Genetic basis of total colourblindness among the Pingelapese islanders.

Complete achromatopsia is a rare, autosomal recessive disorder characterized by photophobia, low visual acuity, nystagmus and a total inability to distinguish colours. In this disease, cone photoreceptors, the retinal sensory neurons mediating colour vision, seem viable but fail to generate an electrical response to light. Achromatopsia, or rod monochromatism, was first mapped to 2p11-2q12 (MIM 216900; ref. 3), where it is associated with missense mutations in CNGA3 (ref. 4). CNGA3 encodes the alpha-subunit of the cone cyclic nucleotide-gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A second locus at 8q21-q22 has been identified among the Pingelapese islanders of Micronesia, who have a high incidence of recessive achromatopsia (MIM 262300). Here we narrow the achromatopsia locus to 1.4 cM and show that Pingelapese achromatopsia segregates with a missense mutation at a highly conserved site in CNGB3, a new gene that encodes the beta-subunit of the cone cyclic nucleotide-gated cation channel. Two independent frameshift deletions establish that achromatopsia is the null phenotype of CNGB3. Combined with earlier findings, our results demonstrate that both alpha- and beta-subunits of the cGMP-gated channel are essential for phototransduction in all three classes of cones.

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

Anterior commissure absence without callosal agenesis: a new brain malformation.

The authors report a novel human brain malformation characterized by the absence of the anterior commissure without callosal agenesis, but associated with gross unilateral panhemispheric malformation incorporating subependymal heterotopia, subcortical heterotopia, and gyral abnormalities including temporal malformation and polymicrogyria. In contrast, a normal anterior commissure was found in 125 control subjects and in 113 other subjects with a range of brain malformations.

Microphthalmos in the presumed homozygous offspring of a first cousin marriage and linkage analysis of a locus in a family with autosomal dominant cerulean congenital cataracts.

A family with autosomal dominant congenital cataracts was studied to determine clinical variability. A total of 159 relatives was ascertained; 17 affected and 19 normal individuals were evaluated and their blood sampled for inclusion in the linkage analysis. The disease was compatible with normal to mildly decreased visual acuity until adult life in all affected except the product of a consanguineous marriage of affected first cousins who was born with bilateral microphthalmos and dense congenital cataracts, attributed to homozygosity of the cataract gene. There were no extraocular abnormalities; the patient was of normal intelligence. Twenty-three markers were typed, 18 of which were informative. Linkage could be excluded for all 18 markers at short distances.

The age-dependent deterioration in light touch sensation on the plantar aspect of the foot in a rural community in India: implications when screening for sensory impairment.

Regular testing for impaired sensation is important in the management of diseases that can cause progressive nerve damage, such as leprosy. It has been shown that light touch sensibility decreases with age in the hands of healthy individuals, but little research has been undertaken to assess possible changes in the feet in developing countries. This information is needed to allow an appropriate level of sensation to be chosen when screening for nerve damage in the foot. To clarify this, a cross-sectional study on male adults was carried out in the rural town of Salur, Andhra Pradesh, India. A range of Semmes-Weinstein monofilaments were employed at 12 locations on the foot to determine sensation to light touch stimuli in individuals from each decade of adult life. It was found that in this population, sensibility threshold in the foot increases with age and this was noted in both soft and callous skin. This shows the increase was due to neurological factors, not merely due to an increase in callous deposition with advancing age. In the majority of individuals in their fifties and sixties, the callous skin at the forefoot and heel was unable to detect the 5.07 monofilament (equivalent to 8-12 g), previously recommended as a method to screen for plantar neuropathy. All areas of all feet were able to detect the 5.46 filament (approximately 30 g). The size of this study (54 individuals) prevents the determination of definitive normal ranges for each decade of life in this population. However, it does demonstrate the degree to which sensation deteriorates with age and could be used as an approximate guide when interpreting the results of sensory testing in similar rural areas of the developing world.

Three-dimensional endoscopic imaging for minimal access surgery.

Three-dimensional endoscopic imaging (3DEndoImaging) is a significant technological advance and has the potential to make minimal access surgery (MAS) easier, quicker, less prone to error and more applicable to advanced procedures. Surgeons involved in MAS will need to have a working knowledge of 3DEndoImaging. This article will enable surgeons to compare stereo systems and evaluate which system would best suit their needs. This paper explains why stereo imaging is important and describes the methods by which stereo images can be produced. The technology required is discussed in simple terms. The types of stereo systems are described and important operational and maintenance issues discussed. Task analysis studies showing significant improvement in performance in stereo are presented. These studies simulated accurately positioning an instrument and threading a small diameter solder lug.

Defective auditory interhemispheric transfer in a patient with a PAX6 mutation.

Heterozygous PAX6 mutation is associated with an absent or hypoplastic anterior commissure and a reduction in the area of the corpus callosum. The authors found deficient auditory interhemispheric transfer in a 53-year-old woman with a PAX6 mutation who had an absent anterior commissure but normal callosal volume.

Quantitative MRI detects abnormalities in relatives of patients with epilepsy and malformations of cortical development.

Malformations of cortical development (MCD) are a common etiology for epilepsy. Laminar heterotopia, bilateral subependymal heterotopia, and lissencephaly have a genetic basis. No gene mutations have yet been identified in patients with focal cortical dysplasias. The aim of this study was to use quantitative morphometric tools to determine if there were gray matter abnormalities in relatives of patients with MCD. We studied 19 relatives of 13 probands with MCD and 58 healthy controls with high-resolution MRI. The relatives and controls had no neocortical abnormalities on visual inspection. MRI data were analyzed with voxel-based morphometry and autoblock analysis. Voxel-based morphometry showed significant increases of gray matter in 9 of 10 probands, 5 of 19 relatives, and 5 of 58 controls. The autoblock analysis showed significant abnormalities in 7 of 8 probands, 8 of 19 relatives, and 2 of 57 controls. This finding suggests structural abnormality in the brains of a greater number of relatives of MCD patients than would be expected, and in the context, a reasonable inference is that this reflects subtle genetically determined cerebral abnormalities, although acquired pathologies are possible and are not excluded.

Cognitive functioning in humans with mutations of the PAX6 gene.

Fourteen patients with PAX6 gene mutations and previously identified MRI abnormalities were administered tests of cognitive functioning. No deficits were found. A subgroup with agenesis of the anterior commissure performed significantly more poorly on measures of working memory than those without this abnormality, suggesting the anterior commissure may play a role in cognitive processing in addition to an earlier identified role in sensory development and processing.

Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human beta-crystallin gene CRYBB2.

Congenital cataracts are a common major abnormality of the eye that frequently cause blindness in infants. At least a third of all cases are familial; autosomal dominant congenital cataract (ADCC) appears to be the most common familial form in the Western world. Cerulean cataracts have peripheral bluish and white opacifications in concentric layers with occasional central lesions arranged radially. Although the opacities may be observed during fetal development and childhood, usually visual acuity is only mildly reduced until adulthood, when lens extraction is generally necessary. We have been studying a family (ADCC-1) with cerulean blue ADCC, in which the affected daughter of a first cousin mating was presumed to be homozygous for the cataract gene. Recently, we mapped an ADCC gene in this family to a region of chromosome 22 containing three beta-crystallin genes. Here we report that a chain-termination mutation in CRYBB2 is associated with ADCC in this family.

Assignment of the Nance-Horan syndrome to the distal short arm of the X chromosome.

There are three types of X-linked cataracts recorded in Mendelian Inheritance in Man (McKusick 1988): congenital total, with posterior sutural opacities in heterozygotes; congenital, with microcornea or slight microphthalmia; and the cataract-dental syndrome or Nance-Horan (NH) syndrome. To identify a DNA marker close to the gene responsible for the NH syndrome, linkage analysis on 36 members in a three-generation pedigree including seven affected males and nine carrier females was performed using 31 DNA markers. A LOD score of 1.662 at theta = 0.16 was obtained with probe 782 from locus DXS85 on Xp22.2-p22.3. Negative LOD scores were found at six loci on the short arm, one distal to DXS85, five proximal, and six probes spanning the long arm were highly negative. These results make the assignment of the locus for NH to the distal end of the short arm of the X chromosome likely.