New phenotypic diversity associated with the mitochondrial tRNA(SerUCN) gene mutation.

We performed detailed clinical, histopathological, biochemical, in vitro translation and molecular genetic analysis in patients from two unrelated families harbouring the tRNA(SerUCN) 7472C-insertion mutation. Proband 1 developed a progressive neurodegenerative phenotype characterised by myoclonus, epilepsy, cerebellar ataxia and progressive hearing loss. Proband 2 had a comparatively benign phenotype characterised by isolated myopathy with exercise intolerance. Both patients had the 7472C-insertion mutation in identical proportions and they exhibited a similar muscle biochemical and histopathological phenotype. However, proband 2 also had a previously unreported homoplasmic A to C transition at nucleotide position 7472 in the tRNA(SerUCN) gene. This change lengthens further the homopolymeric C run already expanded by the 7472C-insertion. These data extend the phenotypic range associated with the 7472C-insertion to include isolated skeletal myopathy, as well as a MERRF-like phenotype.

The role of D-1 and D-2 receptors.

Dopamine receptors in intracerebral motor and endocrine systems have been divided into two main types, D-1 and D-2, dependent on the presence or absence of adenylate cyclase linkage. Here we have investigated a number of dopamine agonist and antagonist drugs in man that have different actions on D-1 and D-2 receptors in animals. Motor and endocrine effects in parkinsonian subjects seem to depend on drug interaction with D-2, but not D-1, receptors. These results may have important implications for the design of anti-parkinsonian and antipsychotic agents.

Amphetamines, growth hormone and narcolepsy.

1 Plasma amphetamine and growth hormone levels have been measured in eight normal and twenty-six narcoleptic subjects following a single dose of (+)-amphetamine (20 mg) or (-)-amphetamine (20 mg) by mouth. 2 Peak plasma levels and the shape of the plasma amphetamine-time curve were similar with both isomers in normal and narcoleptic subjects. 3 In most normal subjects both (+)-and (-)-amphetamine (20 mg) caused an increase in the plasma concentration of growth hormone. The two isomers were approximately equipotent in this respect. Neither (+)- nor (-)-amphetamine (20 mg) caused an increase in plasma growth hormone concentration in narcoleptics. 4 Following amphetamine (30 mg), two of six narcoleptic subjects had an increase in plasma growth hormone concentration. 5 Levodopa (250 mg) with (-)-alpha-methyldopa hydrazine 25 mg (Sinemet) by mouth, caused a rise in plasma growth hormone concentration in most normal subjects. The magnitude of the Sinemet-induced rise in plasma growth hormone concentration in narcoleptics was less than in normal subjects.

Bromocriptine in Parkinsonism: long-term treatment, dose response, and comparison with levodopa.

Thirty-seven patients with Parkinsonism were treated with bromocriptine 2.5-300 mg daily. Bromocriptine, alone or combined with levodopa, caused a 20-30% reduction in disability scores in 11 patients treated for one year. Tolerance did not develop during this period. Bromocriptine treatment was not of value in six patients who had previously not responded or who had lost their response to levodopa. However, in four of five patients with response swings on levodopa due to rapid changes in plasma dopa levels, the addition of bromocriptine caused a more stable response. Dose response curves to bromocriptine 12.5, 25, 50, and 100 mg and to levodopa 250, 500, 1000, and 2000 mg were studied in seven patients. Levodopa 2 g had a greater therapeutic effect and caused a greater rise in plasma growth hormone concentration than bromocriptine 100 mg. Levodopa caused emesis more commonly and hallucinations less commonly than bromocriptine. Bromocriptine appears to be a less potent stimulant than dopamine, and has both pre- and post-synaptic effects. Metoclopramide 60 mg oral was given 30 minutes before bromocriptine or levodopa to establish whether this caused dopamine-receptor blockade. Metoclopramide acted as a competitive antagonist to the anti-Parkinsonism and growth hormone effect of both drugs and in individual cases prevented emesis and hallucinations. The fall in blood pressure due to bromocriptine or levodopa was not antagonised by metoclopramide. Central and peripheral vascular dopamine receptors may be different in nature.

Bromocriptine and dopamine receptor stimulation.

The response to different doses of bromocriptine (12.5, 25, 50 and 100 mg) has been established in six patients with Parkinson's disease. Bromocriptine, like levodopa, causes improved mobility in patients with Parkinsonism, emesis, hallucinations, a fall in supine and erect blood pressure, increase of plasma growth hormone and suppression of prolactin concentration. Bromocriptine (50 or 100 mg) has as great an anti-Parkinsonian effect as average therapeutic doses of levodopa, and a longer duration of action, 6-10 hours. In the dose range studied, bromocriptine appears to be a complete dopamine agonist, although 100 mg was less effective than 50 mg in two patients. The different actions of bromocriptine and other dopamine agonist drugs may result from stimulation of different types of dopamine receptor.