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A New Mitochondrial Point Mutation in the Transfer RNALeu Gene in a Patient With a Clinical Phenotype Resembling Kearns-Sayre Syndrome
Sara Seneca, PhD;
Helene Verhelst, MD;
Linda De Meirleir, MD, PhD;
Françoise Meire, MD, PhD;
Chantal Ceuterick-De Groote, PhD;
Willy Lissens, PhD;
Rudy Van Coster, MD, PhD
Arch Neurol. 2001;58:1113-1118.
ABSTRACT
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Objective To report on the molecular identification of a novel heteroplasmic G-to-A
transition at mitochondrial DNA position 3249 in transfer RNALeu
gene in a patient with a clinical phenotype resembling Kearns-Sayre syndrome.
Patient and Methods A 34-year-old patient had been suffering for more than 10 years from
progressive visual failure, neurosensorial hearing loss, exercise intolerance,
muscle weakness, paresthesia in the lower limbs, and difficulties swallowing.
Clinical examination revealed generalized muscle wasting, ptosis, external
ophthalmoplegia, and ataxia. Ophthalmologic examination showed dystrophic
features in the cornea and retina. In skeletal muscle, morphologic and biochemical
studies of the respiratory chain complexes were performed. Polymerase chain
reaction, single-strand conformation polymorphism, and direct sequencing were
used to screen for mutations in the 22 mitochondrial transfer RNA genes.
Results In skeletal muscle, a significantly decreased catalytic activity of
complex I was detected by spectrophotometric analysis and numerous cytochrome c oxidase–negative ragged-red fibers were seen on
morphologic examination. A G-to-A substitution 3249 (G3249A) mutation was
found in the transfer RNALeu gene of the patient and mutant mitochondrial
DNA represented 85% of the total in skeletal muscle but only 45% in leukocytes.
The mutation was shown to be present in a small fraction in leukocytes from
the unaffected mother and to be absent in leukocytes from the healthy sister.
Conclusions A causal relationship between a heteroplasmic G3249A transfer RNALeu mutation in a patient suffering from progressive external ophthalmoplegia,
retinal dystrophy, ataxia, neurosensorial hearing loss, and muscle wasting
is postulated. To our knowledge, the G3249A mutation has never previously
been described and was not detected in control subjects.
INTRODUCTION
MITOCHONDRIAL DNA (mtDNA) is a multicopy, double-stranded, circular,
extranuclear genome encoding 13 proteins, 2 ribosomal RNA, and 22 transfer
RNA (tRNA) species, all of which are essential for oxidative phosphorylation.
During the past few years, several mtDNA mutations have been identified and
shown to be associated with a wide range of human neurologic diseases.1, 2, 3, 4 Mitochondrial
diseases are most often multisystem disorders with a clinical variability
often related to the phenomenon of heteroplasmy, defined as a variable mixture
of mutant and wild-type mtDNA molecules in the same cell. Phenotypic expression
of mitochondrial cytopathies, therefore, is most likely to occur in tissues
with high-energy requirements. The central nervous system, as well as skeletal
muscle, heart muscle, the kidney, and liver are at highest risk.4
Mitochondrial DNA lesions range from large-scale rearrangements such as deletions
and duplications to single-nucleotide substitutions. To date, more than 70
pathogenic point mutations have been identified in mtDNA, mostly located in
tRNA genes.1, 2, 4, 5
In this article, we describe a patient with clinical signs suggestive
of a mitochondrial disease resembling Kearns-Sayre syndrome, in whom a novel
mutation in a tRNA gene was detected using single-strand conformation polymorphism,
a technique commonly used when screening for point mutations in genes, and
mtDNA sequence analysis.6
MATERIALS AND METHODS
RESPIRATORY CHAIN COMPLEX ACTIVITIES
Previously described spectrophotometric assays were used to measure
nicotinamide adenine dinucleotide–coenzyme Q reductase,7
succinate dehydrogenase, succinate cytochrome c reductase,
cytochrome c oxidase, and citrate synthase.8
MOLECULAR mtDNA ANALYSIS
Mitochondrial DNA was extracted from white blood cells and from muscle
tissue using previously described standard procedures. The more common mutations
associated with mitochondrial cytopathies were analyzed by routine Southern
blot procedures. Single-strand conformation polymorphism was used for detection
of mutations in mitochondrial tRNA genes. Primer sets were designed from published
sequences allowing screening of all 22 tRNA genes and their flanking sequences,
producing 13 different polymerase chain reaction (PCR) fragments.9 Nondenaturating polyacrylamide gels were run at 4°C
and at ambient temperature to improve detection of mtDNA aberrations, using
previously described methods.10 Mitochondrial
DNA fragments with mobility shifts on single-strand conformation polymorphism
gels were further analyzed by direct sequencing of PCR products.
REPORT OF A CASE
The propositus was born as the first child to healthy nonconsanguineous
parents. The family history was unremarkable, except for diabetes mellitus
in the paternal grandmother. He has 2 healthy sons, aged 7 and 4 years. The
proband's mother and sister are in good health. Symptoms were first noticed
in the propositus when he was near the age of 22 years. He began to suffer
from hearing loss and visual problems. He had the feeling of an unsteady gait
that worsened over a period of weeks and even prevented him from walking independently.
During the months thereafter, however, he adapted to these equilibrium problems
and regained the ability to walk unaided. He suffered from progressive muscle
weakness and generalized muscle wasting resulting in a loss of body weight.
Owing to the progression of the hearing loss, he began at the age of 27 years
to use a hearing aid. Since leaving school, he had worked as a car mechanic,
but by the age of 31 years his illness had progressed to the point that he
was no longer able to cope with the requirements of his job. He complained
of difficulties swallowing, excessive fatigue, and paresthesia in the limbs.
Ophthalmologic examination at the age of 24 years revealed retinal dystrophy
with a visual acuity of 4/10 OD and 5/10 OS. Readings from the electroretinogram
were flat. By age 32 years his visual acuity had become less than 1/100 OD
and 1/20 OS. The patient was photophobic. Slitlamp examination showed a bilateral
corneal haze (left eye worse than the right eye) due to endothelial dystrophy.
Audiometry demonstrated significant bilateral neurosensorial hearing loss.
A loss of 50 to 70 dB for low- to high-frequency sounds was detected on the
right side, and 40 to 80 dB on the left side. Electrocardiogram, 24-hour electrocardiogram
registration, and ultrasonography of the heart were normal. Electromyogram
of the deltoid muscles showed bilateral polyphasic potentials with low amplitudes
suggestive of myopathy. Amplitudes of motor action potentials were normal,
as were motor nerve conduction velocities. Results of an aerobic exercise
test revealed low tolerance to physical effort and a low anaerobic threshold.
Blood lactate level was 3.2 mmol/L at 40 W increasing to 5.3 mmol/L at 80
W and 8.5 mmol/L at 100 W. Magnetic resonance images of the brain showed atrophy
of the cerebral cortex and cerebellum, and, on T2-weighted slices, bilaterally
a hypointense aspect of the globus pallidus, substantia nigra, and red nucleus
(Figure 1).
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Figure 1. Magnetic resonance imaging of
the brain showing, on T2-weighed images, an increased hypointensity at the
globus pallidus (A), and red nucleus and substantia nigra (B) bilaterally.
Slight cerebral cortical atrophy and cerebellar atrophy in a more advanced
stage are also seen (C and D).
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At age 33 years, he was examined by one of us (R.V.C.). He was cooperative
and answered questions adequately. His face was long and sharp with bilateral
ptosis, mild external ophthalmoplegia, and lack of facial expression. He was
very thin owing to generalized muscular atrophy. His weight was 36 kg, his
height 164 cm, and his head circumference 51 cm. Muscle strength was reduced
especially in the legs. His gait was severely ataxic. Dysmetria was detected
bilaterally. Tendon reflexes and plantar responses were normal. Routine blood
study results, including complete blood cell count, transaminase levels, creatinine
kinase level, creatinine level, and lipoprotein profile, were normal. Serum
lactate and pyruvate concentrations measured on several occasions during the
course of 1 day were only minimally increased. Maximum lactate concentration
was 2.2 mmol/L (reference range, <2.0 mM) and the pyruvate level was 0.17
mmol/L (reference range, <0.14 mmol/L). Results of an amino acid profile
in serum and urine, the acylcarnitine levels, and very long-chain fatty acids
and phytanic acid concentrations were normal. Urinary organic acid profile
results were normal.
A skeletal muscle biopsy was performed. Morphologic examination showed
the presence of numerous ragged-red fibers on modified Gomori trichrome staining.
Increased staining for nicotinamide adenine dinucleotide–tetrazolium
reductase stain (Figure 2) and succinate
dehydrogenase contrasted with the significantly decreased staining for cytochrome c oxidase in the ragged-red fibers. Electronmicroscopic
examination revealed increased numbers of enlarged mitochondria with abnormal
cristae and type I paracrystalline inclusions.
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Figure 2. Skeletal muscle biopsy specimen
from proband showing numerous ragged-red fibers. Increased activity for nicotinamide
adenine dinucleotide–tetrazolium reductase is illustrated (original
magnification x 98).
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RESULTS
In skeletal muscle, the activity of complex I was significantly decreased.
The activities of complexes II, III, and IV were normal (Table 1). Neither gross rearrangements nor any of the common point
mutations associated with classic mitochondrial myopathy, encephalopathy,
lactacidosis, and strokelike episodes (MELAS) (A3243G), myoclonic epilepsy
and ragged-red fibers (MERRF) (A8344G), nor neuropathy, ataxia, and retinitis
pigmentosa (NARP)/Leigh (T8993C/G) syndromes were found in our patient. A
screening of all mitochondrial tRNA genes was performed. Single-strand conformation
polymorphism analysis revealed a novel tRNA mutation: a G-to-A transition
at position 3249 (Figure 3). The
mutation was heteroplasmic. It was located in the tRNA gene for leucine and
was not found in more than 100 normal control samples.
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Table 1. Activities of the Respiratory Chain Complexes in Isolated
Skeletal Muscle Mitochondria
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Figure 3. Polymerase chain reaction, single-strand
conformation polymorphism analysis of transfer RNALeuon skeletal
muscle of patient (lane 1) and normal control subjects (lanes 2 and 3). The
formation of double-stranded mitochondrial DNA heteroduplexes and the migration
of mutant and wild-type single-stranded mitochondrial DNA illustrates heteroplasmy.
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The mutation creates an NciI restriction site and PCR-restriction fragment
length polymorphism analysis with NciI was used to quantitate the proportion
of mutant mtDNA in the patient and his maternal relatives. Restriction fragment
length polymorphism analysis of PCR fragments amplified from mtDNA extracted
from muscle and leukocytes showed that the transition at 3249 was heteroplasmic,
with 45% of the mutant molecules in leukocytes and 85% in skeletal muscle.
The patient had inherited the mutation from his mother. She carried less than
5% mutant mtDNA molecules in the blood. In the patient's sister the mutation
was not detectable.
COMMENT
We report the identification of a novel mtDNA mutation located in the
tRNALeu gene. The patient suffered from neurosensorial hearing
loss; progressive external ophthalmoplegia; retinopathy, ataxia, and generalized
muscle atrophy; and difficulties swallowing. The finding of progressive external
ophthalmoplegia in a patient as part of a multisystemic syndrome suggested
an underlying mitochondrial defect. The initial diagnosis based on these clinical
findings was Kearns-Sayre syndrome, but neither large-scale mtDNA deletions
nor rearrangements were detected by molecular analysis. Previous reports have
shown that patients with point mutations in mitochondrial tRNA genes, including
the MELAS (A3243G) mutation in tRNALeu can also present with progressive
external ophthalmoplegia (Table 2). Signs of retinopathy are an almost constant finding in Kearns-Sayre syndrome
and NARP (neuropathy, ataxia, and retinitis pigmentosa) but can be seen in
patients with MELAS and MERRF, although less frequently. Corneal transparency
in our patient was decreased owing to stromal edema and possibly endothelial
cell dysfunction. Corneal cells are normally metabolically active. Stromal
lactate accumulation, localized acidosis, and increased osmotic solute load
can account for corneal edema. To our knowledge, corneal dystrophy has never
been reported in patients with mitochondrial defects until now. Cerebellar
atrophy was the most obvious magnetic resonance imaging abnormality in the
proband, which is not an unusual finding in patients with Kearns-Sayre syndrome
and in patients with advanced stages of MELAS. Infarctlike lesions suggestive
of MELAS were not detected in the proband.
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Table 2. Mitochondrial DNA Point Mutations Reported in Association
With Progressive External Ophthalmoplegia and Ragged-Red Fibers*
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In skeletal muscle from the patient, numerous cytochrome c oxidase–negative ragged-red fibers were observed. In patients
with mtDNA defects affecting protein synthesis, including mtDNA deletions,
mtDNA depletion, or tRNA mutations, ragged-red fibers are cytochrome c oxidase–negative. In the skeletal muscle from the
proband, however, mtDNA deletions and mtDNA depletion were excluded by molecular
analysis. Cytochrome c oxidase–negative ragged-red
fibers can also be found in mtDNA mutations located in the cytochrome c oxidase I, II, or III genes, but spectrophotometrical
analysis in the proband showed normal cytochrome c
oxidase activity in isolated mitochondria. Taking these findings into consideration,
the most likely hypothesis was a mutation in a tRNA gene in the proband.
The classic MELAS (A3243G), MERRF (A8344G), and NARP/MILS (maternally
inherited Leigh syndrome) (T8993C/G) mutations were absent in the proband.
In contrast using PCR, single-strand conformation polymorphism, and direct
sequence analysis, a G3249A mutation in tRNALeu was detected. Sufficient
evidence can be found to substantiate the causative role of this mutation.
The base change was heteroplasmic, a common feature of pathogenic mtDNA mutations.
Moreover, the mutation was represented in higher proportions in skeletal muscle
than in leukocytes. The nucleotide involved is evolutionarily well conserved25 and has not been observed in more than 100 control
samples. The mutation was maternally inherited and associated with morphologic
and biochemical abnormalities in skeletal muscle.
The G3249A mutation is located adjacent to a cluster of point mutations
at nucleotides 3250, 3251, 3252, 3254, and 3256, all positioned in the dihydrouridine
loop, or dihydrouridine stem of the tRNALeu gene.14, 26, 27, 28, 29, 30
These mutations, as well as the classic A3243G (MELAS) mutation, are known
to disrupt the tRNA function and are associated with a wide range of phenotypical
presentations such as MELAS, pure myopathy, cardiomyopathy, and encephalopathy.
Until now, more than 10 different pathogenic mutations have been identified
in the tRNALeu(UUR) gene.31 Therefore,
this gene represents a mutational hot spot in the mitochondrial genome.
CONCLUSIONS
We conclude that the G3249A mutation in tRNALeushould be
tested for in patients with clinical symptoms suggestive of Kearns-Sayre syndrome
in whom large-scale mtDNA deletions or rearrangements and classic MELAS and
MERRF point mutations have been excluded. If negative, a thorough screening
for mtDNA mutations, especially in the tRNA genes, is a worthwhile test. We
would like to emphasize that it is impossible to predict that the G3249A mutation
always presents with the Kearns-Sayre–like phenotype, since phenotypic
variability of this point mutation can not be assessed by this single patient
and his asymptomatic mother.
AUTHOR INFORMATION
Accepted for publication September 6, 2000.
This work was supported by a grant from Fund for Scientific Research
(Fonds voor Wetenschappelijk Onderzoek, Vlaanderen, Belgium): contract grant
31507296 (Dr Van Coster); a grant from Fund for Scientific Research Flanders
(Fonds voor Wetenschappelijk Onderzoek, Vlaanderen): contract grant G0181.98
(Dr De Meirleir); and a grant from "Fund for National Scientific Research
(Nationaal Fonds voor Wetenschappelijk Onderzoek, België): contract grant
3.009.94 (Dr Ceuterick-de Groote); and the Research Council of the Vrije Universiteit
Brussel, Brussels, Belgium.
We thank the laboratory staff, especially Ann Bamps and Joél
Smet.
From the Departments of Medical Genetics (Drs Seneca and Lissens) and
Neuropediatrics (Dr De Meirleir), Dutch-Speaking Free University of Brussels,
Brussels; Department of Pediatrics, Division of Pediatric Neurology (Drs Verhelst
and Van Coster) and Ophthalmology (Dr Meire), Ghent University Hospital, Ghent;
and the Department of Neuropathology and Born-Bunge Foundation, University
of Antwerp, Antwerp (Dr Ceuterick-De Groote), Belgium.
Corresponding author: Sara Seneca, PhD, Medical Genetics, Academisch
Ziekenhuis van de Vrije Universiteit Brussel, Laarbeeklaan 101, B 1090 Brussels,
Belgium (e-mail: lgensas{at}az.vub.ac.be).
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