Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?

We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syndrome (WS1) including three in the paired domain, six within or immediately adjacent to the homeodomain and two previously described polymorphic variants in exons 2 and 6. The affected members of one family carried substitutions involving two base pairs separated by one unaltered codon. Two of the deleterious mutations were identical and three others were identical to previously reported mutations.

Cobblestone lissencephaly with normal eyes and muscle.

Cobblestone lissencephaly is the characteristic brain malformation observed in Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS). The diagnostic criteria for all three require the presence of congenital muscular dystrophy, and criteria for MEB and WWS require retinal abnormalities. We report three patients from two consanguineous families of Middle Eastern origin with cobblestone lissencephaly but no abnormalities of the eyes or muscle.

Hereditary multiple exostoses: confirmation of linkage to chromosomes 8 and 11.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage capped prominences that develop from the epiphyses of the long bones. EXT is heterogeneous with three different locations currently identified on chromosomes 8, 11, and 19. Recently, we identified and studied 12 large multigenerational EXT families.

Evaluation of candidate genes for familial brachydactyly.

Type A1 brachydactyly in humans is a recognisable syndrome characterised by shortening of the middle phalanx of all digits with occasional fusion of the middle and terminal phalanges. The purpose of this study was to evaluate candidate genes for type A1 brachydactyly in two families with multiple affected members. Several classes of genes have been implicated in the control of distal limb development including homeobox containing genes (MSX1, MSX2) some members of the homeobox gene family, and genes encoding growth factors of the FGF, TGF, and PDGF families.

Nonsyndromic cleft lip with or without cleft palate: evidence of linkage to BCL3 in 17 multigenerational families.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common craniofacial developmental defect. Recent segregation analyses have suggested that major genes play a role in the etiology of CL/P. Linkage to 22 candidate genes was tested in 11 multigenerational families with CL/P, and 21 of these candidates were excluded.

X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13-p22.11.

Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and excluded all mapped autosomal loci.

Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXT-linked markers on chromosomes II and 8.

Hereditary multiple exostosis (EXT) is an autosomal dominant disorder characterized by bony exostoses at the ends of the long bones. Linkage studies have recently suggested that there are three chromosomal locations for EXT genes, 8q24.1 (EXT1), the pericentric region of 11 (EXT2), and 19p (EXT3).

Genetic heterogeneity in multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) comprises a group of hereditary chondrodysplasias in which there are major anatomic abnormalities of the long tubular bones. The Fairbank and Ribbing types are the most frequently cited types of MED. They are primarily defined radiographically and are autosomal dominant conditions.

A comparison of aztreonam and two regimens of gentamicin in a rabbit model of intra-amniotic infection and sepsis.

Objective: To compare aztreonam in a standard dose with two gentamicin doses in the early treatment of experimental intra-amniotic infection in rabbits induced by intracervical inoculation with Escherichia coli.

Methods: Timed pregnant rabbits on day 21 (70% of gestation) were inoculated intracervically with 10(4)-10(5) colony-forming units of E coli. After inoculation, the animals were treated with one of three regimens: 1) aztreonam at 90 mg/kg/day ("standard" dose in humans), 2) gentamicin at 4.

Cosegregation of codon 807 mutation of the canine rod cGMP phosphodiesterase beta gene and rcd1.

Purpose: To determine if a previously reported nonsense mutation (G to A transition at nucleotide position 2420) in the canine rod cyclic GMP (cGMP) phosphodiesterase beta (PDEB) subunit gene cosegregates with the rod-cone dysplasia 1 disease allele (rcd1) in the rcd1-dog reference colony; to establish the prevalence of this mutation among rcd1-affected Irish setters in the United States; and to screen for this mutation in other forms of canine hereditary progressive retinal atrophy (PRA).

Methods: Exon 21 of canine PDEB, previously reported to contain a nonsense mutation in rcd1-affected dogs, was amplified by polymerase chain reaction from genomic DNA isolated from peripheral blood samples. The mutation was detected in amplified DNA by restriction enzyme digestion and double-stranded conformational polymorphism.

Overcoming limitations in elbow movement in the presence of antagonist hyperactivity.

Background And Purpose: A traditional perspective on rehabilitation of patients with abnormal muscular hyperactivity presumes that relaxation should be facilitated prior to recruitment of antagonists, if effective movement about a joint is to occur. The purpose of the study was to determine the effect of training weak triceps brachii muscles, with hyperactivity present in the opposing biceps brachii muscles, on elbow function in individuals at least 1 year poststroke.

Subjects: Sixteen patients with chronic stroke were randomly assigned to receive electromyographic biofeedback to retrain the triceps muscle (n = 8) or to receive conventional movement training (n = 8).

XLPRA: a canine retinal degeneration inherited as an X-linked trait.

Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission.

Localization of the achondroplasia gene to the distal 2.5 Mb of human chromosome 4p.

Achondroplasia has been mapped to 4p16.3 using 18 multigenerational families with achondroplasia and 10 short tandem repeat polymorphic markers from this region. No evidence of genetic heterogeneity was found.

Linkage of typical pseudoachondroplasia to chromosome 19.

Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition associated with disproportionate short stature, marked joint deformities, and early onset osteoarthritis. Previous linkage studies have excluded linkage to cartilage and noncartilagenous extracellular matrix candidate genes. Here, we report mapping the pseudoachondroplasia gene to chromosome 19.

Genetic heterogeneity in families with hereditary multiple exostoses.

We have carried out a linkage analysis on 11 families segregating gene(s) for hereditary multiple exostoses (EXT). Four highly informative, short tandem-repeat (STR) markers that have been physically mapped to an interval surrounding the Langer-Giedion chromosomal region (8q24.11-q24.

Nonsyndromic cleft lip and palate: no evidence of linkage to HLA or factor 13A.

Nonsyndromic cleft lip with or without cleft palate (CLP) is a common craniofacial anomaly, the etiology of which is not known. Population studies have shown that a large proportion of cases occur sporadically. Recently, segregation analyses applied to CLP families have demonstrated that an autosomal dominant/codominant gene(s) may cause clefting in cases.

Linkage studies of the esterase D and retinoblastoma genes to canine copper toxicosis: a model for Wilson disease.

Canine copper toxicosis, an autosomal recessive disorder, is prevalent among certain dog breeds. It results in liver disease from copper accumulation and toxicity similar to the human autosomal recessive disorder, Wilson disease. The Wilson disease locus has been mapped to 13q and is closely linked to the esterase D and retinoblastoma genes.