disorders may be more susceptible to renal hypoxic. Injury and acute renal failure. Key Words: MELAS, acute renal failure, mitochondrial en- cephalomyopathies.
EDITORIAL Tomas
Berl, EdItor
Denver,
William
Henrich
Mark
Toledo,
OH
Minneapolis,
CO
BROWN Initiated
UNIVERSITY
in 1966, the nephrology
by a second medicine laboratory
year primarily
training
devoted
The Renal
Division
Paller
DIVISION
program
at Brown
to research.
and/or primary nephrology research or for a combined
both subspecialties. fellows each year.
COMMIT1’EE Fred MN
CIty,
OK
OF RENAL DISEASES
University
The program
consists
is designed
of a first year
to prepare
care. Trainees clinical/research
interested in additional year in critical care
includes
full-time
seven
Silva
Oklahoma
of clinical
fellows
training may and nephrology
and nine voluntary
faculty
training followed in academic for a third year of confers eligibility in
for careers apply that
members
and recruits
three
The clinical experience covers all aspects of clinical nephrology, including patient consultation, outpatient nephrology. hemodialysis, peritoneal dialysis, hemofiltratlon, vascular access, hypertension, fluid and electrolyte disorders, and renal transplantation. Trainees rotate at The Rhode Island and Miriam hospitals and also see patients in outpatient dialysis
week
facilities.
in which
students
taking
Major
areas
hypertension, renal effects regulation.
has an extensive
take
nephrology
electives.
of
research
diabetic of diet ion
laboratories
The Division
the fellows
include
and
are equipped
assay;
a dedicated
and
the fellowship
the
transport
for a wide
determination; micropuncture; ELISA; radloimmunoassays,
protection
role.
program
Fellows
for trainees
also teach
progression
of
renal
and
and clinic
program
properties
range
along
the
of techniques,
isolated perfused tubule; receptor assays; cell
PCR; and gel-shift research
Acute Renal Mitochondrial
disease,
Including
full-time
research
is J. Gary Abuelo,
and
Lance
School
Nephrol.
1996;
of Medicine,
Providence,
the
(mitochondrial
November
2 Correspondence
encephalomyopathy
October
21, 1994. Accepted to Dr. L Dworkin,
Hospital, 593 Eddy Street, 1046.6673/0705.0647$03.00/0 Journal of the American
Providence, society
with
lac-
Division
19. 1995.
of Renal Diseases, The Rhode
RI 02806.
of Nephrology
Copyright C 1996 by the American society
of Nephrology
Journal
of Nephrology
of the
American
regulation
whole-animal
conferences
in hypertension
of the division
Society
and
experimental and receptors,
cell
volume pH.
ultrasonic
morphometric and Western
per
residents
of intracellular
physiology;
program
The director
The
blood
flow
image analysis;
analysis; RNase
and renal
disease
is Lance
D. Dworkin,
MD,
MD.
a
syndrome
who
Island
subsequently
developed
acute
renal failure is reported. Although no clear renal insult was evident at the time, the clinical picture was consistent with the diagnosis of acute tubular necrosis. The patient’s
7:647-652)
tic acidosls and stroke-like episodes) is one of a group of heterogeneous yet clinically distinct syndromes ascribed to a defect in mitochondrial function. Here, the case of a patient diagnosed with the 1 Received
to five
of Brown
Dworkin2
ABSTRACT MELAS
and
research
coordinator.
Division of Renal Diseases, The Rhode Island Hospital
University
Soc.
four
hemodynamics.
intracellular Ion fluorescence; culture; Northern, Southern,
assay. There is also a clinical
and
director
Gohh,
F. Hsieh, P. Gohh, L. Dworkin, Department of Medicine,
(J. Am.
glomerular
nephron.
MELAS
Brown
includes
the activities
Failure and the MELAS Syndrome, Encephalomyopathy1
Fred Hsieh, Reginald
and RI
that
direct
nephropathy, molecular control of renal growth and injury repair, growth factors and antihypertensive agents, molecular determinants of cardiac hypertrophy,
exchange
with
didactic
an active
renal
function
subsequently
returned
to baseline. This article reviews the literature concerning renal Involvement in the mitochondrial encephalomyopathies, including MELAS, and proposes a mechanism by which patients suffering from mitochondrial disorders may be more susceptible to renal
hypoxic
Injury
and
Key Words:
acute
MELAS, cephalomyopathies
O human been drial
tance.
ver the function
acute
past have
renal
decade, increasingly
disease. Many ascribed to specific genome and share
Diseases
renal
related
failure. failure,
defects
in
been
of
these mutations a maternal to
mitochondrial
lesions
mitochondrial associated
diseases in the pattern of
en-
with
have now mitochonof inheri-
mitochondrial 647
Acute
Penal
Failure
and the MELAS Syndrome
DNA (mtDNA) can be divided into two groups: pure encephalopathies with no gross morphological muscle abnormalities, and mitochondrial encephalomyopathies that are associated with ragged-red muscle fibers. The latter group of mitochondrial encephalomyopathies encompasses a diverse group of distinct clinical syndromes with characteristic signs and
hancement. This was felt to be consistent with encephalitis. A lumbar puncture revealed clear cerebrospinal fluid with no nucleated cells, no red blood cells, 65 mg/dL ofprotein, and 153 mg/dL ofglucose. Rapid plasma reagin, Lyme, and viral antibody titers were negative. During this time, the patient remained awake, alert, agitated, and vocal but noncommunica-
symptoms. These include myoclonic epilepsy with ragged-red fibers (MERRF), Kearns-Sayre Syndrome (KSS), and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) (1). Renal involvement in patients with mitochondrial encephalomyopathies has been demonstrated by dinical symptomatology, biopsy, and molecular genetic studies. In this paper, we report a case of acute nonoliguric renal failure in a patient with the MELAS syndrome. We review the literature concerning renal involvement in patients with biopsy-proven mitochondrial disorders and propose a mechanism by which these patients may be more susceptible to renal failure as a result of their mitochondrial disease.
tive.
CASE The
REPORT patient
is a 46-yr-old
white
female
admitted
The Hospital The lesion. biopsy
patient
Course underwent
A detailed morphologic has been presented
a brain
biopsy
of her
description elsewhere
cortical
of the brain (E. Stopa,
manuscript submitted). Electron microscopy revealed bizarre, enlarged mitochondria with irregular abnorma! cristae-findings consistent with but not specific for a mitochondrial disorder (Figure 1 ). However, molecular analysis of the brain biopsy revealed that 80% of the mitochondria had the typical genetic mutation associated with MELAS. (J. Gilchrist, personal cornmunication; see Discussion). The serum lactate level ranged between 3. 1 and 4.8 mEq/L on repeated measurements and a diagnosis of MELAS syndrome (mi-
to
the hospital for an acute deterioration in mental status. Nine months before admission, she had two tonic-clonic seizures. Work-up at that time included a magnetic-resonance imaging study of the brain with gadolinium which showed a nonenhancing right temporal lobe lesion consistent with a cerebrovascular accident. The patient did well until 1 wk before admission, when she developed hallucinations and garbled speech. On the day of admission, she was unable to obey commands or answer questions. She had a past medical history of type II diabetes mellitus since age 29, and was now insulin-dependent, with peripheral neuropathy and enteropathy. There was a history of cognitive delays, mild mental retardation, cardiac dysrhythmias, and bilateral sensorineural deafness. Her medications included pheny-
toin On woman
and insulin. examination, with short
the stature.
patient She
was a was alert
thin but
white would
not interact was rate mal
with the examiner. Her blood pressure 150/90 mm Hg, pulse 96 beats/min, respiratory 18 breaths/mm, and temperature 99#{176}F.Abnorfindings were limited to the neurological exam.
She had increased motor tone throughout and an asymmetric Achilles tendon reflex, 2+ on the right and trace on the left. She moved all four extremities without difficulty and withdrew all four extremities to pain. Laboratory studies on admission included a BUN concentration of 1 1 mg/dL, creatinine concentration of 0.9 mg/dL, and glucose level of 386 mg/dL. Further workup included an electroencephalogram that was negative for epileptiform activity. A magnetic resonance imaging study with gadolinium showed a cortical lesion involving the left temporal, parietal, and occipital
648
lobes,
with
patchy,
ill-defined
contrast
en-
Figure 1 . Ultrastructural findings on brain biopsy. This photomicrograph Is remarkable for bizarre, enlarged mitochondna with Irregular, abnormal concentric cristae (original magnification, x55,000).
Volume
7
‘
Number
5
‘
1996
Hsieh
tochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) was made. During the next month, the patient underwent an exploratory laparotomy for a suspected perforated viscus, experienced fluctuating glucose values, had intermittent vomiting and poor food intake by mouth
requiring
(eventually trostomy
tube
percutaneous
placement
for
developed an Escherichta which was treated with During this time period, remained stable.
endoscopic
enteral
feedings),
colt urinary iv ampicillin however, her
tract for renal
gasand
infection, 10 days. function
system. The liver, endocrine glands, and kidney are less often affected. Clinical distinctions between three of the major syndromes are listed in Table 1 . Diagnosis can now be made at a genetic level as well; an A to G point mutation in the tRNALeu gene at nucleotide 3243 has been described in patients with MELAS. Approximately 80% of MELAS patients have been found to have this mutation (3). MELAS mutations can now be detected by molecular analysis of peripheral blood samples (4). Patients affected by mitochondrial encephalomyopathies have both normal and mutant mitochon-
On hospital Day 66, the patient was noted to have a heart rate of 100 bpm, a blood pressure of 92 I 62 mm Hg, BUN concentration of 37 mg/dL, a creatinine concentration of 1 .6 mg/dL and an elevated anion gap
drial DNA heteroplasmy,
of 22 mEq/L (from 13 mEq/L 1 day previously). patient had a baseline blood pressure of 120/70 Hg. She was believed to be volume-depleted and
ment, assort In the
The mm was
given iv fluid therapy with normal saline. Despite this treatment, she became oliguric (200 mL urine output over 24 h) and her serum creatinmne concentration progressively rose to a value of 4.0 mg/dL after 48 h. Urinalysis showed a specific gravity of 1 .005, pH of 6.0, trace protein, and no blood by dipstick, with 0 to 2 red blood cells, 0 to 5 white blood cells, no red blood cell casts, and occasional tubular epithelial cells by microscopic examination. Repeat urinalysis was unchanged. Urine electrolyte studies revealed a urine sodium level of 1 13 mEq/L, urine chloride level of 99 mEq/L, and urine osmolality of 264 mosmol. The serum osmolality was 293 mosmol. As the patient’s creatinine level continued to rise, she developed a progressive metabolic acidosis. On hospital Day 69, her BUN concentration was 62 mgI dL, her creatinine concentration was 4.7 mg/dL, and serum CO2 level was 15 mEq/L, which eventually fell to 1 1 mEq/L. The serum lactate level was 3.9 mEq/L. Therapy with iv bicarbonate was initiated. The patient’s serum creatinine concentration peaked at 5.4 mg/dL 4 days after the initial increase was noted, with a BUN concentration of 71 mg/dL. Additional studies revealed a serum eosinophil percentage of4%, no urine eosinophils, and no skin rash. Subsequently, the patient’s urine output increased to 4.3 L over a 24-h period and then diminished to 1 to 2 L I day. The acidosis improved once renal function returned stopped. fallen to
to normal and bicarbonate therapy The patient’s creatinine concentration 1 . 1 mgldL by the time she was discharged.
was had
DISCUSSION Great heterogeneity mitochondrial diseases,
exists in the but they can
presentation be classified
distinct syndromes. Mitochondrial diseases tisystemic and most commonly affect the the muscle, hence the term encephalomyopathy. ertheless, other organs can be affected as commonly
Journal
the
of the
heart,
American
pancreas,
Society
and
of Nephroiogy
are brain well,
hematopoietic
of into muland Nevmost
et al
ease can mitochondrial
coexisting and variably DNA
in all explains
tissues. This is how mitochondrial
termed dis-
affect many organ systems. If mutation occurs early in develop-
then mitochondria with randomly among daughter process of development,
mutated cells different
a
genomes will during mitosis. cells acquire
varying numbers of mutated and wild-type mtDNA. Cells containing a higher ratio of mutant-to-wild-type mitochondrial genomes will be more likely to show significant clinical dysfunction, particularly in those tissues with high demands for oxidative energy (5). In addition, it has been proposed that tissues with a high mitotic index, such as hematopoietic cells, are able to select against heteroplasmic cells over the course of many generations of cell division, so that the ratio of mutant to normal mitochondria decreases with age. This explains the spontaneous resolution of anemia seen in patients with long-standing mitochondrial disease (6). On the other hand, in tissues with little mitotic activity, including brain and muscle, the ratio of mutant to normal mitochondria will increase with age, which accounts for the later onset of progressive neuromuscular dysfunction (7). The mechanism for selection favoring mtDNA with deletion is unclear, but might be related to an increased mitochondrial proliferation in response to deficient energy production (8). UltImately, the clinical involvement of any
given
organ
will
depend
on at least
percentage ofabnonnal mitochondria ment of that organ for functioning the relative demand on oxidative each individual patient, different
two
factors:
the
and the requiremitochondria (I.e., metabolism) (5). For organ systems will
be
affected to varying degrees. Another interesting feature of these diseases is that both mitochondrial division and mtDNA replication are random processes unconnected to the cell cycle, resulting in mitotic segregation of mtDNA (9). It is for this reason that the proportion of mutant mtDNA can vary both in space (e.g. , different tissues) and in time in heteroplasmic patients. As such, patients may each present with entirely different constellations of symptoms over their lifetimes. Kidney involvement in mitochondrial encephalomyopathies, although infrequent and usually late in the course of disease, has been well-documented. The most commonly observed abnormality is renal tubular dysfunction, which has been associated with a wide
649
Acute
Penal
TABLE
1.
Failure
and the MELAS Syndrome
Mitochondrial
encephalomyopathiesa DistInguIshing
Disorder Kearns-Sayre
Syndrome
Myoclonic
Epilepsy
Ragged-red
Fibers
Previous Reports
Symptoms
Onset before age 20 Opthalmoplegia Retinal degeneration Heart block CSF protein >100 mg/dl Myoclonus
(KSS)
with (MERRF)
of Renal
Involvement
ChronIc renal failure (4), Fanconl’s syndrome (4,5,6), renal Tubular acldosls (7), Bartter’s syndrome (8), Acute nonollgurlc renal failure (6) None reported
Ataxla
Weakness Seizures Mitochondrial
Encephalomyopathy,
Seizures
Lactic Acidosis, and Stroke-like Episodes (MELAS)
Cortical
Symptoms
Common
Proteinurla
Repeated stroke-like episodes neuralogic deficits Hemlparesls, hemlanopsia Cognitive regression Episodic vomiting blindness
Sensorlneural Dementia
to All
Short
(9,10,11)
with
hearing
loss
stature
Weakness Lactic acidosis Ragged-red muscle fibers on biopsy Spongy degeneration of the brain a Data
from Reference
modified
1.
variety of mitochondrial disorders. These include the Kearns-Sayre syndrome ( 10, 1 1), mitochondrial myopathy (12), and Pearson’s syndrome (13), all of which usually present in early childhood. Occasionally, patients may first present with renal abnormalities, including the de Toni-Fanconi-Debre syndrome (12, 13), renal tubular acidosis (10), and defects mimicking Bartter’s syndrome (1 2). Details of the biopsyproven renal findings in patients with mitochondrial pa-
Our patient had the MELAS syndrome and a cornplex hospitalization complicated by acute renal failure. She developed transient oliguria that was unresponsive to the administration of fluids, and a progressive increase in serum creatinine concentration that peaked after 4 days, followed by a vigorous diuresis. Within 10 days, her creatinine level had almost returned almost to baseline. Her clinical course and laboratory studies are most consistent with a diagnosis ofacute tubular necrosis. Notably, no obvious inciting event was identified.
Postmortem study of one patient revealed global gbmerubosclerosis and interstitial fibrosis consistent with an end-stage kidney (14). Biopsy-proven focal gb omeruboscierosis was found in the other two pa-
Hypoxic injury results when energy supply and substrate provision are inadequate to serve a tissue’s metabolic demands (1 9). Although renal blood flow is extremely high, the unique countercurrent anatomical structure of the renal medulla makes it particularly susceptible to ischemic injury. Previous studies
encephalomyopathies Kidney involvement
tients
with
proteinuria
the has
are has
found also
in Table 2. been reported
MELAS syndrome. been noted in three
in
Nephrotic-range cases (14-16).
tients (15, 16). A pedigree study of three generations carrying the MELAS mutation demonstrated heteroplasmic mitochondria in the kidney. Polymerase chain reaction amplification and Southern analysis of DNA retrieved from the kidney of the deceased proband and from the proband’s deceased son revealed 60 to 63% of the mitochondria to be mutant ( 1 7). Acute nonoliguric renal failure has been observed in a patient with
have lesser
Kearns-Sayre isodes as
rest of
tient, tRNA
650
seen
syndrome, in MELAS.
however, did point mutation
who also Muscle
not yield (18).
had stroke-like biopsy of this
evidence
of
the
eppa-
MELAS
delineated extent,
as areas limit the
the thick ascending 53 portion of the
the
of the medulla in availability ofoxygen
which (20).
limbs proximal
structural On the other
the principal determinant of medullary quirement is the rate of active reabsorption thick ascending predictably, ten
limb, times
and higher
oxygen in this
consumption region than
the kidney (2 1). Thus, the combination delivery and high metabolic rate the renal tubules unusually susceptible
poxic
damage.
fact,
renal
tubular
Volume
factors hand,
oxygen along
oxygen make
In
and, to a tubules
rethe is, in the
of low serves to to hy-
involvement
7
.
Number
has
5
‘
1996
Hsieh
TABLE 2. Patients
with mitochondrial
Disorder Kearns-Sayre
disorders
Renal
Syndrome
Renal
(5,7,8)
who
underwent
Symptoms
tubular
renal
Renal
acidosis,
Extensive
hypocalcemla
biopsy
Biopsy
Findings
Ultrastructural
glomerulosclerosis
Enlarged
with
and mononuclear Infiltrate Hyaline casts In distal tubules;
syndrome
Interstitial
fibrosis
inflammatory periglomerular Banter’s
syndrome
Not
Findings
mitochondria
in
epithellum of convoluted tubules with abnormal
tubular atrophy; thick-walled vessels with intimal fibrous tissue
peripherally oriented crlstae Increased numbers of
proliferation
Fanconi’s
et al
and
abnormal
cell infiltrate; fibrosis
mitochondria
in proximal and tubular cells
reported
Increased
distal
number
of
mitochondria but no structural changes in proximal tubules; increased numbers of giant mitochondria with abnormal cristae in distal tubules Kearns-Sayre/Pearson’s
Syndrome
Partial
(4)
Fanconi’s
chronIc failure
syndrome,
nonoliguric
Irregular
renal
retraction
of the
Increased
number
glomerular tuft with dilatation of Bowman’s space; stripe-like atrophy of the medullary ray with
pleomorphic mitochondria disoriented
interstitial
proximal
fibrosis;
PAS-positive
of
with crlstae
in
tubules
fibrillar casts In atrophic tubules, immunofluorescence negative for immunoglobulins or complementa
Pearson’s Syndrome
(4)
Polyuria,
dilation with degenerative changes In tubular epithelium;
metabolic
acidosls,
Giant mitochondria proximal tubules
Tubular
Fanconi’s
syndrome
Immunofluorescence
negative
immunoglobulins,
in
for
complement,
or fibrin a
PAS, periodic
acid-Schlff.
been
demonstrated by both pathologic analysis and molecular genetic studies in mitochondrial encephalomyopathies (6, 10, 13,22). Pathologic studies have demonstrated dilated tubules in patients with MELAS (14, 15) and DNA studies of patients with MELAS have demonstrated the presence of mutated by
mitochondria
genomes
as
well
In our case, we presume patient were heteroplasmic genomes. might
not
however,
it seems
bined
with
mitochondrial
her
produce
might this
that the for mutant
The mild hypotension result in an ischemic
host; to
acute
have procedure
likely
tubular
provided did
more not
During across
Journal
metabolism
because
normal metabolism, the mitochondrial
of the
American
Society
kidneys of our mitochondrial
seen injury that
this
disease,
in
information, indicated
Defects
Q
reductase), complex chrome c reductase),
of
oxidase)
the
Under
reduced
biopsy
but for
in patients with and also noted in
of impairment in oxidaof defective mitochondria.
of Nephrology
chain.
is transported into the mito-
is then
contributes
into to the
in complex
I (NADH coenzyme
the
Krebs
electron
coenzyme Q-cyto-
IV (cytochrome
respiratory
c
chain
have
in patients with MELAS (23). impaired utilization of pyruvate excess NADH accumulates in
anaerobic
to lactate
shutfied electrons
III (reduced and complex
mitochondrial
cytosol.
com-
sufficient
A kidney
pyruvate membrane
transfer
CoA
then
factor,
definitive
seen
2) Acetyl which
been documented Because of the the Krebs cycle,
was
clinically
(Figure cycle,
to
undergo oxidative decarboxylation A (C0A) by pyruvate dehydrogenase
our patient in a healthy
necrosis. seem
this patient. Lactic acidosis, commonly mitochondrial encephalomyopathies this patient, is a consequence
tive
(17).
chondrion to acetyl coenzyine
conditions,
is then and one of ATP is produced. The one equivalent of hydrogen be buffered by extracellular
by lactate
stoichiometric hydrolysis ion, which
equivalent of ATP yields then must
bicarbonate.
Bicarbonate
in the
pyruvate
dehydrogenase
is consumed,
lactate
accu-
mulates, and lactic acidosis develops (24). In summary, the mitochondrial encephalomyopathies are a diverse group of clinical syndromes that present with multiple organ-system involvement, including the kidney. In some cases, kidney dysfunction can be the predominant symptom and patients with
651
Acute
Renal
Failure
and
the
Cytosol
MELAS
Syndrome
ius M: Progressive DNA fraction in
Mitochondrion
glucose NAD’ Glycolysis
1990;28:
NADH+H’
-p-
2 pyruvateh..
2 acetyl
C0A
PDH NADH
anaerobic conditions
+ H’
Lactate Dehydrogenase NAD’
2 lactate’
+
2ATP
+
3 NADH
2HOH
+
H’ and FADH,
ATP hydrolysis
2 lactate’
+
Figure
2. Pathway for lactate production in mitochondrial If pyruvate utilization by the mitochondrion is Imat the level of the electron transfer chain NADH + H will accumulate. NADH + H generated by pyruvate dehydrogenase (PDH) and by the Krebs Cycle cannot be oxidized properly to generate ATP. As a result, acetyl-CoA and disease. paired
NADH/NAD
Any
Increased
lactate, renal ni’s
ratio
demand
precipitating tubular syndrome
will
increase,
a lactic
acidosis, have
downregulating
for AlP will drive acidosis
may result from mitochondrial of the unique susceptibility hypoxia, the mitochondrial dispose patients to tubular drome of acute renal failure.
13.
PDH.
the formation
of 14.
(24).
Bartter’s syndrome, been described. Lactic
or Fancoacidosis
dysfunction. Because of the renal medulla to syndromes may also prenecrosis and the syn-
are
grateful
to
and
Drs.
Interpreting
the
Stopa electron
and
Michael
micrograph
Sikirica used
for in
this
18.
article.
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A, Tulin-
T, Sano T, Nakano 5, Matsuda H, Okada 5: mitral valve replacement for MELAS. Pediatr 1993;9:391-393.
Remes AM, Majamaa K, Herva R, Hassinen I: Adultonset diabetes mellitus and neurosensory hearing loss in maternal relatives of MELAS patients in a family with the tRNA Leu(UUR) mutation. Neurology 1993;43: 10 151020. Zupanc ML, Moraes CT, Shanske 5, Langman CB, Ciafaloni E, DiMauro 5: Deletion of mitochondrial DNA in patients with combined features of Kearns-Sayre and MELAS syndromes. Ann Neurol 1991;29:680-683. Gronow GHJ, Cohen JJ: Substrate support for renal function during hypoxia in the perfused rat kidney. Am J Physiol
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Brezis M, Rosen 5: Hypoxia of the renal medulla-its implications for disease. N Engi J Med 1995;332:647655. 2 1 . Brezis M, Rosen 5, Silva P, Epstein FH: Renal ischemia: A new perspective. Kidney mt 1984;26:375-383. 22. Mon K, Narahara K, Ninomiya 5, Goto Y, Nonaka Renal and skin involvement in a patient with complete Kearns-Sayre syndrome. Am J Med Genet 199 1;28:583-
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Yoneda M, Tanaka M, Nishikimi M: Pleotropic molecular defects in energy-transducing complexes in mitochondrial encephalomyopathy (MELAS). J Neurol Sci 1989;
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Van Bierviiet JBGM, Bruinvis L, Ketting D, deBrec PK, Van der Heiden C, Wadman 5K: Hereditary mitochondrial myopathy with lactic aciduria, a de Toni-FanconiDebre syndrome, and a defective respiratory chain in voluntary striated muscles. Pedlatr Res 1977; 11:10881090. Majander A, Suomalainen A, Vettenranta K, Sariola H, Perkkio M, Holmberg C, Pihko H: Congenital hypoplastic anemia, diabetes, and severe renal tubular dysfunction associated with a mitochondrial DNA deletion. Pediatr Res 1991;30:327-331. Ban SI, Mon N, Saito K, Mizukami K, Suzuki T, Shimislil H: An autopsy case of mitochondrial encephalomyopathy (MELAS) with special reference to extraneuromuscular abnormalities. Acta Pathol Jpn 1992;42: 818-824.
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17. We
Res
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2W
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8. Larsson NG, Holme E, Kristiansson B, Oldfors A, Tulinius M: Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome. Pediatr Res 1990;28: 131-136. 9. Schon EA, DiMauro 5: Mitochondrial diseases. Karger Gazette 1994;58:2-4. 10. Eviatar L, Shanske 5, Gauthier B, et at.: Kearns-Sayre syndrome presenting as renal tubular acidosis. Neurology 1990;40:1761-1763. 1 1 . Goto Y, Itami N, Kajii N, Tochimaru H, Endo M, Horal 5: Renal tubular involvement mimicking Bartter syndrome in a patient with Kearns-Sayre syndrome. J Pediatr
aerobic conditions
2 pyruvate
increase of the mutated Kearns-Sayre syndrome.
Koo B, Becker LE, Chuang 5, et at.: Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): Clinical, radiological, pathological, and genetic observations. Ann Neurol 1993;34:25-32. Stacpoole PW: Lactic acidosis. Endocrinol Metab Chin North
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Volume
7
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1996
