SCA Functional Index: a useful compound performance measure for spinocerebellar ataxia.

OBJECTIVE: To evaluate the usefulness of functional measures in patients with spinocerebellar ataxia (SCA). METHODS: We assessed three functional measures-8 m walking time (8MW), 9-hole peg test (9HPT), and PATA repetition rate-in 412 patients with autosomal dominant SCA (genotypes 1, 2, 3, and 6) in a multicenter trial. RESULTS: While PATA rate was normally distributed (mean/median 21.7/20.5 per 10 s), the performance times for 8MW (mean/median 10.8/7.5 s) or 9HPT (mean/median 47.2/35.0 s in dominant, 52.2/37.9 s in nondominant hand) were markedly skewed. Possible learning effects were small and likely clinically irrelevant. A composite functional index (SCAFI) was formed after appropriate transformation of subtest results. The Z-scores of each subtest correlated well with the Scale for the Assessment and Rating of Ataxia (SARA), the Unified Huntington's disease Rating Scale functional assessment, and disease duration. Correlations for SCAFI with each of these parameters were stronger (Pearson r = -0.441 to -0.869) than for each subtest alone. Furthermore, SCAFI showed a linear decline over the whole range of disease severity, while 9HPT and 8MW had floor effects with respect to SARA. Analysis of possible confounders showed no effect of genotype or study site and only minor effects of age for 8MW. CONCLUSION: The proposed functional measures and their composite SCAFI have favorable properties to assess patients with spinocerebellar ataxia.

Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.

HMBS mutations in Chinese patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP), an autosomal dominant disorder, is caused by partial deficiency of hydroxymethylbilane synthase (HMBS) affecting heme biosynthesis. Patients with AIP are characterized by recurrent abdominal pain, port-wine urine, and motor paresis. The disease can be provoked by changes in hormone levels, drugs and fasting. Molecular analysis for twenty-four unrelated Chinese AIP patients from Taiwan identified twenty-five HMBS mutations. There were 10 missense (40%), four nonsense (16%), five frame-shift (20%) and six splice site (24%) mutations. More than a half (15/25, 60%) of these mutations are predicted to produce a truncated protein. Four (c.33 + 5C>A, Arg26Cys, Arg26His, Arg325X) occurred more than once among the 24 families and one individual carried two mutations in the same allele, a missense (Gly221Asp) and a splice site mutation (c.652-1G>A). Of the 25 mutations, eleven were novel (Arg149Pro, Gly218Arg, Asn322X, Gly221Asp, Pro313X, c.88-4_-16delAAGTCTCTACCCG, c.1008_1019delCAGCCTGGCCAA, c.113delT, c.88-4_-16delAAGTCTCTACCCGinsCA, c.160delA, c.902_909delTCCCTGCC). No correlation between genetic defect and phenotype (both clinical and biochemical) was observed in this study.

Quantitative trait loci affecting prion incubation time in mice.

Although the gene encoding prion protein (PrP) is the major determinant of susceptibility to prion disease, other genes also affect prion incubation time in mice and may be involved in prion replication. Scrapie incubation time was analyzed as a quantitative trait using crosses between SJL/J and CAST/Ei mice; these mouse strains encode identical PrP molecules but have different incubation periods. Our analysis revealed loci on Chromosomes 9 and 11 that affect prion susceptibility.

The impact of antidepressants on sleep and anxiety: a comparative study of fluoxetine and dothiepin using the Leeds Sleep Evaluation Questionnaire.

Fluoxetine (20 mg) was compared to dothiepin (150 mg) in a multicentre, prospective, double blind, randomised clinical trial involving 125 patients with major depression treated for an initial phase of 6 weeks and then followed up for a further 6 months. There was no difference in the efficacy of the two drugs based on the results of established rating scales (MADRS, HAM-D, BPRS). The impact of both drugs on sleep measured using the Leeds Sleep Evaluation Questionnaire showed no significant differences between treatments, however drowsiness and disturbed sleep were reported more frequently as side effects with dothiepin. Symptoms of anxiety responded equally well to both treatments. The short term and long term tolerability of dothiepin was inferior to that of fluoxetine. The place of dothiepin in treatment should be reassessed in the light of its anticholinergic adverse event profile, particularly in the elderly. Copyright 2000 John Wiley & Sons, Ltd.

Report and abstracts of the Sixth International Workshop on chromosome 9.

A meeting on chromosome 9 was held on Tuesday, 27 October 1998 in Denver, with 38 participants (see appendix). Since the last meeting several of the positional cloning efforts on chromosome 9q have come to fruition, and the most detailed discussion was on 9p. Dr Ian Dunham from the Sanger Centre explained the strategy to be used for sequencing chromosome 9, and encouraged collaboration in the preparatory mapping. He indicated that some priority could be given to those regions where people in the field had a strong interest and could identify relevant PAC clones. At this short meeting it was clearly not possible to construct a comprehensive map of chromosome 9, and it was decided that efforts should be made to maintain links to sources of information on the chromosome 9 web page (http:@www.gene.ucl.ac.uk/chr9/). The discussions at the meeting are summarized in four sections: 9p, 9cen-q31, 9q32-9q34 and comparative mapping. Many of the posters presented at the meeting were also presented at the ASHG meeting (28-31 October 1998). They are listed here and are published in The American Journal of Human Genetics, vol. 63 (supplement). Abstracts for posters presented only at this meeting are appended to this report.

Analysis of the Kit and Pdgfra genes in the patch-extended (Phe) mutation.

The patch (Ph) locus allele, patch-extended (Phe), has significantly less pigmentation than the original mutation and homozygotes have been known to survive to term. Analysing intersubspecific F1 hybrids, we were able to demonstrate that Phe is a deletional mutation encompassing the platelet-derived growth factor receptor alpha subunit (Pdgfra). The deletion does not appear to extend into the coding sequence of the Kit gene (a related tyrosine kinase receptor). However, we were able to demonstrate that, while the Kit gene is transcribed, it does not encode a functionally active receptor.

Mouse rump-white mutation associated with an inversion of chromosome 5.

The rump-white (Rw) mutation in the mouse was previously mapped as part of a cluster of spotting genes on Chromosome (Chr) 5 that includes the dominant spotting (W) and patch (Ph) loci. Recent studies have shown that the W locus encodes the KIT tyrosine kinase cell surface receptor and that Ph is a deletional mutation encompassing the platelet-derived growth factor receptor alpha subunit (Pdgfra) gene. However, the molecular basis of the Rw mutation remains to be established. We have analyzed an interspecific Mus spretus backcross segregating Rw and several loci proximal and distal to the W/Ph/Rw region to study the basis of this mutation. These studies indicated that loci within the En2 to Kit region of the chromosome do not recombine with one another even though they have been separated in other mapping studies presented here and elsewhere. We conducted a series of fluorescent in situ hybridization (FISH) studies with genomic probes to En2, Msx1, D5Buc1, and Kit to compare the physical order of these loci on the Rw and wild-type chromosomes. The Kit locus mapped to approximately the same region on both chromosomes of the Rw heterozygotes, while the positions of En2, Msx1, and D5Buc1 were reversed on the two chromosomes. Taken together, both the genetic and physical mapping data establish that the Rw mutation is associated with an inversion involving loci in the proximal region of Chromosome 5.