Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

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Purpose: The functional organization of the human cerebellum involved in saccadic eye movements was investigated using functional magnetic resonance imaging (fMRI). Methods: The subjects were 7 normal volunteers aged 18–34 years. Visual stimuli were back-projected onto a screen placed at the subjects’ feet. The stimulation period of 30 s consisted of a saccade target jumping back and forth horizontally by 20° once per second. The control period of 30 s consisted of a fixed target. The stimulation and control periods were alternated 10 times during the presentation. Functional images were collected with a 1.5-tesla clinical MRI scanner. The significance of activation was determined by Statistical Parametric Mapping (SPM 99) at a threshold of p < 0.001 (uncorrected), and significantly activated areas were superimposed on the T₁-weighted images. Results: Significantly activated areas related to visually guided saccades were observed in the cerebellar vermis (declive and folium), in the bilateral cerebellar hemispheres (mainly the superior semilunar lobule) of the cerebellum, in the frontal eye field, in the supplementary eye field and in parts of the parietal lobule of the cerebrum. Conclusion: Our results suggest that the cerebellar posterior vermis and bilateral hemispheres are related to saccades in humans. These results are consistent with neurophysiological data obtained in primates.

Point mutations in mitochondrial (mt) tRNA genes are associated with a variety of human mitochondrial diseases. We have shown previously that mt tRNA(Leu(UUR)) with a MELAS A3243G mutation and mt tRNA(Lys) with a MERRF A8344G mutation derived from HeLa background cybrid cells are deficient in normal taurine-containing modifications [taum(5)(s(2))U; 5-taurinomethyl-(2-thio)uridine] at the anticodon wobble position in both cases. The wobble modification deficiency results in defective translation. We report here wobble modification deficiencies of mutant mt tRNAs from cybrid cells with different nuclear backgrounds, as well as from patient tissues. These findings demonstrate the generality of the wobble modification deficiency in mutant tRNAs in MELAS and MERRF.