Combination of mtDNA mutations in a patient with a mitochondrial multisystem syndrome

Abstract

A 51-year-old woman had suffered from severe hypertrophic cardiomyopathy with arrhythmia and bilateral hearing impairment since her thirties. At age 41 years, hypothyroidism became manifest. Serum free thyroxine (FT)3 and thyroid stimulating hormone (TSH) levels were reduced. Thyroid autoantibodies were negative. Hyperglycemia was also found, and non-insulin-dependent diabetes mellitus (NIDDM) was confirmed by an oral glucose tolerance test. After informed consent was obtained, muscle biopsy showed decreased cytochrome c oxidase (COX) staining in 10% of the ragged-red fibers (RRF) found. Biochemically, COX was also reduced (65% residual activity). Her condition worsened, with generalized muscle weakness and moderate ptosis, but there was no extraocular muscle involvement. Her mental state deteriorated progressively. A brain computed tomography (CT) scan showed bilateral calcifications in the pallidus and thalamus. When she was back at home, the patient suddenly suffered seizures and died of cardiopulmonary arrest.Her 28-year-old daughter has non-specific ovary and thyroid gland dysfunction, but is otherwise asymptomatic. Neurophysiologic evaluation showed reduced nerve conduction velocities and abnormal visual evoked potentials. The patient's brother is healthy. No other relatives were tested. Results and discussionClinically, in the patient, a disorder of the type seen in multisystem mitochondrial disorders or in mitochondrial encephalomyopathy, stroke-like episodes, and lactic acidosis (MELAS) was sustained by the morphological and biochemical findings in muscle, and indicated that an mtDNA disorder was likely. Southern blot analysis showed a relatively low proportion (17%) of the so-called "common" mtDNA deletion in muscle, but not in blood, from the Abstract We report a patient who manifested a heterogeneous clinical presentation, including hypertrophic cardiomyopathy and hypothyroidism, with initially limited central nervous system involvement, and who harbored the mitochondrial (mt)DNA A3243G mutation. MtDNA analyses also revealed deleted genomes in muscle and blood. This atypical molecular combination may have influenced the clinical phenotype.

Complex Neurologic Syndrome Associated With the G1606A Mutation of Mitochondrial DNA

“…onset and additional symptoms, including migraine, hypothyroidism, and retinitis pigmentosa. While retinitis pigmentosa and migraine are common in mitochondrial encephalomyopathies, hypothyroidism has been reported only in association with large-scale rearrangements of mtDNA 6 andwiththeA-to-Gsubstitutionatnucleotide3243(MELAS) mutation. 7 Although both patients had similar mutational loads in muscle, our patient had only electrophysiologic and pathologic evidence of myopathy without overt weakness.…”