Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motoneuron disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene and for which no curative therapy exists. However, since recent research may provide opportunities for medical treatment, information concerning the natural history of SBMA would be beneficial in planning future clinical trials. We investigated the natural course of SBMA as assessed by nine activities of daily living (ADL) milestones in 223 Japanese SBMA patients (mean age at data collection = 55.2 years; range = 30-87 years) followed from 1 to 20 years. All the patients were diagnosed by genetic analysis. Hand tremor was an early event that was noticed at a median age of 33 years. Muscular weakness occurred predominantly in the lower limbs, and was noticed at a median age of 44 years, followed by the requirement of a handrail to ascend stairs at 49, dysarthria at 50, dysphagia at 54, use of a cane at 59 and a wheelchair at 61 years. Twenty-one of the patients developed pneumonia at a median age of 62 and 15 of them died at a median age of 65 years. The most common cause of death in these cases was pneumonia and respiratory failure. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that although the onset age of each ADL milestone depends on the CAG-repeat length in the AR gene, the rate of disease progression does not. The levels of serum testosterone, an important triggering factor for polyglutamine-mediated motoneuron degeneration, were maintained at relatively high levels even at advanced ages. These results provide beneficial information for future clinical therapeutic trials, although further detailed prospective studies are also needed.

Short-term benefit of intensive rehabilitation was evident in patients with degenerative cerebellar diseases. Although functional status tended to decline to the baseline level within 24 weeks, gains were maintained in more than half of the participants.

Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

Patients with multiple system atrophy-parkinsonism show more severe and more widespread cognitive dysfunctions than patients with multiple system atrophy-cerebellar ataxia. Our results also indicate that cognitive dysfunction in patients with multiple system atrophy-parkinsonism may be associated with prefrontal involvement.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, lower motor neuron disease caused by an aberrant elongation of a CAG repeat in the androgen receptor (AR) gene. The main symptoms are weakness and atrophy of bulbar, facial and limb muscles, but sensory disturbances are frequently found in SBMA patients. Motor symptoms have been attributed to the accumulation of mutant AR in the nucleus of lower motor neurons, which is more profound in patients with a longer CAG repeat. We examined nerve conduction properties including F-waves in a total of 106 patients with genetically confirmed SBMA (mean age at data collection = 53.8 years; range = 31-75 years) and 85 control subjects. Motor conduction velocities (MCV), compound muscle action potentials (CMAP), sensory conduction velocities (SCV) and sensory nerve action potentials (SNAP) were significantly decreased in all nerves examined in the SBMA patients compared with that in the normal controls, indicating that axonal degeneration is the primary process in both motor and sensory nerves. More profound abnormalities were observed in the nerves of the upper limbs than in those of the lower limbs. F-waves in the median nerve were absent in 30 of 106 cases (28.3%), but no cases of absent F-waves were observed in the tibial nerve. From an analysis of the relationship between CMAPs and SNAPs, patients were identified with different electrophysiological phenotypes: motor-dominant, sensory-dominant and non-dominant phenotypes. The CAG repeat size and the age at onset were significantly different among the patients with motor- and sensory-dominant phenotypes, indicating that a longer CAG repeat is more closely linked to the motor-dominant phenotype and a shorter CAG repeat is more closely linked to the sensory-dominant phenotype. Furthermore, when we classified the patients by CAG repeat size, CMAP values showed a tendency to be decreased in patients with a longer CAG repeat (> or =47), while SNAPs were significantly decreased in patients with a shorter CAG repeat (<47). In addition, we found that the frequency of aggregation in the sensory neuron cytoplasm tended to inversely correlate with the CAG repeat size in the autopsy study, supporting the view that the CAG repeat size differentially correlates with motor- and sensory-dominant phenotypes. In conclusion, our results suggest that there are unequivocal electrophysiological phenotypes influenced by CAG repeat size in SBMA.