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Biomedical subjects

R J Gardner

Publications and source records attributed to R J Gardner.

At least 19 recordsLinked to original sources
PubMed2005

Shape discrimination by total curvature, with a view to cancer diagnostics.

This paper investigates the use of total curvature for shape discrimination of objects via profiles of their planar sections (not assumed to be star shaped). Methods of estimating total curvature from observation of a finite number of points on the boundary of the object are investigated, including a simple discrete approximation method and various interpolation methods. Total curvature is capable of revealing shape differences on a local scale, as demonstrated by the analysis of two data sets of malignant and normal or benign tumour cell nuclear profiles.

Algorithms↗
PubMed2001

A new autosomal dominant pure cerebellar ataxia.

A kindred is described with a dominantly inherited "pure" cerebellar ataxia in which the currently known spinocerebellar ataxias have been excluded. In the eight subjects studied, a notable clinical feature is slow progression, with the three least affected having only a mild degree of gait ataxia after three or more decades of disease duration. Pending an actual chromosomal locus discovery, the name spinocerebellar ataxia (SCA)15 is expectantly applied.

Adult↗
PubMed2001

Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2.

The hereditary disorders of peripheral nerve form one of the most common groups of human genetic diseases, collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis we have identified a new locus for a form of CMT that we have called "dominant intermediate CMT" (DI-CMT). A genomewide screen using 383 microsatellite markers showed strong linkage to the short arm of chromosome 19 (maximum LOD score 4.3, with a recombination fraction (straight theta) of 0, at D19S221 and maximum LOD score 5.28, straight theta=0, at D19S226). Haplotype analysis performed with 14 additional markers placed the DI-CMT locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested the most likely location at D19S226 (maximum multipoint LOD score 6.77), within a 10-cM confidence interval. This study establishes the presence of a locus for DI-CMT on chromosome 19p12-p13.2.

Charcot-Marie-Tooth Disease↗
PubMed2001

Prevalence and nature of connexin 26 mutations in children with non-syndromic deafness.

OBJECTIVE: To determine (1) the prevalence and nature of connexin 26 mutations in a cohort of Australian children with non-syndromic hearing loss, and (2) the carrier frequency of the common connexin 26 mutation (35delG) in the general population. DESIGN: A cohort, case-finding study. Mutation analysis was performed on DNA extracted from white blood cells, buccal cells, or Guthrie blood spots. SETTING: A hearing loss investigation clinic and a deafness centre in two Australian capital cities, 1 January 1998 to 31 October 2000. PARTICIPANTS: (1) 243 children (age range, 4 weeks to 16 years; median, 4 years), attending hearing loss clinics in Sydney and Melbourne; (2) 1000 blood samples obtained from anonymous Guthrie card blood spots collected in 1984 [corrected] by the Victorian Clinical Genetics Service as part of the newborn screening program. MAIN OUTCOME MEASURES: (1) The prevalence and types of connexin 26 mutations in a cohort of children with prelingual deafness; (2) the carrier frequency of the common connexin 26 mutation, 35delG, in the general population. RESULTS: Connexin 26 mutations were identified and characterised in 52 (21%) of the 243 children; 14 different mutations, including four previously unreported mutations (135S, C53R, T123N and R127C), were identified. The common 35delG mutation was found in 56 of the 104 alleles (ie, 86 of the connexin 26 alleles in which a mutation was positively identified). The mutations V371 and M34T were also relatively common. The carrier frequency of connexin 26 mutations and of the common 35delG connexin 26 mutation in the Victorian population was estimated to be 1 in 54 and 1 in 100, respectively. CONCLUSIONS: Mutations in the connexin 26 gene (especially the 35delG mutation) are a common cause of prelingual hearing loss in Australia.

Adolescent↗
PubMed2001

New variant of familial cerebellar ataxia with hypergonadotropic hypogonadism and sensorineural deafness.

Cerebellar ataxia and hypergonadotropic hypogonadism comprise a rare and presumably heterogeneous association. Inheritance in most cases appears to be autosomal recessive, and associated features include deafness, intellectual impairment, and neuropathy. Typically, onset of ataxia is in the first decade and hypogonadism results in primary amenorrhoea in females. We describe two sisters with a previously undescribed pattern of adult onset progressive cerebellar ataxia and secondary amenorrhoea due to hypergonadotropic hypogonadism. Sensorineural deafness with vestibular hypofunction and peripheral sensory impairment were also present, and intellect was normal. Onset of neurological symptoms was in the third decade, with secondary amenorrhoea occurring at the ages of 16 and 32 years, respectively. The association of ataxia and hypergonadotropic hypergonadism has been classified both as a variant of Holmes type ataxia and as a variant of Perrault syndrome, but we suggest the use of a separate category of ataxia with hypergonadotropic hypogonadism.

Adolescent↗
PubMed2001

Near-total absence of the cerebellum.

We report five cases of near-total absence of the cerebellum with accompanying pontine hypoplasia. The cerebellar remnant in each case comprised only antero-superior masses, the posterior fossa being otherwise fluid filled. Three of these patients, two teenagers and an infant, presented a fairly consistent clinical and neuroradiological phenotype, and a few similar cases are recorded in the literature. The cerebellar remnant was irregular and asymmetrical, and no ventral pontine prominence was discernible. In at least the older two, cerebellar motor functions were not greatly compromised, and intellectual handicap was of a mild degree. We propose that these cases represent a distinct entity of "near-total absence of the cerebellum with flat ventral pons, and relatively mild clinical affection". All cases have been sporadic, implying that the risk of recurrence within a family may be low. Quite different clinical pictures, of considerably greater severity, are demonstrated in the remaining two cases. One had pontocerebellar hypoplasia type 2, while the other had a complex cerebellar and cerebral malformation.

Adolescent↗
PubMed2001

Microlissencephaly with cardiac, spinal and urogenital defects.

We describe two children with a brain defect similar to that described as 'microlissencephaly', as defined in Barkovich et aL [(1998) Neuroped 29: 113-119]. Concomitant malformations (cardiac, spinal, urogenital) may represent components of a wider syndrome complex; alternatively, or additionally, there may have been a valproate teratogenic effect. The inheritance is likely to be autosomal recessive, although X-linkage cannot be excluded.

Abnormalities, Drug-Induced↗
PubMed2001

Chromosomal abnormalities in idiopathic congenital bilateral vocal cord paralysis.

Idiopathic congenital bilateral vocal cord paralysis (BVCP) can occur as an isolated abnormality or as part of a multisystem disorder. The chromosomal abnormalities found in 4 children who presented with idiopathic congenital BVCP in association with other congenital abnormalities between January 1991 and April 1999 are described. Three children had abductor paralysis, and tracheostomy was required in 1. The fourth child had adductor paralysis and required a feeding gastrostomy for management of aspiration. There was no clinically significant improvement in vocal cord function observed in any child. Idiopathic congenital BVCP, when associated with other congenital disorders, may occur as a consequence of an underlying chromosomal abnormality, and chromosome studies should be performed in this group of children. Similarly, the possibility of vocal cord dysfunction should be considered in children who are found to have chromosomal abnormalities. A chromosomal abnormality appears to preclude the possibility of early spontaneous improvement in vocal cord function.

Abnormalities, Multiple↗
PubMed2000

An imprinted locus associated with transient neonatal diabetes mellitus.

Recently, we reported the localization of a gene for transient neonatal diabetes mellitus (TNDM), a rare form of childhood diabetes, to an approximately 5.4 Mb region of chromosome 6q24. We have also shown that TNDM is associated with both paternal uniparental disomy (UPD) of chromosome 6 and paternal duplications of the critical region. The sequencing of P1-derived artificial chromosome clones from within the region of interest has allowed us to further localize the gene and to investigate the methylation status of the region. The gene is now known to reside in a 300-400 kb region of 6q24 which contains several CpG islands. At one island we have demonstrated differential DNA methylation between patients with paternal UPD of chromosome 6 and normal controls. In addition, two patients with TNDM, in whom neither paternal UPD of chromosome 6 nor duplication of 6q24 have been found, show a DNA methylation pattern identical to that of patients with paternal UPD of chromosome 6. Control individuals show a hemizygous methylation pattern. These results show that TNDM can be associated with a methylation change and identify a novel methylation imprint on chromosome 6 associated with TNDM.

Blotting, Southern↗
PubMed2000

Two novel members of the interleukin-1 receptor gene family, one deleted in Xp22.1-Xp21.3 mental retardation.

X-linked mental retardation is estimated to affect approximately 1 in 600 males. Although numerous genes responsible for syndromic mental retardation have been identified, the study of non-syndromic mental retardation suffers from intrinsic issues of genetic heterogeneity. During the investigation of three brothers with a contiguous gene deletion syndrome of Becker muscular dystrophy, glycerol kinase deficiency, congenital adrenal hypoplasia, and mental retardation, we found their dystrophin gene to be fused tail-to-tail with a gene encoding a novel member of the interleukin-1 receptor family, IL1RAPL1. This gene has a close relative in Xq22, which we call IL1RAPL2. Both IL1RAPL1 and IL1RAPL2 have novel C-terminal sequences not present in other related proteins, and are encoded by very large genes. The 1.8-megabase deletion in these patients removes not only the last exon of the dystrophin gene, the entire glycerol kinase and DAX-1 genes, and the MAGE-B gene cluster, but also three exons encoding the intracellular signalling domain of IL1RAPL1. The literature contains multiple reports of patients with non-syndromic mental retardation in association with an Xp22.1-Xp21.3 microdeletion of a marker which lies within the IL1RAPL1 gene. The gene is also wholly or partially deleted in patients with mental retardation as part of a contiguous deletion syndrome. We suggest that IL1RAPL1, and perhaps IL1RAPL2, are strong candidates for X-linked non-syndromic mental retardation loci, and that molecules resembling IL-1 and IL-18 play a role in the development or function of the central nervous system.

5' Untranslated Regions↗
PubMed2000

Syntelencephaly presenting with spastic diplegia.

Two children with syntelencephaly presented with the predominant clinical picture of spastic diplegia. Brain scanning showed deficient formation of the interhemispheric fissure with fusion of occipital and parietal lobes, and an infolding and protrusion of occipital cortex into the telencephalic ventricle. The fusion extended further posteriorly than the cases of "middle interhemispheric fusion" thus far reported. One 7-year old has poor language development, while the other is regarded, at her present age of 3 years, as being cognitively within the normal range.

Agenesis of Corpus Callosum↗
PubMed2000

Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes.

Transient neonatal diabetes (TND) is a rare type of diabetes that presents soon after birth, resolves by 18 months, and predisposes to diabetes later in life. A total of 30 patients were ascertained and investigated for aberrations of chromosome 6. A genotype/phenotype study was also performed. Genotypically, these patients can be classified into 4 etiologic groups. Group 1 had paternal uniparental isodisomy of chromosome 6 (11 cases, including 1 set of identical twins). Group 2 had a duplication involving chromosome band 6q24, which was paternal in origin where tested (4 sporadic cases and 7 familial cases from 2 families). Group 3 consisted of 1 patient with a loss of methylation at a CpG island within the TND critical region (1 sporadic case). Group 4 had no identifiable rearrangement of chromosome 6 (7 sporadic cases). Most patients were growth retarded at birth, presented at a median age of 3 days, and recovered at a median age of 12 weeks. In group 2, 2 relatives of the TND patients who presented with type 2 diabetes and no early history of TND had inherited an identical duplication. An abnormality of chromosome 6 was identified in approximately 70% of sporadic TND cases and in all familial cases. No significant clinical differences were found between the 4 etiological groups. The study has broadened the clinical spectrum of TND to include type 2 diabetes presenting in later life with no neonatal presentation. The findings are consistent with an imprinted gene for diabetes mapping to 6q24, which we predict will have an important function in normal pancreatic development.

Aneuploidy↗
PubMed1999

Clinical and genetic study of Friedreich ataxia in an Australian population.

Friedreich ataxia is an autosomal recessive disorder caused by mutations in the FRDA gene that encodes a 210-amino acid protein called frataxin. An expansion of a GAA trinucleotide repeat in intron 1 of the gene is present in more than 95% of mutant alleles. Of the 83 people we studied who have mutations in FRDA, 78 are homozygous for an expanded GAA repeat; the other five patients have an expansion in one allele and a point mutation in the other. Here we present a detailed clinical and genetic study of a subset of 51 patients homozygous for an expansion of the GAA repeat. We found a correlation between the size of the smaller of the two expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. There was no significant correlation between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size correlated with bladder symptoms and the presence of foot deformity. The duration of disease is correlated with wheelchair use and the presence of diabetes, scoliosis, bladder symptoms and impaired proprioception, and vibration sense but no other complications studied.

Adolescent↗
PubMed1999

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Genetics, Medical↗