Case Report
Am J Nephrol 1998;18:551–556

Fumio Kurogouchi a
Tomomasa Oguchi a
Eiichirou Mawatari a
Shuichi Yamaura a
Kazuhiko Hora a
Manabu Takei a
Yoshiki Sekijima b
Shu-ichi Ikeda b
Kendo Kiyosawa a
a Second and
b Third Department of Internal Medicine,

Received: September 29, 1997
Accepted: November 17, 1997

A Case of Mitochondrial Cytopathy
with a Typical Point Mutation
for MELAS, Presenting with
Severe Focal-Segmental
Glomerulosclerosis as Main
Clinical Manifestation

Shinshu University School of Medicine,
Matsumoto, Japan

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Key Words
Mitochondrial cytopathy
Mitochondrial encephalomyopathy
Mitochondrial cardiomyopathy
Focal-segmental glomerulosclerosis
Ragged-red fibers
Hypertrophic cardiomyopathy

Abstract
A 27-year-old female with short stature and mild hearing loss was diagnosed as
having focal-segmental glomerulosclerosis by renal biopsy at our hospital. One
year later she developed progressive renal dysfunction and cardiac failure and
was admitted again to our hospital for evaluation. Though her only neurological disorder was mild hearing loss, her short stature and elevated lactate and
pyruvate values in cerebrospinal fluid suggested mitochondrial cytopathy. A
muscle biopsy specimen of the left biceps brachii, using modified Gomori
trichrome stain, showed a typical image of ragged-red fibers, and an increased
number of giant mitochondria with paracrystalline inclusions were visible by
electron microscopy. Mitochondrial DNA from the skeletal muscle showed an
A-to-G transition at 3243 of transfer RNALeu(UUR), the common point mutation for mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. These data confirmed the diagnosis of atypical mitochondrial
cytopathy with renal and heart involvement. Mitochondrial cytopathies are
often associated with hypertrophic cardiomyopathy but rarely with renal disease. Among the few reported cases with associated renal disease, most
included renal tubular disorders; few cases with focal glomerular sclerosis are
known. The present case of atypical mitochondrial cytopathy was characterized by a unique clinical course and rare complications with focal-segmental
glomerulosclerosis.
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Mitochondrial encephalomyopathies are clinically divided into three distinct subgroups: (1) cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stro-

ABC

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kelike episodes (MELAS); (2) cases of myoclonus epilepsy
associated with ragged-red fibers, and (3) cases of chronic
progressive external ophthalmoplegia (CPEO), including
Kearns-Sayre syndrome [1–3].

Fumio Kurogouchi, MD
2nd Department of Internal Medicine
Shinshu University School of Medicine
3-1-1 Asahi, Matsumoto, Nagano-ken, 390 (Japan)
Tel. +81 263 32 2632, Fax +81 263 32 9412

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Introduction

Fig. 1. Light microscopic findings of the
renal biopsy specimen obtained in September 1995, showing global sclerosis in 10 of 12
glomeruli in the kidney tissue specimen and
FSGS in 1 of the other 2 glomeruli. Severe
tubular atrophy, interstitial fibrosis, and
mononuclear cell infiltration were also observed. PAM. !50.

552

Am J Nephrol 1998;18:551–556

Case Report
A 27-year-old woman was referred to our hospital in June 1995
for further examination of proteinuria accompanied by progressive
peripheral edema and common-cold-like symptoms. As a child the
patient had no outstanding health problems until the age of 3, at
which time it first appeared that her growth might be stunted. She
undertook further examinations on her stature at a hospital, but no
specific abnormalities were detected. At around the age of 18, she
began to develop mild hearing loss, for which several institutes made
complete examinations and concluded only that she had a sensorineural hearing loss of unknown etiology. During a routine high
school checkup the same year, she was also found to have proteinuria. Intermittent peripheral edema followed, but the patient pursued no further examination or treatment. No specific hereditary disorders were known in her family’s medical history.
Upon admittance to our hospital, the patient was well oriented
and alert and showed no signs of mental retardation. Pitting edema
of especially the bilateral lower limbs was noted. Head, neck, skin,
chest, and abdomen were normal. Neurologically, no abnormalities
were found except for a bilateral sensorineural hearing loss. Hematological analysis showed mild anemia: red blood cell count 410 ! 104/
Ìl, hematocrit 35.8%, and hemoglobin 12.5 g/dl. Blood chemical and
serological analyses revealed normal values of renal function, liver
function, and electrolytes. Urinalysis revealed ++ proteinuria (24hour urinary excretion of protein 2 g), + hematuria, (1–2 erythrocytes
and some hyaline casts per high-power field in the sediments), and
otherwise normal findings. A chest radiograph showed mild cardiomegaly (a cardiothoracic ratio of 50%) without pulmonary congestion and pleural effusion. Light microscopic examination of a
renal biopsy specimen performed in September 1995 showed global
sclerosis in 10 of 12 glumeruli of the kidney tissue as well as segmental sclerosis in 1 of the other 2 glomeruli and severe tubular atrophy,

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Recent studies have revealed mutations in the mitochondrial DNA of patients with these diseases. A large
deletion ranging from 1 to 8 kbp has been shown in
CPEO, including Kearns-Sayre syndrome [4, 5]; a single
point mutation at 8344 in tRNALys(UUR) has been shown
in the tRNALys(UUR) gene in myoclonus epilepsy associated with ragged-red fibers [6, 7], and an A-to-G transition
has been shown at 3243 in tRNALeu(UUR) in MELAS
[8, 9].
It remains uncertain, however, whether these mutations are specific to the diseases in which they were discovered. Inui et al. [10] detected an A-to-G tansition at
3243 in tRNALeu(UUR), a common point mutation for
MELAS, in some MELAS patients with atypical and
unclassifiable clinical symptoms. Mitochondrial cytopathies are, therefore, regarded as a heterogeneous group of
multisystem disorders involving many organs [11].
We present an extremely rare case of mitochondrial
cytopathy with a common point mutation for MELAS.
The patient had severe renal dysfunction due to focal-segmental glomerulosclerosis (FSGS) and severe heart failure
with a diffusely hypertrophic left ventricular wall, but
manifested no neurological abnormalities other than mild
hearing loss.

Fig. 2. T1-weighted MRI of the heart,
demonstrating diffusely hypertrophied left
ventricular wall and papillary muscle.

interstitial fibrosis, and mononuclear cell infiltration. Immunohistochemical examination revealed focal-segmental deposits of immunoglobulin M. These findings indicated a definite diagnosis of advanced FSGS (fig. 1). Electron microscopic examination demonstrated normal renal tubules and blood capillaries in the kidney. Glomeruli and vascular smooth muscle cells could not be examined electron microscopically. The patient was discharged upon disappearance of edema in September 1995.
Seven months later, peripheral edema, general fatigue, and dyspnea appeared, following common-cold-like symptoms; body weight
gain, progressive cardiomegaly, and massive pleural effusion led to
her second hospitalization in December 1996. On admission, the
patient was well oriented and alert. Her body height was 143 cm, and
her weight 34 kg, and her vital signs were as follows: blood pressure
150/76 mm Hg, heart rate 120 beats/min, body temperature 37.2 ° C,
and the respiration rate 13/min. On physical examination, hypoactive breathing was audible over her lower lungs, a systolic murmur of
3/6 grade at her left sternal border, and an increased S2 sound and S3
gallop at the apex. An abdominal examination showed only hepatomegaly, and her extremities were covered with a massive pitting
edema. Hematological findings showed mild anemia (red blood cells
341 ! 104/mm3, hemoglobin 10.8 g/dl, hematocrit 31.5%). Blood
chemical analysis revealed renal dysfunction (blood urea nitrogen
46 mg/dl, serum creatinine 4.2 mg/dl) but otherwise normal findings.
Serum lactate and pyruvate values were within normal limits. No
other abnormalities were found. A cerebral spinal fluid examination
showed substantial increases in the values for lactate and pyruvate; to
35 and 1.5 mg/dl, respectively. Echocardiography detected severe left
ventricular systolic dysfunction (ejection fraction 20%) with diffuse
hypertrophy of the left ventricular wall. Magnetic resonance imaging
(MRI) of the heart showed diffuse hypertrophy of the left ventricular
wall and papillary muscle with high intensity on both T1- and T2weighted images (fig. 2). Due to the poor general health of the

patient, cardiac muscle biopsy was not performed. MRI of the brain
demonstrated diffusely atrophic cerebral and cerebellar cortices and
enlargement of the ventricles. No other abnormal intensities were
noted.
In view of these data, the most likely diagnosis was mitochondrial
cytopathy, with a resemblance to MELAS. A muscle biopsy specimen
of the left biceps brachii showed moderate variation in fiber size and
typical ragged-red fibers by modified Gomori-trichrome staining
(fig. 3); NADH staining of the muscle gave specific evidence of mitochondrial abnormalities. Electron microscopic examination of the
biceps brachii showed numerous enlarged abnormal mitochondria
containing extremely proliferated cristae and paracrystalline inclusions (fig. 4).
The DNA samples extracted from leukocytes and muscle were
analyzed for the point mutation associated with MELAS. Amplified
DNA fragments encompassing that mutation site were digested with
endonuclease Apa I using polymerase chain reaction. Primers 1 and 2
were dTTCACAAAGCGCCTTCCCCC for nucleotides 3153–3172
and dGCGATGGTGAGAGCTAAGGTC for nucleotides 3551–
3531, respectively [9]. The restriction enzyme analysis of amplified
mitochondrial DNA disclosed a mutant at nucleotide 3243 in the
transfer RNALEU(UUR) gene.
These results confirmed the diagnosis of an atypical case of mitochondrial encephalomyopathy having the common point mutation
for MELAS.

Mitochondrial Cytopathy with FGS

Am J Nephrol 1998;18:551–556

Discussion
It has been reported that each type of mitochondrial
encephalopathy has several mitochondrial DNA mutations [1–9]. However, it is uncertain whether these muta-

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553

Fig. 3. Frozen sections from the biceps brachii muscle specimen, demonstrating a moderate variation in fiber size.
Modified Gomori-trichrome staining shows numerous ragged-red fibers and scattered pathological fibers with mitochondrial clusters. No necrotic or regenerative fibers are visible. !200.

Fig. 4. Electron microscopic visualization of a specimen from biceps brachii, revealing some structural abnormalities of mitochondria, including numerous enlarged
abnormal mitochondria containing extremely increased cristae and paracrystalline inclusions. Mitochondria with parallel arrays
of cristae arranged in a circular fashion are
also found. !1,700.

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tions are specific for each type. Goto et al. [8] reported
that an A-to-G transition at 3243 in the tRNALeu(UUR)
gene mutation was detected in 84% of the patients with
MELAS and in 3.4% of the cases with CPEO, suggesting
that this mutation may cause clinical symptoms other
than MELAS. Furthermore, Inui et al. [10] detected the
same mutation of tRNA in some patients with atypical
clinical symptoms that were not indicative of any known
diseases. But the relationships between each of these
mutations and the various organ disorders have yet to be
determined.
The single quantitative alteration in the genotype, an
A-to-G transition at position 3243 in the tRNALeu(UUR)
gene, is pleitropic, causing a number of small but distinct
effects, each of which contributes in a quantitative way to
the overall reduction in mitochondrial function, including
respiratory chain [12]. But, the exact molecular mechanism by which the clinical distinction of MELAS occurs
has not been established. In this patient, except for the
existence of the point mutation described above and the
normal findings of the karyotype, neither the qualitative
and quantitative changes of proteins in mitochondria,
including respiratory chain, nor mitochondrial and genomic DNA could be investigated.
The present case showed prominent clinical manifestations of chronic renal failure due to FSGS and chronic
heart failure due to hypertrophic cardiomyopathy
(HCM). Clinically, the only other symptoms were mild
hearing loss and short stature without any other neurological or muscular insufficiencies.
With regard to diagnosis, these symptoms and test
findings were not indicative of any of the major clinical
categories of mitochondrial encephalomyopathy. However, the ragged-red fibers of the skeletal muscles and the
A-to-G transition of tRNALeu(UUR) at 3243 suggested a
diagnosis of atypical mitochondrial encephalomyopathy
presenting with cardiac failure with HCM and severe
renal failure as the main symptoms.
In a report by Anan et al. [13], 2 out of 3 patients with
MELAS exhibited symmetric left ventricular hypertrophy. Obayashi et al. [14] detected an A-to-G transition at
position 3243 in the tRNALeu(UUR) gene in 2 out of 6
patients with nonautosomal dominant HCM, suggesting a
close relationship between this point mutation and nonautosomal dominant HCM. Thus this point mutation has
been known to have close causal relations to HCM as well
as to MELAS.
In the present case as well, there was an A-to-G transition at position 3243 in tRNALeu(UUR) in association with
cardiomyopathy showing diffuse hypertrophic left ven-

tricular papillar muscle and wall on echocardiography
and MRI of the heart. Furthermore, MRI findings of the
heart demonstrated specifically a high intensity on both
T1- and T2-weighted images. Though many reports have
shown HCM accompanied by mitochondrial disease, the
present characteristics of the left ventricular wall, as
shown on the MRI, have not been reported. This unique
intensity on MRI might result from the contents of the
cardiac muscle, and specifically from the striking accumulation of lipids in the cardiac muscle. Because mitochondria play an active role in certain portions of lipid metabolism, mitochondrial dysfunction could result in lipid
accumulation, as reported [15]. Therefore, these MRI
findings might support the diagnosis of secondary HCM
due to mitochondrial disease.
Renal involvements in mitochondrial encephalomyopathies have been reported in 21 patients [10, 16, 17]; the
renal disease consisted of some form of tubular dysfunction, including Fanconi syndrome and renal tubular acidosis, in 8 cases [18, 19] and nephrotic syndrome in 4;
renal dysfunction with proteinuria of unknown etiology
and FSGS were observed in 6 and 3 patients, respectively.
The age at onset ranged from 4 weeks to 37 years, with
only 2 cases older than 20 years, as the present case [16].
Only 3 cases of mitochondrial cytopathy complicated by
FSGS have ever been reported to the best of our knowledge. All 3 cases were clinically diagnosed as having
MELAS, and in 2 of them an A-to-G transition at 3243 in
tRNALeu(UUR) was confirmed [10, 15, 17].
Sakuta and Nonaka [20] showed that mitochondrial
cytopathies, including MELAS, show striking abnormalities in blood vessels due to marked accumulation of giant
mitochondria, and that these abnormalities might decrease the blood supply. Ban et al. [15] reported on a case
of MELAS with FSGS and showed that the smooth muscle cells of the arterial capillaries in the kidneys were filled
with increased numbers of enlarged mitochondria and
cristae. Thus, these vascular changes in the kidneys might
lead to renal hemodynamic insufficiency and might result
in FSGS [21]. The relation between FSGS and the mitochondrial disorders might be explained by the mitochondrial abnormalities in the vascular smooth muscle cells in
the kidney. Although no mitochondrial abnormalities
were found in the kidneys in the present case, our examination was limited by an insufficiency of glumeruli and
capillaries in the biopsy specimens, and this matter
should be investigated further in the future.
Some primary HCMs without any other complications
have been revealed to have specific mitochondrial DNA
abnormality [14]; however, there have been no reports

Mitochondrial Cytopathy with FGS

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concerning the relationship between mitochondrial abnormality and primary renal diseases. We do not conclude that FSGS in this patient was caused by mitochondrial abnormality. But considering the small size of the
renal biopsy specimen in this case, the extremely rare
complication of FSGS with mitochondrial cytopathy
seems to indicate a close relation between mitochondrial
abnormality and FSGS and furthermore between the Ato-G transition at 3243 in tRNALeu(UUR) and FSGS. For
this reason, patients with renal disease involving FSGS
should be carefully examined for possible mitochondrial

diseases, even when none of the neurological manifestations characteristic of mitochondrial cytopathy are
present.
In summary, we have reported a case of atypical progressing mitochondrial cytopathy with HCM and FSGS,
in association with no neurological abnormalities other
than mild hearing loss. Though the association between
FSGS and MELAS or the A-to-G transition at 3243 in
tRNALeu(UUR) still remains obscure, this case suggests the
close causal relation among them. To clarify this matter,
further investigations should be done in the future.

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