract infections, and 4
(50%) of these had life-threatening or neurodegenerative sequelae. Mitochondrial
disease followed an episodic course, with periods of stasis or slow developmental
progress, punctuated by neurodegenerative events in 18 (60%) of 30 patients.
Intercurrent infection was recognized as a precipitant of neurodegenerative
events in 13 (72%) of 18 patients with a history of episodic degeneration.
Conclusions Children and adults with mitochondrial disorders are at high risk for
hearing loss and life-threatening complications of intercurrent infections.
A constellation of audiologic abnormalities, multiorgan system involvement,
and history of neuromuscular setbacks with infection strongly suggests mitochondrial
disease. Knowledge of these features can lead to more rapid diagnosis and
improved medical and surgical management for this special group of patients
with fundamental defects in bioenergy metabolism.
INTRODUCTION
MITOCHONDRIA are intracellular organelles that house the mechanism for
oxidative phosphorylation, and in this way produce the energy storage molecule
adenosine triphosphate. Mitochondria are also required for the synthesis of
hundreds of other compounds that are essential for cellular function, including
compounds needed for protein, fatty acid, pyrimidine, and carbohydrate metabolism.1 Hundreds to thousands of these organelles exist in
each cell, depending on the cell type and its metabolic needs. Each mitochondrion
contains 2 to 10 copies of the mitochondrial DNA (mtDNA)—a circular,
double-stranded DNA molecule 16 569 base pairs (bp) in length. Mitochondrial
DNA encodes only 13 of the more than 1000 proteins required for mitochondrial
biogenesis and function. All other mitochondrial genes are encoded in the
nucleus, and the encoded proteins must be imported into mitochondria. For
this reason, many mitochondrial disorders are inherited in classic mendelian
patterns.
Mitochondrial DNA undergoes a higher rate of spontaneous mutation than
nuclear DNA. These mutations can accumulate over time. The variability in
expression of mitochondrial disorders is in part related to the variable energy
requirements of tissues and the ratio of mutated vs healthy mtDNA, a condition
known as heteroplasmy, which can increase with time.
MITOCHONDRIAL DISORDERS
More than 400 diseases are grouped under the general heading of mitochondrial
disorders. Specific disease entities in the patients studied in this series
include Mitochondrial Encephalomyopathy with Lactic acidemia and Strokelike
episodes (MELAS); Neuropathy or neurogenic muscular weakness with Ataxia and
Retinitis Pigmentosa (NARP); Kearns-Sayre syndrome; Pearson Marrow-Pancreas
Syndrome; Cytochrome-c Oxidase (complex IV) deficiency;
Pyruvate Dehydrogenase deficiency; Complex I deficiency; and 3-Hydroxyisobutyric
aciduria with lactic acidemia. Eight (20%) of the 40 patients described in
this series had unknown mitochondrial disorders. These patients demonstrated
lactic acidemia and abnormal muscle biopsy findings. However, the precise
molecular basis of the mitochondrial defects was not determined. Several recent
reviews on the clinical features of mitochondrial disease have been published.1-6
HEARING LOSS AND MITOCHONDRIAL DISEASE
More than 40 different genetic loci that lead to hearing loss have been
identified.7 These have been traditionally
categorized as recessive, dominant, or X-linked disorders. It has become increasingly
clear that another group of genetic diseases, mitochondrial diseases, plays
a role in the large proportion of previously unexplained, inherited hearing
loss.8-9 It remains unclear how
many of these cases of hearing loss will ultimately be explained by mitochondrial
disease. Mitochondrial disorders can be inherited in a traditional mendelian
manner, in addition to strict maternal inheritance. Sporadic inheritance patterns
are also possible, in which spontaneous mutations in DNA occur during oogenesis
or early embryogenesis.2 Because of the progressive
nature of mitochondrial disease, normal findings of an initial hearing evaluation
do not rule out the possibility of later hearing loss as part of any mitochondrial
disorder.
Mitochondrial disorders are usually first manifest in tissues with high
metabolic demands, such as nerves and muscles. This finding places the complete
auditory pathway, peripherally from the cochlea and centrally to the brainstem,
at risk in mitochondrial disease and helps to explain the common finding of
hearing loss as part of the initial presentation of a mitochondrial disorder.
UPPER RESPIRATORY TRACT INFECTIONS AND MITOCHONDRIAL DISEASE
Because of the relative novelty of mitochondrial disorders, no reports
in the literature have quantified the risk for neurodegenerative events triggered
by infections in patients with mitochondrial disease. However, a well-known
clinical correlation of upper respiratory tract infections (URIs) and other
common infections with neurodegenerative setbacks in mitochondrial disease
exists.3 This association is quantified in
this report.
PATIENTS AND METHODS
PATIENT POPULATION
From June 15, 1994, through December 31, 1999, more than 300 patients
underwent evaluation for possible mitochondrial disease. Forty of these patients
fulfilled the following 2 requirements for enrollment in this study: (1) lactic
acid levels in the blood or cerebrospinal fluid of 30 mg/dL or greater ( 3
mmol/L), and (2) an objective defect in mtDNA or oxidative phosphorylation.
Medical records for these 40 patients were reviewed from The Mitochondrial
and Metabolic Disease Center at the University of California–San Diego.
Brainstem auditory evoked response (BAER) examinations were performed in 35
of 40 patients as part of an initial multisystem evaluation of those patients
with confirmed mitochondrial disease. In addition, careful medical histories
were obtained, and physical examinations were performed on all patients. The
age and the presentation of each patient were recorded from these initial
histories and physical examination findings.
INFORMED CONSENT
All patients or their guardians provided informed consent and underwent
evaluation and initial ascertainment under an institutional review board–approved
human subjects protocol at the University of California–San Diego School
of Medicine for 1994 through 1999.
BRAINSTEM AUDITORY EVOKED RESPONSES
Thirty-five patients of the study group (88%) underwent a diagnostic
BAER examination. The BAER data were examined for neuroaudiologic conduction
delay (I-V interval), waveform morphology, and auditory threshold. Evaluation
of conduction delay was limited to the I-V interval, as this was the most
consistently recorded variable on the BAER summary available for review. The
I-V interval was converted to a z score to correct
for age differences in reference BAER test results. The z score was calculated by taking the recorded interval in milliseconds,
subtracting the reference value,10 then dividing
by the SD.10 An abnormal z score was defined as being more than 2 SDs from the reference value
for the patient's age. The number of patients with at least 1 abnormal z score for the I-V interval is recorded. Asymmetry was
determined by subtracting the right from the left z
score, with the result being equal to or greater than 2.
A description of waveform morphology was also consistently present on
the BAER report. Waveform morphology was recorded to be normal, normal with
conduction delay, unilaterally abnormal, or bilaterally abnormal. In patients
undergoing multiple examinations, we noted waveform morphology remaining unchanged,
becoming worse, or, in some instances, improving to normal.
Threshold data were obtained in 29 (83%) of the 35 patients undergoing
BAER examinations. Thresholds were reported to be abnormal if the recorded
threshold was greater than 30 dB. The distributions of abnormal brainstem
conduction, waveform morphology, and abnormal thresholds were then grouped
based on the type of mitochondrial disease.
INFECTIONS
Caregivers were interviewed with attention to the number of URIs and
episodes of acute otitis media (OM) in the year preceding this study. The
caregivers were also questioned regarding episodes of neurodegeneration and
those episodes that were temporally related to an infection. This telephone
interview information was combined with information obtained from the hospital
medical chart regarding numbers of URIs and episodes of acute OM (as reported
in the medical history at initial evaluation). The medical chart reviews and
interviews also attempted to collect information regarding surgical procedures
performed or other treatments rendered for recurrent OM or URI.
STATISTICAL ANALYSIS
Results were reported and listed descriptively. The incidence of audiologic
abnormalities, infection rates, neurodegenerative episodes, and proportion
of various presenting symptoms were estimated using 95% confidence intervals.
We used a normal approximation to the binomial distribution or simulation
(1000 repetitions) to compute the confidence intervals, depending on the magnitude
of the number of events. To determine if patients with mitochondrial disease
had an abnormal number of infections, we estimated the incidence of infections
with a 95% confidence interval. We then compared this interval estimate with
the number of infections per year reported for a control population of children
and adults.11 We developed a Venn diagram to
reflect the distribution of the numbers of abnormal URIs and neurologic setbacks
associated and not associated with infection among the subjects.
RESULTS
PRESENTING SIGNS AND SYMPTOMS
No disease-specific presenting signs were present among patients with
mitochondrial disease (Table 1
and Table 2). The most common
presenting abnormality was motor and/or language developmental delay, which
occurred in 16 (40%) of 40 patients. Of the 23 patients who presented at younger
than 5 years, 20 (87%) had significant developmental delays. The next most
common presenting symptom was a strokelike episode (SLE), which occurred in
10 (25%) of 40 patients, and was not restricted to patients with MELAS. Patients
with Pyruvate Dehydrogenase deficiency, Complex I deficiency, Cytochrome-c Oxidase (complex IV) deficiency, and NARP also experienced
SLEs at presentation (Table 1
and Table 2). Eight patients (20%)
had miscellaneous neurologic symptoms, which were initially unexplained. These
symptoms included deafness, tongue weakness, swallowing dysfunction, nystagmus,
seizures, ophthalmoplegia, hypotonia, and decreased visual acuity. Two neonates
received diagnoses of severe lactic acidosis shortly after birth. Two infants
had as their initial symptom failure to thrive. One child had dizziness as
the initial complaint. The range of ages at presentation was also highly variable,
from birth to 53 years (Table 1).
The mean age at presentation was 8.4 years. The median age at presentation
was 3.3 years (Table 1).
|
|
|
|
Table 1. Recurrent Infection and Complications of Infections in Mitochondrial
Disease*
|
|
|
|
|
|
|
Table 2. Presenting Signs and Symptoms of Mitochondrial Disease*
|
|
|
HEARING LOSS
Thirty-five of 40 patients underwent diagnostic BAER examinations (Table 3). The results of the audiologic
studies were then summarized according to disease diagnosis (Table 4). Twenty (57%) of 35 patients had central (brainstem) defects,
as documented by a significant delay or absence of the I-V interval in at
least 1 ear. Fourteen (40%) of 35 patients had a significant delay of the
I-V interval in the right and left ears. Five (14%) of 35 patients had significant
asymmetry of the I-V interval between the right and left ear. Thirty-three
of those undergoing BAER examinations had a description of waveform morphology.
Twenty-two (67%) of these had abnormal waveform morphology. Thirteen (39%)
had bilateral abnormalities, and 9 (27%) had a unilateral abnormality. Two
(6%) of the 33 had normal waveform morphology with significant conduction
delay (Table 3). Nine (27%) of
33 patients had normal waveform morphology and conduction times. Thirty of
the 35 patients undergoing a screening BAER underwent testing for hearing
sensitivity or hearing threshold. Of these, 23 (77%) had abnormalities in
at least 1 ear (Table 4). In the
recorded histories, physical examination findings, and subsequent BAER findings,
no patients were noted to have OM at the time of threshold evaluation. Overall,
audiologic evaluation in patients with mitochondrial disease showed that 28
(80%) of 35 patients had significant hearing dysfunction at the time of first
evaluation. Only 7 (20%) of 35 patients had normal hearing.
|
|
|
|
Table 3. Auditory Conduction and Threshold Abnormalities in Mitochondrial
Disease*
|
|
|
|
|
|
|
Table 4. Audiologic Abnormalities Associated With Mitochondrial Disease*
|
|
|
DISEASE-SPECIFIC AUDIOLOGIC ABNORMALITIES
Individual disease states were evaluated for differences that might
exist between them in the measured hearing or infectious disease variables.
The 40 patients in this study were distributed among 9 diagnostic categories
(Table 4 and Table 5). No significant differences were detectable with the small
numbers of patients within each category. The 10 patients with MELAS tended
to be older at diagnosis than other groups, with a mean age at presentation
of 22.5 years (Table 5). However,
3 patients with MELAS (30%) presented before age 15 years (Table 1). In all 3 children, the presenting symptom was an SLE,
with or without documented antecedent URI.
|
|
|
|
Table 5. Risks for Recurrent Infection and Associated Neurologic Degeneration
in Mitochondrial Disease*
|
|
|
RISK OF INFECTIONS AND NEURODEGENERATION
Information on infections was available from 27 (68%) of the 40 patients
in this study. Four (15%) of 26 patients had abnormally increased rates of
recurrent OM. Overall, 94 infections were reported by 27 patients in the year
before our survey, leading to an estimate of 3.5 infections per year, with
a 95% confidence interval of 2.1 to 4.9 infections per year (Table 5). A Poisson distribution is expected when infections are
relatively rare and independent. We found that a frequency distribution of
the hit rate of infections among patients with mitochondrial disease was positively
skewed (Figure 1) and suggested
a Poisson distribution. Eight (30%) of 27 patients had abnormally frequent
(recurrent) URIs, defined as more than 6 per year (Table 5).
|
|
|
|
Figure 1. Frequency distribution of annual
infections reported in patients with mitochondrial disease. Ninety-four infections
were reported among 27 patients with mitochondrial disease in the year before
the study. The mean number of infections per patient was 3.5 (95% confidence
interval, 2.1-4.9; SD, 3.5).
|
|
|
Mitochondrial disease was episodic, with periods of stasis or slow developmental
progress, and punctuated by neurodegenerative events in 18 (60%) of 30 patients.
Intercurrent infection was recognized as a precipitant of neurodegenerative
events in 13 (72%) of 18 patients. Of the 8 patients with a history of recurrent
URI, 4 (50%) also had neurodegenerative events associated with infection.
These results are summarized in the Venn diagram shown in Figure 2.
|
|
|
|
Figure 2. The relationship between infection
and neurodegeneration in patients with mitochondrial disease (N = 40). We
constructed a Venn diagram from data reported in Table 1 to reflect the relationship between neurodegenerative events
and infections in patients with mitochondrial disease. URI indicates upper
respiratory tract infection.
|
|
|
The timing of the infection and the neurodegenerative event varied.
In a few patients (3/13), the neurologic setback occurred early in the course
of infection. In most patients (10/13), the neurologic event occurred 3 to
7 days after the onset of infection and frequently appeared at a time when
the infection was resolving. This pattern of delayed neurodegeneration in
association with infection is depicted graphically in Figure 3. The pattern was similar to that reported for Reye syndrome,
now known to be frequently associated with mitochondrial defects in fatty
acid oxidation.12
|
|
|
|
Figure 3. Timing of infection-associated
neurologic setbacks in patients with mitochondrial disease. The temporal delay
in the onset of neurodegenerative events associated with infection in most
patients was similar to that described in Reye syndrome by Partin.12
|
|
|
COMMENT
Several specific mitochondrial diseases with hearing loss as a well-recognized
component have been described. Patients with the A1555G mitochondrial DNA
mutation exhibit mild high-frequency, progressive hearing loss without aminoglycoside
injection and are highly susceptible to profound otologic injury with the
administration of aminoglycoside antibiotics.13-14
A study of patients with MELAS reported significant sensorineural hearing
loss.15 The loss is sometimes the sole manifestation,
but more commonly the hearing loss is asymmetric with an early onset and marked
by a stepwise progression and/or partial reversibility. Patients with Kearns-Sayre
syndrome were found to have a significantly prolonged I-V interval in 1 study.16 Results of BAER examinations in patients with Leigh
disease have shown progressive disturbances of the brainstem wave components.17 Additional BAER data have corroborated abnormalities
in the BAER data of patients with Leigh disease, but found the abnormalities
to be inconsistent.18-19 Other
reports have emphasized the importance of mtDNA mutations in nonsyndromic
and syndromic deafness20 and have discussed
biochemical defects associated with mitochondrial hearing loss.21
The site of the functional lesion leading to hearing loss in mitochondrial
disease has been reported to be the cochlea in MELAS.15
The stria vascularis was considered to be the principle site of the defect.
However, in our patients with MELAS, we found that the entire auditory pathway,
from cochlea to brainstem, was at risk (Table 1 and Table 3).
In our study, a 34-year-old patient with MELAS (patient 12) had normal otoacoustic
emissions with a grossly abnormal BAER finding (absent waves III and V, with
elevated thresholds for 1 ear). These results showed that the cochlear responses
in this patient with MELAS were normal, and that the site of the defect was
restricted to a central abnormality. Collectively, a central cause was present
in 57% of patients with mitochondrial disease, as documented by conduction
delay associated with abnormal waveform morphology on the BAER findings (Table 4).
In a seminal report,22 hearing loss was
documented in 19.8% of patients with mitochondrial disease. This finding was
necessarily an underestimate, as not all of the patients included in that
study underwent formal hearing evaluations. Those patients who had not undergone
a hearing evaluation were assumed to have normal hearing. In our population,
hearing dysfunction was not recognized before formal testing in 12 (43%) of
the 28 patients. In most cases, the reason for this oversight was the young
age of the patients, combined with the presence of multiorgan system disease
that overshadowed the presence of hearing dysfunction.
Among the 40 patients with lactic acidemia and mitochondrial disease
in our study, the rate of hearing loss was 80% (Table 4). Our population may represent more severe forms of mitochondrial
disease, since all enrolled patients had to meet the requirements of documented
respiratory chain disease and baseline lactic acid in blood or cerebral spinal
fluid of 30 mg/dL or greater. However, our study confirms and extends the
earlier report that hearing loss is common, and may be the presenting symptom
in mitochondrial disease.
We found no disease-specific presenting symptoms or characteristic age
of presentation of mitochondrial disease (Table 1 and Table 2), although developmental delay was observed in 40%, and SLEs occurred in 25%.
The broad clinical spectrum is one of the hallmarks of mitochondrial disease.1, 5-6 Signs and symptoms that
were not present early in the course of disease may appear as the disease
progresses. The absence of a specific sign is not evidence of the absence
of mitochondrial disease. The pattern of abnormalities should alert the practitioner.
Some presentations may cause a patient to undergo evaluation by an otolaryngologist
before the diagnosis of mitochondrial disease. Some of these common presenting
reasons for otolaryngology referral include swallowing dysfunction, dizziness,
tongue weakness, or head and neck infections (URI or OM) complicated with
a neurologic event. Patients with mitochondrial disease may also be referred
to an otolaryngologist very early in the disease process because of an abnormal
BAER finding and the question of hearing loss. This occurrence is probably
increasing owing to universal infant screening for hearing loss in the United
States.
The overall number of infections per year in our series (mean, 3.5 per
year; 95% CI, 2.1-4.9) was not significantly different than the infection
rates (4.1 per year) reported in a general population of children and adults.11 However, in sharp contrast to a general population,
18 (60%) of 30 patients with mitochondrial disease had a history of neurodegenerative
events (Table 5). In 13 (72%)
of these 18 patients, the neurodegenerative event was associated with infection.
The risk of neurodegeneration associated with infection led some parents in
the study group to home school their children to avoid exposure to infectious
disease. At present, it is unclear if the increased risk of neurodegeneration
associated with infection in patients with mitochondrial disease is related
to the production of host-defense cytokines and their effects on mitochondria
or to a specific cellular, humoral, or mucosal immune defect, or is secondary
to impaired mucociliary function related to reduced adenosine triphosphate
output from ciliary mitochondria. Regardless of the cause, it is critical
to recognize that children with mitochondrial disease are at risk for disease
progression with recurrent infection. Acute management should be swift and
decisive. The first signs of bacterial infection should be treated with empiric
antibiotics and culture of the infection, with a change in antibiotic coverage
based on the culture results. Long-term, preemptive otolaryngological management
should be considered early in patients who have demonstrated a recurrent risk
of infection, because as many as 50% of these will eventually have a neurodegenerative
event associated with infection (Figure 2). Bilateral myringotomy and tympanostomy tube placement was effective
and safe in 3 of our patients who had recurrent OM. The risk of recurrent
infection far exceeds the risks associated with general anesthesia required
for tube placement. However, certain precautions are required before subjecting
any patient with mitochondrial disease to general anesthesia.23
In our series, all 3 patients who underwent bilateral myringotomy and tympanostomy
tube placement required several surgeries. Therefore, use of long-term myringotomy
tubes initially may be warranted in this special group of patients who may
retain a lifetime risk for recurrent infections.
DIAGNOSTIC EVALUATION OF MITOCHONDRIAL DISEASE
None of the 40 patients with mitochondrial disease we studied had fewer
than 3 separate organ systems affected (data not shown). When a history of
neurometabolic setbacks with infection and the involvement of 3 or more organ
systems are noted and not otherwise explained by a patient's referring diagnosis,
the otolaryngologist is justified in raising the question of mitochondrial
disease. If neurometabolic consultation is immediately available, then secondary
referral is appropriate. If specialty consultation is not immediately available,
several baseline studies may be ordered to provide the neurometabolic specialist
with useful information that may accelerate the diagnostic process.
A CHECKLIST OF BASIC STUDIES
The following 7 diagnostic studies are considered fundamental in evaluation
of any suspected mitochondrial disease: (1) polymerase chain reaction and
Southern blot analyses of blood samples for mitochondrial DNA; (2) testing
of blood and cerebrospinal fluid for lactate and pyruvate; (3) gas chromatography–mass
spectroscopy analysis of urine for organic acids; (4) testing of plasma and
urine for amino acids; (5) testing of blood and urine for carnitine; (6) magnetic
resonance imaging of the brain, with or without magnetic resonance spectroscopy;
and (7) open muscle biopsy. Open muscle biopsy (with specimens sent for neuropathologic
examination, electron microscopy, mitochondrial respiratory chain analysis,
fresh mitochondrial polarography, and polymerase chain reaction and Southern
blot analyses of muscle mtDNA) is often required for definitive diagnosis,
if the mitochondrial DNA studies from blood have proven nondiagnostic. However,
a muscle biopsy for mitochondrial disease diagnosis is sufficiently specialized
that it is advisable for this last element of the mitochondrial disease workup
to be managed in consultation with a neurometabolic specialist.
CONCLUSIONS
Patients with mitochondrial diseases may present with symptoms that
result in referral to an otolaryngologist before a definitive diagnosis of
respiratory chain disease has been established. The history of neuromuscular
setbacks associated with infection and the presence of dysfunction in 3 or
more organ systems are clues that mitochondrial disease may be the cause of
the patient's otolaryngologic symptoms.
Auditory dysfunction was found in 80% of patients with mitochondrial
disease and lactic acidemia in this study, whereas only 3 of 40 patients reported
hearing loss to be the presenting symptom leading to diagnosis. Objective
auditory dysfunction was the single most common clinical abnormality found
in this series of patients with mitochondrial disease.
Mitochondrial disease was episodic, with periods of stasis or slow developmental
progress, punctuated by neurodegenerative events in 60% of patients. Intercurrent
infection was recognized as a precipitant of these neurodegenerative events
in 72% of patients. The mechanistic basis of this is not understood at the
present time. Infections should be managed aggressively in this metabolically
fragile group of patients.
AUTHOR INFORMATION
Accepted for publication September 19, 2001.
This study was supported in part by grants from the Lennox Foundation,
the University of California–San Diego Foundation Christini Fund, the
Scott Pawlowski Mitochondrial Research Fund (Chicago, Ill), the Tyler Riff
Ferguson Mitochondrial Research Fund (Lake Charles, La), and grant M01 RR00827
from the National Institutes of Health, Bethesda, Md (University of California–San
Diego General Clinical Research Center).
Corresponding author and reprints: Robert K. Naviaux, MD, PhD, The
Mitochondrial and Metabolic Disease Center, University of California–San
Diego School of Medicine, 200 W Arbor Dr, San Diego, CA 92103-8467 (e-mail: naviaux{at}ucsd.edu).
From the Departments of Otolaryngology, Children's Hospital, San Diego,
Calif (Drs Edmonds and Kearns); University of Kansas Medical Center, Kansas
City (Dr Kirse); and the Departments of Family and Preventive Medicine (Dr
Deutsch), Pediatrics (Dr Spruijt), and Medicine (Dr Naviaux), University of
California–San Diego. Dr Edmonds is now with the Department of Otolaryngology,
Texas Children's Hospital, Houston; Dr Spruijt is now with the Department
of Clinical Genetics, Academic Hospital, Maastricht, the Netherlands.
REFERENCES
1. Naviaux RK, McGowan KA. Organismal effects of mitochondrial dysfunction. Hum Reprod. 2000;15(suppl 2):44-56.
2. Naviaux RK. Mitochondrial DNA disorders. Eur J Pediatr. 2000;159(suppl):S219-S226.
|
