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Biomedical subjects

P J Willems

Publications and source records attributed to P J Willems.

At least 19 recordsLinked to original sources
PubMed2003

Poor outcome in Down syndrome fetuses with cardiac anomalies or growth retardation.

The outcome of Down syndrome fetuses presenting with sonographic abnormalities in the second or third trimester is unclear. Therefore, we studied 55 pregnancies referred because of sonographically suspected fetal structural anomalies or growth retardation due to trisomy 21. A detailed ultrasound scan was performed in all cases to delineate the structural anomalies. Congenital heart malformations (CHMs) were diagnosed pre- and postnatally in 29 out of 55 Down fetuses (53%), with complete or incomplete atrioventricular septal defects (AVSDs) and ventricular septal defects (VSDs) being the most frequent anomalies. The most frequent noncardiac findings were a short femur (45%) and a small-for-gestational age (SGA) fetus (27%). Termination of pregnancy was carried out in 25 out of 55 pregnancies (45%). Of the 30 continued pregnancies, 10 ended with intrauterine death. The remaining 20 pregnancies resulted in the delivery of a live-born infant whose prognosis was poor, with a 1-year survival of only 60%. Combining intrauterine death and death in the first year indicated that the overall survival rate was only 40%. Fatal outcome was noted in 68% (13/19) in the presence of CHM, in 83% (10/12) in SGA fetuses, in 86% (6/7) in combined CHM and SGA, but only in 17% (1/6) in the absence of CHM and SGA. This study indictes that second- and third-trimester in utero diagnosis of Down syndrome has a poor outcome when associated with CHM and/or SGA. This is important in the genetic counseling of the parents.

Abortion, Induced↗
PubMed2003

Genetic epidemiology of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurological disorder, caused by the loss of motor neurons in the brain and spinal cord. Familial aggregation of ALS, with an age-dependent but high penetrance, is a major risk factor for ALS. Familial ALS (FALS) is clinically and genetically heterogeneous. Three genes and linkage to four additional gene loci have been identified so far and may either predominantly lead to ALS (ALSI-ALS6) or cause multisystem neurodegeneration with ALS as an occasional symptom (tauopathies, ALS-dementia complex). This review presents a tentative classification of the "major" ALS genes and ALS "susceptibility" genes, that may act as susceptibility factors for neurodegeneration in interaction with other genetic or environmental risk factors. Considering that mutations in ALS genes explain approximately 10% of familial as well as sporadic ALS, and most remaining cases of the discase are thought to result form the interaction of several genes and environmental factors, ALS is a paradigm for multifactorial discases.

Age Factors↗
PubMed2003

Homozygosity mapping of a gene for arterial tortuosity syndrome to chromosome 20q13.

BACKGROUND: Arterial tortuosity syndrome (ATS) is an uncommon connective tissue disorder of unknown aetiology. The most prominent feature is tortuosity of the large arteries, but lengthening, stenosis, and aneurysm formation are also frequent. METHODS: We performed a genomewide screen by homozygosity mapping of three consanguineous multiplex families, two from Morocco, and one from Italy, which included 11 ATS patients. The two families from Morocco may possibly have a common ancestor. RESULTS: We mapped the ATS gene to chromosome 20q13. Recombinations within an extended haplotype of 11 microsatellite markers localised the ATS gene between markers D20S836 and D20S109, an interval of 9.5 cM. CONCLUSIONS: Cloning and completing functional and structural analysis of the ATS gene may provide new insights into the molecular mechanisms of elastogenesis.

Adolescent↗
PubMed2002

Prenatal diagnosis and confirmation of the acrofacial dysostosis syndrome type Rodriguez.

The group of acrofacial dysostosis (AFD) syndromes is very heterogeneous and contains many different entities. In 1990, Rodriguez et al. [1990: Am J Med Genet 35:484-489] described a new type of AFD characterized by severe mandibular hypoplasia, phocomelia and oligodactyly of the upper limbs, absence of fibulae, microtia, cleft palate, internal organ anomalies including arrhinencephaly and abnormal lung lobulation, and early lethality. We describe another case of AFD type Rodriguez, identified by prenatal ultrasonography at 25 weeks of gestation.

Abnormalities, Multiple↗
PubMed2002

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease.

Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOST gene in sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination.

Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. Qualitative examination of human brain autopsy material has shown that fragile-X patients exhibit abnormal dendritic spine lengths and shapes on parieto-occipital neocortical pyramidal cells. Similar quantitative results have been obtained in fragile-X knockout mice, that have been engineered to lack the fragile-X mental retardation protein. Dendritic spines on layer V pyramidal cells of human temporal and visual cortices stained using the Golgi-Kopsch method were investigated. Quantitative analysis of dendritic spine length, morphology, and number was carried out on patients with fragile-X syndrome and normal age-matched controls. Fragile-X patients exhibited significantly more long dendritic spines and fewer short dendritic spines than did control subjects in both temporal and visual cortical areas. Similarly, fragile-X patients exhibited significantly more dendritic spines with an immature morphology and fewer with a more mature type morphology in both cortical areas. In addition, fragile-X patients had a higher density of dendritic spines than did controls on distal segments of apical and basilar dendrites in both cortical areas. Long dendritic spines with immature morphologies and elevated spine numbers are characteristic of early development or a lack of sensory experience. The fact that these characteristics are found in fragile-X patients throughout multiple cortical areas may suggest a global failure of normal dendritic spine maturation and or pruning during development that persists throughout adulthood.

Adult↗
PubMed2001

Deformation and three-dimensional displacement of fibers in isometrically contracting rat plantaris muscles.

In this study, the deformation of different fibers of the rat m. plantaris during "isometric" contractions at different muscle lengths was considered. Because the m. plantaris has an obviously inhomogeneous architecture, its fibers on the medial side of the muscle belly are judged to be shorter than those on the lateral side of it. It was expected that longitudinal deformation of different fibers would vary accordingly. A 3D video analysis of contracting muscle showed that longitudinal strain of fibers as a function of muscle length does not differ between fibers on different sides of the muscle. Apart from longitudinal shortening, the fibers were also displaced laterally during a contraction. The fibers displaced during a contraction in a direction perpendicular to their longitudinal axis. The displacement of the fibers occurred asymmetrically, resulting in a helical deformation of the whole muscle. It is concluded that the asymmetric displacement and the helical deformation must result from transversal forces between the fibers. It is hypothesized that these transversal forces cancel out differences in longitudinal strains that might exist between fibers.

Animals↗
PubMed2001

In situ assessment of shortening and lengthening contractile properties of hind limb ankle flexors in intact mice.

The availability of animal models with disrupted genes has increased the need for small-scale measurement devices. Recently, we developed an experimental device to assess in situ mechanical properties of isometric contractions of intact muscle complexes of the mouse. Although this apparatus provides valuable information on muscle mechanical performance, it is not appropriate for determining contractile properties during shortening and lengthening contractions. In the present study we therefore developed and evaluated an experimental apparatus for assessment of shortening and lengthening contractile properties of intact plantar and dorsal flexors of the mouse. The current through a custom-built, low-inertia servomotor was measured to assess contractile muscular torque ranging from -50 to mN.m. Evaluation of the fixation procedure of the animal to the apparatus via 3-D monitoring of the muscle-tendon complex length showed that the additional shortening in length due to a contraction with maximal torque output has only minor effects on the measured torque. Furthermore, misalignment of the axis of rotation of the apparatus relative to the axis of rotation in the ankle joint, i.e. eccentricity, during a routine experiment was estimated to be less than 1.0 mm and hence did not influence the measured torque output under our experimental conditions. Peak power per unit muscle mass (mean +/- SD) of intact dorsal and plantar flexors was 0.27 +/- 0.02 and 0.19 +/- 0.03 W.g-1, respectively. The angular velocity at maximal peak power generated by the dorsal flexor complex and the plantar flexor complex was 1100 +/- 190 and 700 +/- 90 degrees.s-1, respectively.

Animals↗
PubMed2001

Hereditary multiple exostoses: from genetics to clinical syndrome and complications.

OBJECTIVE: To give an overview of genetic, clinical and radiological aspects in two families over four generations with known hereditary multiple exostoses (HME). METHODS AND MATERIAL: After linkage analysis in both families to localize the defective gene, mutation analysis was performed in these genes to identify the underlying mutation. In the 31 affected individuals, location, number and morphology and evolution of exostosis, evolution of remodeling defects at the metaphysis, and the extent of possible complications were evaluated on clinical and imaging (plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI)) data over a lifetime period. RESULTS AND CONCLUSIONS: Both families demonstrate the gene defect in the same EXT-2 gene locus on chromosome 11p. Exostoses are preferentially located in the lower extremity (hip, knee and lower leg), humerus, and forearm. Any other bone may be involved, except for the calvaria of the skull and the mandible. Exostoses are rather sessile than pedunculated. Exostosis is rarely present at birth but develops gradually and may persist to grow slowly after closure of the growth plates. Preferential expression of the remodeling defect was seen in the hip, distal femur (trumpet-shaped metaphysis) and forearm (shortening of the ulna with secondary bowing of the radius and development of a pseudo-Madelung deformity). These radiological manifestations start at the age of 4-5 years and become more obvious as the enchondral bone formation progresses with age. Reported complications in these families consist of local entrapment phenomenons (vessel, tendon, nerve), frictional bursitis, and sarcomatous transformation. MRI was able to suggest these complications and is the imaging technique of choice in the evaluation of symptomatic exostoses.

Chromosome Mapping↗
PubMed2000

Unexpected life-threatening complications in Kabuki syndrome.

Kabuki syndrome is a rare multiple congenital anomalies/mental retardation syndrome comprising a distinct facial appearance and fetal fingertip pads. We observed two patients with Kabuki syndrome and describe unusual life-threatening complications, including stenosis of the central airways (not previously reported), extrahepatic biliary atresia, and congenital diaphragmatic hernia.

Abnormalities, Multiple↗
PubMed2000

Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna.

Foramina parietalia permagna (FPP) is an autosomal dominant condition characterized by cranial defects of the parietal bones. It can be present as an isolated feature, but it is also one of the characteristics of a contiguous gene syndrome associated with deletions on chromosome 11p11-p12. One of the proteins known to be involved in skull development is the MSX2 homeobox protein. Previously, MSX2 has been shown to be mutated in patients suffering from Boston type craniosynostosis. We have now analyzed the MSX2 gene in five families affected with FPP. An intragenic microsatellite marker did not reveal any recombination and a cumulated LOD score of +3.2 at theta = 0 was obtained. Sequence analysis further showed that in four out of five families an MSX2 mutation was responsible for the skull defect. Moreover, it appears that FPP is caused by haplo-insufficiency of the MSX2 gene. This implies that Boston type craniosynostosis and FPP are allelic variants of the same gene, with FPP caused by loss of MSX2 function and craniosynostosis Boston type due to gain of MSX2 function.

Base Sequence↗
PubMed2000

Accurate assessment of in situ isometric contractile properties of hindlimb plantar and dorsal flexor muscle complex of intact mice.

An isometric torque sensor for measuring in situ contractions of plantar or dorsal flexors of intact mouse hindlimb has been developed and evaluated. With this device, muscle torque can be accurately measured within the range of -14 mN.m to +14 mN.m. Special attention was paid to fixation of the mouse hindlimb to the measurement device. Halothane-anaesthetized Swiss wild-type mice were positioned on the thermostatic measurement platform, and fixated with a hip and foot fixation system. The novel fixation unit was evaluated by measuring knee and ankle displacements during a contraction. A mathematical muscle model was used to quantify the effects of these displacements on the contractile parameters. Measured ankle and knee displacement, due to non-absolute fixation. resulted in a calculated muscle fibre shortening of 2.5%. Simulations of a contraction with this degree of fibre shortening, using the mathematical muscle model, showed only minor effects on maximal torque generation and the temporal parameters (half-relaxation time and 10-50% rise time). Furthermore, we showed that muscle torque in our set-up is hardly affected by eccentricity between ankle and measurement axis. Measured tetanic muscle torques of intact dorsal and plantar flexors were 3.2+/-0.4 mN.m and 11.8+/-1.6 mN.m, respectively. The half-relaxation time of plantar flexors was significantly higher than that of dorsal flexors (12.9+/-2.7 ms versus 8.8+/-1.2 ms), whereas the 10-50% rise time was longer in plantar (14.9+/-0.6 ms) than in dorsal (11.8+/-2.0 ms) flexors.

Animals↗
PubMed2000

Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3).

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Abnormalities, Multiple↗
PubMed2000

Audiometric analysis of a Belgian family linked to the DFNA10 locus.

OBJECTIVE: To report the otologic and audiometric characteristics of a nonsyndromic postlingual sensorineural hearing impairment in a Belgian family linked to DFNA10. STUDY DESIGN: Retrospective study of the otologic and audiometric data of 17 genetically affected persons. SETTING: Tertiary referral center. PATIENTS: All members of a Belgian kindred who carried the haplotype linked to the inherited hearing impairment of DFNA10. INTERVENTIONS: Diagnostic otologic and audiometric analysis. MAIN OUTCOME MEASURES: Pure-tone audiometry. RESULTS: To find the frequencies that were most affected by the genetic defect, the excess hearing loss of the 17 patients was calculated per frequency in comparison with the respective p50 and p95 thresholds of the normal population. CONCLUSIONS: The genetically affected persons of a Belgian family shared a progressive symmetric sensorineural hearing loss that started in the first to fourth decade. Thirty-five percent of the affected family members had tinnitus, and only one patient had very mild vestibular complaints. At onset, hearing losses were mainly situated at the midfrequencies. With increasing age, all frequencies became affected. The hearing loss was initially mild, with a spontaneous evolution to a moderate or severe hearing impairment. The progression of the hearing loss for the pure-tone average (between 0.5 and 4 kHz) was 1.08 dB/year for this family, compared with 0.50 dB/year and 0.35 dB/year at the 95th and 50th percentiles of the normal population, respectively.

Adult↗
PubMed1999

CAG repeat contraction in the androgen receptor gene in three brothers with mental retardation.

We report on three brothers with mental retardation and a contracted CAG repeat in the androgen receptor (AR) gene. It is known that expansion of the CAG repeat in this gene leads to spinal and bulbar muscular atrophy (SBMA or Kennedy disease); however, contracted repeats have not yet been implicated in disease. As the range of the length of CAG repeats in the AR gene, like those of other genes associated with dynamic mutations, follows a normal distribution, the theoretical possibility of disease at both ends of the distribution should be considered.

Adolescent↗
PubMed1999

Postmortem examination of two fragile X brothers with an FMR1 full mutation.

Large expansions of the CGG repeat in the 5' untranslated region of the FMR1 gene are found in patients with the fragile X syndrome. Amplified CGG repeats in FMR1 are unstable and show intergenerational increase from mother to offspring. The exact timing of repeat amplification, however, is unknown. We have compared the extent of CGG expansion in various tissues of this deceased fragile X patient, and found only limited variation in repeat expansion. The repeat was fully methylated in all tissues examined. Therefore, no evidence for extensive mitotic expansion of the CGG repeat during fetal or postnatal life of a fragile X patient was found, in contrast to dynamic mutations caused by CAG/CTG repeat expansion. Extensive pathological examination of this patient and his affected brother revealed no evidence for specific abnormalities relevant to fragile X syndrome; cerebellar hypoplasia, which has been reported in this disorder, was not evident in either patient.

Adult↗