Psoriatic arthritis and psoriasis: role of patient advocacy organisations in the twenty first century.

All the psoriatic arthritis and psoriasis patient advocacy organisations are devoted to promoting public awareness and patient education; supporting access to effective treatments and physicians committed to the welfare of patients; working with physicians and other organisations to facilitate development of new treatments; and supporting research for more effective treatments and a cure for psoriasis and psoriatic arthritis. They have participated in the remaking of health politics in the late twentieth century. This was an era in which small patient support and advocacy groups were transformed into sophisticated national health organisations integral to the formation of national health policy and research, treatment, and education funding by working with physicians, legislators, pharmaceutical companies, third party payors, and the media. As we enter the twenty first century, some of these groups have done critical surveys of patients and physicians to discern needs that are redirecting their programming and reshaping directions in the field. Many national leagues have united to form international organisations. Although differences in their national healthcare systems, the age of their organisations, and the diseases they cover are reflected in the focus of their individual activities, much unites them. Whatever their size, as their roles have come to be recognised in the healthcare community, the patient advocacy organisations welcome being invited to the decision making table. This report describes a sampling of these organisations.

Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome.

Hemifacial microsomia (HFM) is a common birth defect involving first and second branchial arch derivatives. The phenotype is extremely variable. In addition to craniofacial anomalies there may be cardiac, vertebral and central nervous system defects. The majority of cases are sporadic, but there is substantial evidence for genetic involvement in this condition, including rare familial cases that exhibit autosomal dominant inheritance. As an approach towards identifying molecular pathways involved in ear and facial development, we have ascertained both familial and sporadic cases of HFM. A genome wide search for linkage in two families with features of HFM was performed to identify the disease loci. In one family data were highly suggestive of linkage to a region of approximately 10.7 cM on chromosome 14q32, with a maximum multipoint lod score of 3.00 between microsatellite markers D14S987 and D14S65. This locus harbours the Goosecoid gene, an excellent candidate for HFM based on mouse expression and phenotype data. Coding region mutations were sought in the familial cases and in 120 sporadic cases, and gross rearrangements of the gene were excluded by Southern blotting. Evidence for genetic heterogeneity is provided by the second family, in which linkage was excluded from this region.

Identification of a point mutation and germinal mosaicism in a Duchenne muscular dystrophy family.

Duchenne and Becker muscular dystrophies (DMD and BMD) are allelic X-linked disorders arising from mutations in the (2.4 Mb) dystrophin gene at Xp21. We have applied the reverse transcriptase-polymerase chain reaction (RT-PCR) to identify a larger than normal dystrophin mRNA from a male with Duchenne muscular dystrophy and his younger affected brother. The increased size of the dystrophin mRNA was due to a splice-site mutation at the exon 26:intron 26 junction where a T to G substitution prevented normal RNA processing. A cryptic splice-site, downstream of the mutation, was activated during processing, resulting in the inclusion of 117 bases of intron 26. This insertion introduced an in-frame stop codon into the mature dystrophin mRNA. An allele-specific test was developed to identify the mutation and was applied to this family. Interestingly, the mother of the two affected boys did not carry the mutation, as determined by allele-specific amplification and direct DNA sequence analysis, indicating gonadal mosaicism. Her eldest daughter, designated as a carrier based upon conventional testing and haplotype analysis, also did not carry the family mutation. Initial haplotyping of the family appeared to be straightforward with gonadal mosaicism becoming evident only after allele-specific analysis. The application of linked markers to identify the disease allele for conventional genetic counselling would have been erroneous in this family and highlights the diagnostic power of precise identification of the disease-causing mutation.

Two distinct mutations in a single dystrophin gene: chance occurrence or premutation?

We report on a kindred segregating 2 distinct mutations of a dystrophin gene. DNA analysis showed that the second mutation, a deletion, arose in the same gene carrying the primary defect which produced a Becker phenotype in the affected males. The DNA data for this family are reported and the alternative explanations of chance occurrence and premutation are discussed to explain these unusual findings.

A TaqI map of the dystrophin gene useful for deletion and carrier status analysis.

We describe a partial TaqI map of the dystrophin gene, obtained mainly by analysis of 87 overlapping DMD/BMD deletions with small fragments of the dystrophin cDNA probes; exon 6 of the dystrophin gene was identified on the TaqI map using the polymerase chain reaction. The cDNA probes detect five polymorphisms with TaqI, more than with HindIII (one), BglII (four), or PstI (three). The five polymorphisms are analysed concomitant with screening for deletions on the TaqI map, and in the one-third of DMD/BMD cases with no detected deletion the polymorphism information may be used for counselling. Correlation of the TaqI map with the HindIII map in the region of probes 5b-7 and 8 has allowed the establishment of reading frame. In this region of the dystrophin gene, all of 41 DMD deletions resulted in a shift of reading frame and all of 10 BMD patients maintained reading frame, in agreement with the 'reading frame hypothesis'.

Identification of Duchenne muscular dystrophy genomic probe P20 constant Taql fragment corresponding to the EcoRV and Mspl polymorphisms.

The majority of Duchenne and Becker muscular dystrophy cases are caused by deletions observable in Southern blots with cDNA probes for the gene. When the deletion includes polymorphic probes, they may be used to determine carrier status by deletion segregation analysis: non-inheritance of parental alleles, or heterozygosity. The polymorphic genomic probe P20 is deleted in a large percentage of probands. P20 hybridizes with two constant fragments of 6.7 and 0.8 kb in Taql digests. In a number of probands, only the larger P20 Taql fragment is deleted. This study demonstrates that this fragment corresponds with the polymorphic EcoRV and Mspl fragments of P20. Families in which the upper Taql fragment is deleted may be screened for carrier status using non-inheritance of parental alleles or heterozygosity of P20 in EcoRV or Mspl digests.

The diagnosis of Duchenne and Becker muscular dystrophies: two years' experience in a comprehensive carrier screening and prenatal diagnostic laboratory.

This article describes the diagnostic algorithm being used for the management of the 148 families affected by Duchenne or Becker muscular dystrophy who are known to the Molecular Neurogenetics Laboratory in the Department of Neuropathology, Royal Perth Hospital. In 60 families from whom DNA has been obtained, 41 mutations (39 deletions and two duplications) of the Duchenne muscular dystrophy gene (DMD) have been identified by means of complementary DNA (cDNA) probes. DNA-based screening has clarified the carrier status of 45 at-risk women, and 13 pregnancies have been monitored. In addition, cDNA screening of all relevant patients with autosomal recessive muscular dystrophy, spinal muscular atrophy or limb-girdle muscular dystrophy facilitated the correct diagnosis of Becker muscular dystrophy in three patients.

Differentiation of Becker muscular dystrophy from limb-girdle muscular dystrophy and Kugelberg-Welander disease using a cDNA probe.

A 31-year-old man previously investigated for a neuromuscular disorder was diagnosed as having either limb-girdle dystrophy, spinal muscular atrophy, or Becker muscular dystrophy. Extensive clinical and special neurological investigations failed to clarify this differential diagnosis. However, recent DNA studies have shown a deletion of the dystrophin gene, thereby providing an unequivocal diagnosis of Becker muscular dystrophy. The application of molecular genetic techniques in the diagnosis of inherited neuromuscular disorders is discussed.