Biomedical subjects

A J Pinckers

Publications and source records attributed to A J Pinckers.

At least 37 records · Page 2Linked to original sources

PubMed1996

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1.

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X-linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide-exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.

Amino Acid Sequence↗

PubMed1996

Stable and progressive hearing loss in type 2A Usher's syndrome.

Audiograms were traced or additionally performed on 23 Usher's syndrome patients in 10 Dutch multi-affected families, all linked to chromosome 1q (USH2A locus). Serial audiograms, available in 13 patients, were used for a regression analysis of binaural pure tone average on age (follow-up, 9 to 32 years) to test for "significant progression," ie, a significant regression coefficient, here called the "annual threshold increase" (ATI, expressed in decibels per year). A significant ATI (> 1 dB/y) was observed in 3 patients. Analysis of variance of ATI demonstrated significant heterogeneity; hearing loss was either stable or progressive. This implies a significant clinical heterogeneity. A similar analysis performed on our progressive USH2A cases and "type III" cases previously reported by others (ATI of 1 to 5 dB/y), some of which were recently linked to chromosome 3q (USH3 locus), failed to show any significant heterogeneity in the progression of hearing loss.

Adolescent↗

PubMed1995

Carrier detection of Batten disease (juvenile neuronal ceroid-lipofuscinosis).

Batten disease, or the juvenile form of neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder manifesting with progressive blindness, seizures, and dementia, leading to an early death. The CLN3 locus which is involved in Batten disease had been localized to chromosome 16p11.2. Linkage disequilibrium has been observed between CLN3 and polymorphic microsatellite markers D16S288, D16S299, and D16S298, making carrier detection and prenatal diagnosis by haplotype analysis possible. For the purpose of carrier detection, haplotypes from Dutch Batten patients and their families were constructed. Most patients share the same D16S298 allele, suggesting the presence of a founder effect in the Dutch population. In a large inbred Dutch family, in which Batten disease occurs with high frequency, haplotype analysis has been carried out with high accuracy for carrier detection.

Alleles↗

PubMed1995

Autosomal recessive Melnick-Needles syndrome or ter Haar syndrome? Report of a patient and reappraisal of an earlier report.

We report on a patient with congenital glaucoma, brachycephaly with flat occiput, large anterior fontanel, hypertelorism, anteverted nostrils, thoracolumbar kyphosis, prominent coccyx with skin fold, short hands and feet, flexion deformity of fingers, and clubfeet. He had a double-outlet right ventricle with ventricular septal defect, and severe tricuspid insufficiency. Mild skeletal changes included short tubular bones, absence of distal phalanges of toes, caliber variation of ribs, and scalloping of the anterior surface of vertebrae. The patient died at age 21 months. He belongs to the same extended family as 3 similarly affected patients, previously described by ter Haar et al. [1982: Am J Med Genet 13:469-477] as representing an autosomal recessive form of Melnick-Needles syndrome. We believe this diagnosis is no longer tenable. After having reviewed the relevant literature, we conclude that most probably we are dealing with a new autosomal recessive syndrome. We propose to name this entity ter Haar syndrome.

Diagnosis, Differential↗

PubMed1995

Effect of steady hypothermia and normothermia on multimodality evoked potentials in human poikilothermia.

OBJECTIVE: To assess the effects of steady-state spontaneous hypothermia on multimodality evoked potentials and on peripheral nerve conduction in human poikilothermia. DESIGN AND SETTING: Case series at a university hospital. PATIENTS: Four patients (four women, aged 28 to 37 years) with acquired poikilothermia. MAIN OUTCOME MEASURES: Short-latency somatosensory, brain-stem auditory, and visual evoked potentials as well as motor and sensory peripheral nerve conduction velocity during steady-state spontaneous hypothermia and normothermia. RESULTS: The marked latency prolongation of all evoked potentials and decreased peripheral nerve conduction velocity observed during steady-state spontaneous hypothermia (mean +/- SD core temperature, 33.5 +/- 0.3 degrees C) compared with normothermia (36.9 +/- 0.4 degrees C) agrees with previous findings during short-term induced hypothermia. CONCLUSIONS: The unequivocal effect of sustained mild spontaneous hypothermia on evoked potentials and peripheral nerve conduction velocity underlines the importance of meticulous attention to even small alterations in core temperature in interpreting neurophysiological investigations.

Adult↗

PubMed1995

Discriminative power of visual evoked potential characteristics in multiple sclerosis.

To investigate the discriminative power of pattern-reversal visual evoked potential characteristics (peak latencies and amplitude) and to test whether the addition of visual evoked potential amplitude can increase the power of the visual evoked potential in the diagnosis of multiple sclerosis, we retrospectively studied visual evoked potentials in 59 patients with definite multiple sclerosis and 126 control subjects. Two check sizes (17' and 10') were used. Females had significantly higher amplitudes and shorter latencies than males. N80 latency showed a gradual increase and P100 amplitude a decrease with age. P100 latency was stable between the ages of 20 and 55 years but was increased in childhood and the elderly. The significance of visual evoked potential peak latencies and amplitude in separating the two groups was investigated by means of a (multivariate) discriminant analysis. The visual evoked potential with a pattern of 10' could be measured in 58% of patients with multiple sclerosis. The exclusive use of the P100 amplitude in the discriminant analysis resulted in a percentage of correctly classified cases of 84%, whereas for P100 and N80 latency it was 85% and 90%, respectively. With the 17' pattern, the N80 latency yielded also a higher correct percentage than did the P100 latency. Although N80 latency is, to a greater extent than P100 latency, influenced by age, sex and size of stimulus pattern, when these influences are accounted for, the N80 latency is a more sensitive measure than P100 latency in the classification of multiple sclerosis. Combined use of latency and amplitude for discriminant analysis yielded no significant improvement of the percentage of correctly classified cases.

Adolescent↗

PubMed1995

The Usher syndrome type 2A: clinical findings in obligate carriers.

Ten obligate carriers of Usher syndrome type 2A from 5 different families with 2 affected persons all underwent audiologic, vestibular and ophthalmologic examinations. They had a sensorineural hearing loss which was in excess of that expected for their age at all of the frequencies (0.25-8 kHz) tested, however, only a 10 dB (average) excess in hearing loss at 0.25-0.5 kHz proved to be significant. The speech discrimination scores obtained conformed with the hearing thresholds. Tympanometry, acoustic reflex and brain stem auditory-evoked potential findings were generally normal. Some vestibular abnormalities were found in a minority of the carrier sample, but not beyond the level of false positivity. Ophthalmologic findings were essentially normal, although in 5 carriers there was a subnormal electrooculography (EOG). These findings are not sufficient specific for carrier detection.

Acoustic Impedance Tests↗

PubMed1995

Multipoint linkage analysis and homogeneity tests in 15 Dutch X-linked retinitis pigmentosa families.

Linkage analysis and homogeneity tests were carried out in 15 Dutch families segregating X-linked retinitis pigmentosa (X L R P). The study included segregation data for eight polymorphic DNA markers from the short arm of the human X chromosome. The results of both multipoint linkage analysis in individual families and heterogeneity analysis support the view that there are only two X L R P loci on the short arm of the human X chromosome, with one locus near the OTC gene and one in the vicinity of DXS255. Furthermore, our data confirm the hypothesis that a tapetal reflex in female carriers can be observed more frequently, if not exclusively, in X L R P families of the R P 3 type.

Adolescent↗

PubMed1995

Ophthalmologic findings in Usher syndrome type 2A.

Thirty-seven patients, comprising 24 familial cases and 13 isolated patients with Usher syndrome type II (USH2), underwent ophthalmologic examination. Based on the degree of hearing loss, normal vestibular function, and gene-linkage analysis, familial cases were assumed to have USH2A. An analysis of genetic heterogeneity failed to reveal the presence of a second locus in the Dutch population. Although the patients appear to belong to a genetically homogeneous group, remarkable ophthalmologic variability was found. Corrected visual acuity decreased with age and remarkable differences in visual acuity were found within one family. Fundoscopic findings were classified as type A if attenuated vessels and bone corpuscles in all quadrants were found or as type B if findings other than these were found. The prevalence of type A significantly increased with age.

Adolescent↗

PubMed1992

Carrier detection in X-linked ocular albinism of the Nettleship-Falls type by DNA analysis.

X-linked ocular albinism (XOA) is characterized by anomalies of the eyes and hypopigmentation or absence of pigment in skin, hair and eyes due to a hereditary inborn error of metabolism affecting the pigment cells. The gene of XOA of the Nettleship-Falls type (OA1) has been mapped to Xp22.3, and several closely linked RFLP loci have been identified. Linkage analysis and deletion mapping have established the marker gene order Xpter-STS-DX237-(OA1,DXS143,DXS85)-DXS1 6-DXS43-Xcen. Although the position of OA1 has yet not been fully resolved, we report on the first carrier detections in OXA of the Nettleship-Falls type by DNA analysis using markers which unquestionably flank OA1.

Albinism, Ocular↗

PubMed1992

Detection and characterization of point mutations in the choroideremia candidate gene by PCR-SSCP analysis and direct DNA sequencing.

By making use of positional cloning strategies we recently isolated a candidate gene for choroideremia (CHM), which is transcribed in retina, choroid, and/or retinal pigment epithelium. The gene contains an open reading frame that is structurally altered in 10 CHM patients with sizable deletions and in a female patient with a balanced translocation involving the Xq21 band. Employing PCR-SSCP analysis and direct DNA sequencing we have now detected and characterized different point mutations in five patients with CHM. Each of these mutations introduces a termination codon into the open reading frame of the CHM candidate gene, thereby predicting a distinct truncated protein product. Together these findings provide convincing evidence for the candidate gene being identical with the choroideremia gene.

Amino Acid Sequence↗

PubMed1991

Multipoint linkage analysis in X-linked ocular albinism of the Nettleship-Falls type.

An extensive linkage analysis was performed by studying ten Xp22 loci in ten families segregating for X-linked ocular albinism of the Nettleship-Falls type (XOA). Linkage was confirmed between the XOA locus (OA1) and both DXS16 (theta max = 0.10, zeta max = 4.09) and DXS237 (theta max = 0.12, zeta max = 2.53). Linkage was found between OA1 and the loci DXS85 (theta max = 0.00, zeta max = zeta max = 4.37), DXS143 (theta max = 0.04, zeta max = 3.74), STS (theta max = 0.05, zeta max = 2.48), DXF30S1 (DXS278) (theta max = 0.07, zeta max = 8.79) and DXF30S2/3 (DXS278) (theta max = 0.00, zeta max = 14.93). An indication for linkage was found between OA1 and the loci DXS43 (theta max = 0.10, zeta max = 1.58) and DXS31 (theta max = 0.12, zeta max = 1.55). The analysis of multiple informative meioses suggests the order Xpter-(DXS31, DXS89)-(DXF30S1, DXS237)-(DXF30S2/3, OA1)-DXS143-(DXS16, DXS43)-Xcen. Various multipoint linkage analyses using the DNA loci order DXF30S1-STS-DXS237-DXS143-DXS16 significantly favour the position of OA1 between DXS237 and DXS143. These results further determine the genetic map around the XOA locus on the distal Xp and may be useful for DNA diagnosis in families with XOA.

Albinism, Ocular↗

PubMed1991

Myotonic dystrophy. Predictive value of normal results on clinical examination.

Myotonic dystrophy (DM) is well known for its highly variable clinical picture, including the age at which symptoms are first detected. In order to assess the proportion of asymptomatic gene carriers at different ages, we have used linked DNA markers to study individuals at 50% genetic risk of DM, in whom neurological examination, slit-lamp examination and electromyography (EMG) had failed to show diagnostic signs. A total of 139 asymptomatic offspring of DM patients were studied. Our analyses identified 11 out of these 139 as probable gene carriers. Our data show that penetrance of the DM gene increases with age. After correction for the possibility of genetic recombination between the DM gene and the DNA markers used, we calculated the residual chance of carrying the DM gene as 8.3% for clinically normal offspring aged between 20 and 39 yrs. We evaluated several factors that might influence this figure. Neither the sex of the propositus nor that of the affected parent modified the risk of carrying the DM gene. Presence of aspecific lens opacities also did not correlate with the risk of having inherited the DM gene. Since a significant proportion of DM gene carriers are not detected by neurological examination, including slit-lamp examination and EMG, these results confirm the need for DNA analysis in asymptomatic offspring of DM patients.

Biomarkers↗

PubMed1990

The electro-oculogram in uveal melanoma. A prospective study.

The electro-oculogram in 52 patients with a suspected malignant melanoma of the choroid or ciliary body was plotted in a diagram constructed for the differential diagnosis of malignant melanoma, metastasis, naevus and retinal detachment. Thirty-one patients were diagnosed as suffering from malignant melanoma on clinical grounds (19 histologically confirmed). Twenty-six were classified correctly as a melanoma using our EOG probability score. Rupture of Bruch's membrane and tumor localization were of no influence on the EOG classification. Accompanying retinal detachment lowered the Lp/Dt-ratio significantly without affecting the Dt, as was also the case in tumors with a prominence equal to or greater than 6 mm when compared with smaller tumors. However melanomas were still classified correctly in the majority of the patients by means of EOG. We conclude that an acceptable differentiation can be made between melanomas, retinal detachments and naevi. Melanomas cannot be differentiated from choroidal metastases.

Choroid Neoplasms↗

PubMed1990

Early findings in central areolar choroidal dystrophy.

We examined 69 members of two caucasian families with an autosomal dominant form of central areolar choroidal dystrophy using ophthalmoscopy and fundus photography. In five members who had a good visual acuity macular lesions were found. In three of them retinal function tests were performed, which turned out to be normal. These 5 patients underwent fluorescein angiography. Early symptoms of central areolar choroidal dystrophy are small parafoveal hyperfluorescent areas due to retinal pigmentepithelium loss and areas of pigment mottling in the macula. Until now the early lesions of central areolar choroidal dystrophy in patients with a good visual acuity in both eyes have not been described clearly.

Adult↗

PubMed1990

Deletions in patients with classical choroideremia vary in size from 45 kb to several megabases.

Making use of the p1bD5 probe (DXS165), we have isolated several markers from the choroideremia locus by chromosomal jumping, preparative field-inversion gel electrophoresis, and cloning of a deletion junction fragment. With these clones we were able to identify and characterize eight deletions in 69 choroideremia patients investigated. The deletions are heterogeneous, in both size and location. The smallest deletion (patient LGL1134) comprises approximately 45 kb of DNA, whereas the largest ones (patients 25.6 and LGL2905) span a DNA segment of at least 5 megabases, which is comparable in size to the smallest deletion detected in a TCD patient (patient XL45) showing a complex phenotype. The TCD deletions encompass variable parts of 150-200-kb DNA segment that is flanked by p1bD5 (DXS165) at the centromeric side and by pZ 11 at the telomeric side. The deletions in patients 33.1, LGL1101, and LGl1134 do not span a translocation breakpoint which was previously mapped on the X chromosome of a female with TCD. The clones isolated from the TCD locus are valuable diagnostic markers for deletion analysis of patients or carrier females. In addition, they should be useful for the isolation of expressed sequences that are part of the TCD gene.

Blotting, Southern↗

PubMed1988

Immune responsiveness to retinal S-antigen and opsin in serpiginous choroiditis and other retinal diseases.

The immune responsiveness to bovine retinal S-antigen and opsin has been investigated in some retinal disorders by means of in vitro lymphocyte proliferation, leukocyte migration inhibition and enzyme linked immune sorbent assays (ELISA). Sensitisation to S-antigen was observed in serpiginous choroiditis, but not in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) or retinitis pigmentosa. No significant immune responsiveness was detected to opsin in any of the three diseases. Elevated antibody titers to S-antigen were observed in some individual patients and healthy subjects. However, none of the patient groups exhibited an elevated antibody titer as compared to the control group. Although serpiginous choroiditis and APMPPE share some prominent clinical characteristics, the sensitisation in the former disease may perhaps be attributed to more severe and prolonged damage of the photoreceptor cells and blood-retina barrier. A combination of previous and present results suggests that in immunological investigations of retinitis pigmentosa patients it is more effective to use human than bovine S-antigen as test antigen because a species specific epitope seems to be involved.

Antibody Formation↗

PubMed1986

Optic atrophy in Wolfram syndrome.

The clinical and electrophysiologic findings in 11 cases of Wolfram syndrome are presented. These findings suggest that optic atrophy in Wolfram syndrome is not secondary to retinal pathology, but probably represents part of a generalized degeneration of neural structures. The relationship of diabetes mellitus to this process of neural degeneration remains unclear.

Adolescent↗