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Pathophysiological and clinical consequences of the mitochondrial DNA 3243A→G mutation

Abstract
This study describes clinical and biochemical consequences
of the 3243A→G mutation in the tRNALeu(UUR)
gene
of the mitochondrial DNA. Mitochondrial encephalomyopathy, lactic
acidosis and stroke-like episodes (MELAS syndrome) is usually caused
by this mutation.

Demyelinating polyneuropathy was observed as a novel feature
in a patient with the mutation. Based on electrodiagnostic examination
the polyneuropathy was defined as being of the demyelinating, mixed
(motor more than sensory) type. In a 1 year follow-up an approximately
7% reduction in both the motor and sensory nerve conduction
velocities were observed.

The effect and mechanism of action of nicotinamide treatment
in a MELAS patient with the 3243A→G was studied. The blood
NAD concentration increased linearly, being 24-fold elevated at 6
weeks of treatment. Blood lactate and pyruvate concentration decreased
by 50% within three days and 24 h urine lactate content
within 2 weeks. A clinical improvement together with a decrease
in the lesion volume in magnetic resonance imaging within the first
month were observed. Alleviation of the lactate accumulation during
the nicotinamide treatment suggested that an increase in the cellular NAD+NADH
concentration led to enhancement of the oxidation of reducing equivalents,
suggesting that complex I of respiratory chain operates at non-saturating
substrate concentration.

Myoblasts cultured from patients carrying the 3243A→G
mutation and from controls were used to measure ATP, ADP, catalase
and superoxide dismutase activity, population growth, apoptotic
cell death and the morphology of cytoskeletal components. ATP and
ADP concentrations were decreased, suggesting a decrease in the
adenylate pool. The superoxide dismutase and catalase activities
were higher than in control cells, suggesting an increased production
of reactive oxygen species due to respiratory chain dysfunction.
No increase in apoptotic cell death was observed in proliferating myoblasts,
but randomization of vimentin filament direction and length was
observed and decreased population growth was associated with the
mutation.

The results show that the 3243A→G mutation leads
to numerous secondary pathophysiological events. Based on the literature
and the results of this study, similarities were found between the pathophysiology
of 3243A→G mutation and other neurodegenerative diseases
and aging.

Identiferoai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5538-0
Date31 January 2000
CreatorsRusanen, H. (Harri)
PublisherUniversity of Oulu
Source SetsUniversity of Oulu
LanguageEnglish
Detected LanguageEnglish
Typeinfo:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion
Formatapplication/pdf
Rightsinfo:eu-repo/semantics/openAccess, © University of Oulu, 2000
Relationinfo:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234

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