Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients.

We describe 36 patients (six were apparently sporadic cases and 30 were cases from nine families) with amyotrophic lateral sclerosis (ALS) characterized by a distinct phenotype associated with homozygosity for an Asp90Ala mutation in the CuZn-superoxide dismutase gene. The presenting motor manifestation in all patients was paresis in the legs, with slow progression to the upper extremities and finally to the bulbar muscles. The age of ALS onset varied from 20 to 94 years, with a mean of 44 years. Mean survival time was 13 years for the 11 deceased patients. However, this is probably biased and untypical (low) when compared with the disease duration in the surviving patients, and when considering other medical complications in the deceased patients. The rate of progression was highly variable, even within families. All patients showed signs of involvement of both upper and lower motor neurons. Other neurological features included painful muscle spasms and paraesthesiae in the lower extremities. Two-thirds of patients experienced difficulty with micturition. Electrophysiological studies confirmed the slow progression and spatial distribution of clinical symptoms in the peripheral motor system. Furthermore, [corrected] potentials evoked by transcranial magnetic stimulation (MEP) were compared with those evoked by cervical or lumbosacral electrical stimulation and often revealed marked slowing of transmission in central motor pathways. In Sweden and Finland ALS patients homozygous for the Asp90Ala mutation constitute a phenotypically characteristic subset of motor neuron disease.

Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.

Recent reports have shown heterozygosity for some twenty different mutations in the CuZn-superoxide dismutase (CuZn-SOD) gene in familial amyotrophic lateral sclerosis (FALS), and analysed samples from patients have shown decreased enzymic activity. Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland. The erythrocyte CuZn-SOD activity is essentially normal. Our findings suggest that this CuZn-SOD mutation causes ALS by a gain of function rather than by loss, and that the Asp90Ala mutation is less detrimental than previously reported mutations.

Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description.

A family of Finnish descent with very-early-onset Alzheimer's disease has been identified. Genetic analysis of this family eliminated the amyloid precursor protein gene as the pathogenic locus, but strongly implicated a locus on chromosome 14q23.4 between D14S52 and D14S55. The early age at onset of the disease (average, 36 years; range, 35-39 years), the rapid progression, and the early and prominent myoclonus, while they appear to be frequent findings in the chromosome 14-encoded form of Alzheimer's disease, raised the clinical suspicion of prion disease. However, sequencing the prion gene-coding region of 2 affected members of the pedigree failed to show any abnormality. Apart from the presence of modest cortical vacuolar change, the pathological features of our index patient appeared typical of Alzheimer's disease with abundant senile plaques immunoreactive with beta-amyloid, but not with prion protein antibodies.

Ergotamine abuse: results of ergotamine discontinuation, with special reference to the plasma concentrations.

Twenty-three patients suffering from continuous headache linked with habitual daily use of ergotamine tartrate were studied. Their headaches were classified clinically, and possible side effects of ergotamine medication, plasma levels of ergotamine, and occurrence of withdrawal symptoms after discontinuation of drug abuse were recorded. Seventeen of the patients were clinically diagnosed as suffering from "ergotamine headache", and seven of them complained of coldness in the extremities. Plasma ergotamine levels were measured by using a radioimmunoassay. In almost half of the patients the 1 h plasma levels after the daily dose were below the detection limit of the procedure (0.12 ng/ml). The duration and severity of the withdrawal symptoms did not correlate with the doses and plasma levels of ergotamine. In only 4 of the 21 patients who were followed up for 3 to 6 months did headache symptoms not improve after ergotamine withdrawal. The results indicate that even small (0.5-1.0 mg/day) doses of ergotamine tartrate taken regularly may cause continuous headache symptoms and withdrawal symptoms after discontinuation.

Correlation between pharmacokinetics and clinical effects of ergotamine in patients suffering from migraine.

The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headache free state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6 h. Their mean plasma levels at 30 min (0.33 ng/ml) and 1 h (0.40 ng/ml) were significantly higher than those (0.06 and 0.08 ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10 ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11 ng/ml) responders appeared later (at 3 h) than in good responders (at 1 h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20 ng/ml or more is achieved within 1 hour after oral or rectal administration.

Systemic availability of ergotamine tartrate in continuous medication.

There seems to be great individual differences in the bioavailability of ergotamine in continuous use. The great tolerance to ergotamine in some patients using the drug on a daily basis, even in high doses, may be due to the low-bioavailability of ergotamine in these subjects. This may also explain the infrequency of serious complications among migraine patients.

Systemic availability of ergotamine tartrate in healthy subjects after single and repeated oral doses.

The studies presented indicate that ergotamine tartrate taken orally in single or repeated 2 mg doses is biologically available in most of the subjects examined. The peak plasma concentration of the drug in the ng/ml range is attained at 1-2 hours. It seems probable that there is a second rise in the plasma concentrations of the drug, possibly indicating an accumulation of ergotamine or some of its immunoreactive metabolites, and this needs further evaluation.

Juvenile amyotrophic lateral sclerosis. A report of two cases in a single family.

This paper presents two juvenile cases of familial amyotrophic lateral sclerosis. They are the first and fourth child in a family with seven children from the eastern part of Finland. All seven children, as well as the parents, were examined by our group. In the first case the disease showed a rather mild course, while in the second a noticeable progression was observed even during a period of 10 months. The patients come from a rural area with a stable population and low immigration, which may favor an enrichment of certain genes and therefore support the possible hereditary basis for the disease.

Systemic availability of ergotamine tartrate after oral, rectal and intramuscular administration.

Plasma ergotamine levels were measured in 33 volunteers (subgroups 11, 12 and 10) after a single dose of ergotamine administered by various routes. Ergotamine tartrate was given in doses normally used in the treatment of acute migraine--2.0 mg orally, 2.0 mg combined with 100 mg caffeine rectally and 0.5 mg i.m. Plasma ergotamine concentrations were determined by radioimmunoassay. The highest and longest lasting levels were found after i.m. administration, the peak concentration being 1.94 +/- 0.34 (SEM) ng/ml at 1/2 h. The corresponding maximum concentrations after oral and rectal administration were 0.36 +/- 0.08 ng/ml at 2 h and 0.42 +/- 0.09 ng/ml at 1 h. In most of the subjects the plasma ergotamine level began to rise again at 24 to 48 h. The cause of the elevation is not known but it might favour possible accumulation of the drug. Absorption from suppositories was at least as good as after oral administration and the former route may therefore be advantageous for migraine patients in whom nausea and vomiting during an attack may prevent efficient oral medication.