Acute Renal Failure and the MELAS Syndrome, a ... - Semantic Scholar

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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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ACKNOWLEDGMENTS providing

16:904-9

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.

15.

17. We

Res

131-136.

1990;1

2W

12.

the

mitochondrial Pediatr

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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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