Novel heteroplasmic mtDNA mutation in a family with heterogeneous clinical presentations

Abstract

The protean manifestations of a novel maternally inherited point mutation of the mitochondrial genome are reported. The proband showed isolated, spastic paraparesis. A brother, who had suffered from a multisystem progressive disorder, ultimately died of cardiomyopathy. Another brother is healthy. The proband's mother showed truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, distal cyclones, and diabetes mellitus. A muscle biopsy performed in the proband failed to show the morphological abnormalities typical of mitochondrial disorders; the activities of respiratory chain complexes were normal. However, complex I and IV activities were low in the muscle homogenate of the affected mother and brother. Sequence analysis of mtDNA showed a heteroplasmic mutation of the tRNA(Ile) gene (G4284A). The mutation load was approximately 55%, 80%, and 90% in the muscle mtDNA of the proband, his mother, and his affected brother, respectively. Mutation was undetected in the healthy brother, as well as in 100 control samples. Several cybrid clones containing homoplasmic mutant mtDNA from the proband showed significant reductions of complex IV activity and maximum oxygen consumption rate, compared with homoplasmic wild-type clones derived from the same subject.

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNAGlu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

“…Adult-onset spastic paraparesis is a feature that is rarely associated with mtDNA disease (26,27); however, our patient had progressive lower limb spasticity. This spasticity might be attributable to axonal and myelin degeneration and loss affecting the left anterior limb and genu of the internal capsule.…”

Mitochondrial Mutations in Left Ventricular Hypertrophy

“…Lin Z, et al [12] found G8584A mtDNA mutation may influence LVH in hypertensives. In particular, several point mutations such as G4284A [13] , A4295G [14] , A4269G [15] , A4317G [15] and A4300G [16] located in tRNA Ile contribute to hypertrophic cardiomyopathy to certain degree. A systematic and extended mutational screening for the mitochondrial genome has been initiated in a large cohort of Chinese population by the Geriatric Cardiology Clinic at the Chinese PLA General Hospital, Beijing, China.…”

Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

“…The mutation load was approximately 55%, 80% and 90% in the muscle DNA of the patient, his mother and his affected brother respectively. 268 …”