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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.
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.
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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