22 research outputs found
Erfelijkheidsvoorlichting : van Mendel naar klinische genetica
Rede bij de openbare aanvaarding van het ambt van lector in de
Anthropogenetica aan de faculteit der Geneeskunde van de
Erasmus Universiteit Rotterdam op woensdag 20 februari 198
Prenatal diagnosis of congenital diseases
Prenatal diagnosis of a number of congenital diseases is possible by amniocentesis
in the 14th - 16th week of pregnancy and subsequent analysis of cultured
amniotic fluid cells or amniotic fluid supernatant. Parents at risk for a child
with a chromosomal disorder, an X-linked disease, a neural tube defect or a
metabolic disease may use this new tool in genetic counseling to limit their
further offspring to unaffected children by requesting termination of a pregnancy
when a fetal abnormality has been detected.
The present thesis describes methodological studies in the field of prenatal diagnosis
of metabolic diseases and clinical applications of prenatal monitoring
in a series of 350 pregnancies with an elevated risk for a chromosomal aberration,
an X-linked disease, a metabolic genetic disorder or a neural tube
defec
Prenatal diagnosis by ultrasound in pregnancies at risk for autosomal recessive polycystic kidney disease
Abstract
In 15 pregnancies at risk of the autosomal recessive type of polycystic kidney disease (ARPKD), there were six recurrences (40%), five of which were diagnosed prenatally between 17 and 26 weeks (mean, 22 weeks). In the remaining affected case, normal kidney size and echogenicity were still present at 30 weeks of gestation. Fetal kidney enlargement and increased echogenicity are the key ultrasonographic signs for the detection of ARPKD. Absent fetal bladder filling and oligohydramnios were only documented in two of the six affected pregnancies. The variability in onset, the intrafamilial variability and the limitations of excluding ARPKD by second trimester ultrasound have to be considered when counselling a couple at risk for this particular disorder
Prenatal diagnosis of type A1 brachydactyly
Brachydactyly can occur as an isolated malformation or as part of numerous syndromes. Prenatal assessment of brachydactyly may be especially helpful in multiple anomaly syndromes associated with hand and/or finger anomalies. In isolated type A1 brachydactyly, which is an autosomal dominant disorder, all middle phalanges of the fingers and toes are affected. We present a fetus with type A1 brachydactyly inherited from the mother and grandmother
Dilemmas in counselling females with the fragile X syndrome
The dilemmas in counselling a mildly retarded female with the fragile X
syndrome and her retarded partner are presented. The fragile X syndrome is
an X linked mental retardation disorder that affects males and, often less
severely, females. Affected females have an increased risk of having
affected offspring. The counselling of this couple was complicated by
their impaired comprehension which subsequently impaired their thinking on
the different options. The woman became pregnant and underwent CVS, which
showed an affected male fetus. The pregnancy was terminated. Whether
nondirective counselling for this couple was the appropriate method is
discussed and the importance of a system oriented approach, through
involving relatives, is stressed
The cystic fibrosis defect approached from different angles - New perspectives on the gene, the chloride channel, diagnosis and therapy
Abstract
The search for the basic defect in cystic fibrosis (CF) has reached a decisive stage since the recent identification of the responsible gene. Electrophysiological and biochemical research had defined the CF defect as a dysregulation of epithelial chloride channels. The putative protein product of the now identified gene shares properties with other known transport proteins, but it is not necessarily itself a chloride channel protein. Elucidation of the primary cellular defect will certainly have important aetiological and hopefully therapeutic implications. The identification of the major gene mutation already has significant consequences for genetic counselling and prenatal diagnosis. Heterozygote detection at the population level awaits identification of the probably heterogenous mutations on about 30% of the CF chromosomes. At present, about 50% of CF patients are homozygous for the recently identified major CF mutation
Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability
Mutations in the androgen receptor (AR) gene result in a wide range of
phenotypes of the androgen insensitivity syndrome (AIS). Inter- and
intrafamilial differences in the phenotypic expression of identical AR
mutations are known, suggesting modifying factors in establishing the
phenotype. Two 46,XY siblings with partial AIS sharing the same AR gene
mutation, R846H, but showing very different phenotypes are studied. Their
parents are first cousins. One sibling with grade 5 AIS was raised as a
girl; the other sibling with grade 3 AIS was raised as a boy. In both
siblings serum levels of hormones were measured; a sex hormone-binding
globulin (SHBG) suppression test was completed; and mutation analysis of
the AR gene, Scatchard, and SDS-PAGE analysis of the AR protein was
performed. Furthermore, 5alpha-reductase 2 expression and activity in
genital skin fibroblasts were investigated, and the 5alpha-reductase 2
gene was sequenced. The decrease in SHBG serum levels in a SHBG
suppression test did not suggest differences in androgen sensitivity as
the cause of the phenotypic variation. Also, androgen binding
characteristics of the AR, AR expression levels, and the phosphorylation
pattern of the AR on hormone binding were identical in both siblings.
However, 5alpha-reductase 2 activity was normal in genital skin
fibroblasts from the phenotypic male patient but undetectable in genital
skin fibroblasts from the phenotypic female patient. The lack of
5alpha-reductase 2 activity was due to absent or reduced expression of
5alpha-reductase 2 in genital skin fibroblasts from the phenotypic female
patient. Exon and flanking intron sequences of the 5alpha-reductase 2 gene
showed no mutations in either siblin
Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: Report of five infants
Five infants (two girls and three boys) from four families all had severe pre- and post-natal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seizures. Four infants developed Wilms tumors, and one showed cystic lesions in bilateral kidneys. All five infants showed variegated mosaic aneuploidy in cultured lymphocytes. In two infants whose chromosomes were prepared by us, 48.5%-83.2% lymphocytes showed total premature chromatid separation (PCS). Their parents had 3.5%-41.7% of their lymphocytes in total PCS. The remaining three infants and their parents, whose chromosomes were prepared at outside laboratories, tended to show lower frequencies of total PCS. Another five infants reported with the disorder were reviewed together with the five infants we described. Together, their clinical and cytogenetic manifestations were similar enough to suggest a syndrome. Seven of the 10 infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2-16 months. The tumors were bilateral in four infants and unilateral in three infants, and cystic changes were present in six infants. Two infants developed botryoid rhabdomyosarcoma. The carriers of the syndrome are thus liable to tumorigenesis. The possible role of mitotic checkpoint defects, proven in two infants with the syndrome (Matsuura et al. [2000: Am J Hum Genet 69:483-486]), was discussed in connection with tumor development and progression
High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands
Mutations in microtubule-associated protein tau recently have been
identified in familial cases of frontotemporal dementia (FTD). We report
the frequency of tau mutations in a large population-based study of FTD
carried out in the Netherlands from January 1994 to June 1998.
Thirty-seven patients had >/=1 first-degree relative with dementia. A
mutation in the tau gene was found in 17.8% of the group of patie
Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1
Objective. To establish the prevalence of endocrinologic disorders in children with neurofibromatosis type 1 (NF1) and the relationship between these disorders and cerebral abnormalities on magnetic resonance imaging. Design. A prospective follow-up study. Setting. A multidisciplinary neurofibromatosis clinic. Patients. A total of 122 children diagnosed with NF1 according to diagnostic criteria set by the National Institutes of Health. Results. Central precocious puberty (CPP) was diagnosed in 3 children and growth hormone deficiency (GHD) in 3 children. Optic pathway gliomas were observed in 15 children; in 9 of the 15 cases, the optic chiasm was involved. Of the 3 children with CPP, only 1 showed a chiasma glioma on magnetic resonance imaging. In 1 case with GHD, an optic chiasm glioma was detected on neuroimaging. Two of the 9 children with an optic chiasm glioma presented with CPP or GHD. Conclusions. It has been suggested that CPP in children with NF1 is found exclusively in the presence of a chiasma glioma. We conclude that chiasma glioma may not be obligatory in children with NF1 and CPP or GHD. Moreover, we report a prevalence of GHD in children with NF1 of 2.5%, which has not been established earlier