Epileptogenesis: clinical genetic and genetic epidemiologic aspects.
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Chromosome Mapping↗
Biomedical subjects
D Lindhout
Publications and source records attributed to D Lindhout.
The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome.
BACKGROUND: People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis. Hepatic glucuronidating activity, essential for efficient biliary excretion of bilirubin, is reduced to about 30 percent of normal. METHODS: We sequenced the coding and promoter regions of the gene for bilirubin UDP-glucuronosyltransferase 1 (bilirubin/uridine diphosphoglucuronate-glucuronosyltransferase 1)--the only enzyme that contributes substantially to bilirubin glucuronidation--in 10 unrelated patients with Gilbert's syndrome, 16 members of a kindred with a history of Crigler-Najjar syndrome type II, and 55 normal subjects. RESULTS: The coding region of the gene for the enzyme was normal in the 10 patients with Gilbert's syndrome. These patients were homozygous for two extra bases (TA) in the TATAA element of the 5' promoter region of the gene (A(TA)7TAA rather than the normal A(TA)6TAA). The presence of the longer TATAA element resulted in the reduced expression of a reporter gene, encoding firefly luciferase, in a human hepatoma cell line. The frequency of the abnormal allele was 40 percent among the normal subjects. The 3 men in the control group who were homozygous for the longer TATAA element had significantly higher serum bilirubin levels than the other 52 normal subjects (P = 0.009). Among the kindred with a history of Crigler-Najjar syndrome type II, only the six heterozygous carriers who had a longer TATAA element on the structurally normal allele had mild hyperbilirubinemia, characteristic of Gilbert's syndrome. CONCLUSIONS: Reduced expression of bilirubin UDP-glucuronosyltransferase 1 due to an abnormality in the promoter region of the gene for this enzyme appears to be necessary for Gilbert's syndrome but not sufficient for the complete manifestation of the syndrome.
Adolescent↗
Application of chromosome 16 markers in the differential diagnosis of neuronal ceroid-lipofuscinosis.
Accurate diagnosis of neuronal ceroid lipofuscinosis (NCL) is important for a correct prognosis of the disease and for genetic counseling. Up to now, no direct diagnostic test has been available for NCL. The clinical diagnosis is made on the basis of symptoms, neurophysiological, neuroradiological, and specific lipopigment pattern data. Recent advances in the genetics of NCL have enabled us to use polymorphic DNA markers linked to the CLN1 and CLN3 loci as a tool in the differential diagnosis of NCL. We have applied genetic analysis with polymorphic DNA markers flanking the CLN3 gene on chromosome 16 to two consanguineous families in which NCL occurs. In the first family, which is of Turkish extraction, two patients suffering from a protracted form of juvenile NCL previously had been diagnosed with juvenile NCL. Haplotypes from this family indicate that the patients and their healthy sibling are haplo-identical, suggesting that this protracted form of juvenile NCL is not linked to the CLN3 locus. In the second family, which is of Moroccan origin, one patient suffers from the early juvenile variant of NCL (Lake-Cavanagh). In this family, the patient and one of the healthy siblings have identical haplotypes, excluding linkage of early juvenile NCL to the CLN3 locus on 16p12.1-11.2. Therefore, these cases from different populations demonstrate that haplotype analysis can be used as an additional method to exclude the diagnosis of juvenile NCL.
Adult↗
Somatic mosaicism and clinical variation in tuberous sclerosis complex.
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Child, Preschool↗
Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura.
Migraine is a common neurological disease of two main types: migraine with aura and migraine without aura. Familial clustering suggests that genetic factors are involved in the etiology of migraine. Recently, a gene for familial hemiplegic migraine, a rare autosomal dominant subtype of migraine with aura, was mapped to chromosome 19p13. We tested the involvement of this chromosomal region in 28 unrelated families with the common forms of migraine with and without aura, by following the transmission of the highly informative marker D19S394. Sib-pair analysis showed that affected sibs shared the same marker allele more frequently than expected by chance. Our findings thus also suggest the involvement of a gene on 19p13 in the etiology of the common forms of migraine.
Base Sequence↗
Genetic heterogeneity of familial hemiplegic migraine.
Familial hemiplegic migraine (FHM) is a distinctive form of migraine with an autosomal dominant mode of inheritance. The migraine-like attacks are associated with transient hemiparesis. A locus for FHM has recently been assigned to chromosome 19 by linkage mapping. In the present study, five unrelated pedigrees with multiple members suffering from hemiplegic migraine were investigated. In two of the pedigrees additional symptoms, cerebellar ataxia and benign neonatal convulsions, respectively, were observed in affected members. Three pedigrees showed linkage to loci D19S391, D19S221, and D19S226 at chromosome 19p13. Haplotyping suggested a location of a FHM gene between D19S391 and D19S221. In the two remaining families, evidence against linkage was found. These results confirm the localization of a gene for familial hemiplegic migraine to the short arm of chromosome 19, but locus heterogeneity not corresponding to the observed clinical heterogeneity is likely to exist.
Chromosome Mapping↗
Waardenburg syndrome and neural tube defects.
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Humans↗
Refined localization of TSC1 by combined analysis of 9q34 and 16p13 data in 14 tuberous sclerosis families.
Tuberous sclerosis (TSC) is a heterogeneous trait. Since 1990, linkage studies have yielded putative TSC loci on chromosomes 9, 11, 12 and 16. Our current analysis, performed on 14 Dutch and British families, reveals only evidence for loci on chromosome 9q34 (TSC1) and chromosome 16p13 (TSC2). We have found no indication for a third locus for TSC, linked or unlinked to either of these chromosomal regions. The majority of our families shows linkage to chromosome 9. We have refined the candidate region for TSC1 to a region of approximately 5 cM between ABL and ABO.
Chromosome Mapping↗
Etiological aspects of congenital diaphragmatic hernia: results of a case comparison study.
We report the results of a parental questionnaire concerning possible etiological and teratological factors, such as exposure to herbicides, in the development of congenital diaphragmatic hernia (CDH). The herbicide Nitrofen interferes with lung development in rats, can induce diaphragmatic hernia and greatly resembles thyroid hormone. No association with the studied teratogens nor with maternal thyroid dysfunction was found. The questionnaire was completed by 33 parents whose baby had CDH, and by 43 couples whose baby had oesophageal atresia. The resemblance of Nitrofen to thyroid hormone, a well-known growth factor for the developing lung, is of particular interest from a pathogenetic point of view in the development of CDH.
Case-Control Studies↗
The evolution of renal angiomyolipomas in patients with tuberous sclerosis.
In 1986, 23 patients with renal angiomyolipomas as part of tuberous sclerosis were assessed by ultrasonography. In 1991, 20 patients in this group were reexamined with special attention paid to the renal pathological condition. Ultrasonography was performed by the same radiologist who performed the examination in 1986. Of 20 patients 7 had severe hemorrhage necessitating hospital admission (5 had a renal lesion larger than 3.5 cm. in diameter). In 2 patients the exact diameter of the renal angiomyolipomas could not be determined and they underwent nephrectomy. Three patients underwent successful selective embolization of the bleeding angiomyolipoma. One patient died. The hemorrhage resolved spontaneously in 1 patient and treatment was not feasible. In 4 patients the lesions increased in size between 1986 and 1991. Based on these results there is a relationship between the size of the angiomyolipomas and the risk of bleeding. Renal angiomyolipomas larger than 3.5 cm. in diameter have a substantial risk for severe hemorrhage. Some angiomyolipomas show progression. Periodic followup is mandatory every 6 months. For angiomyolipomas larger than 3.5 cm. in diameter an aggressive approach is advised. Selective embolization is the initial method of choice.
Adult↗
The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q.
Triphalangeal thumb is a developmental anomaly, sometimes dominantly transmitted, characterized by a long, finger-like thumb with three phalanges instead of two. The underlying genetic defect is unknown, but presumably involves genes that regulate the differentiation of the developing forelimb. In two large kindreds with triphalangeal thumb, evidence for linkage to the long arm of chromosome 7 was obtained with a maximum lod score of 12.61. Multipoint linkage and haplotype analysis placed the gene close to the telomere of the long arm. To our knowledge this is the first time that a human gene involved solely in the pathologic morphogenesis of the hand and feet has been localized.
Chromosome Mapping↗
Teratogenic effects of antiepileptic drugs: implications for the management of epilepsy in women of childbearing age.
Exposure to antiepileptic drug (AED) treatment in utero occurs in 1 of every 250 newborns. The absolute risk of major malformations in these infants is about 7-10%, approximately 3-5% higher than in the general population. Specific risk factors include high maternal daily dosage or serum concentrations of AED, low folate levels, polytherapy, and generalized seizures during pregnancy. Adverse pregnancy outcomes, including congenital heart malformations, facial clefts, spina bifida aperta, hypospadias, growth retardation, and psychomotor and mental retardation, are associated with, although not necessarily caused by, AED exposure. Specific cognitive defects, hypertelorism, and nail hypoplasia can be causally related to specific AED exposures. To prevent teratogenic side effects, the prospective mother should be treated with AEDs only when absolutely necessary. Monotherapy with the AED that is most effective in the lowest possible daily dose (divided into at least two or three administrations) should be prescribed. High-dose folate supplementation (4-5 mg/day) reduces the risk of a neural tube defect in a child whose sibling had such a defect, but its impact on the specific teratogenic risks of AEDs is unknown. A substantial proportion of fetal malformations may be secondarily prevented by prenatal diagnosis, consisting of a fetal structural ultrasound examination at weeks 18 and 20 of gestation and, with VPA or CBZ administration, an alpha 1-fetoprotein analysis of amniotic fluid at week 16. Determination of a specific defect prevention strategy depends largely on parental attitudes toward prenatal diagnosis and termination of pregnancy, which should be discussed before conception.(ABSTRACT TRUNCATED AT 250 WORDS)
Abnormalities, Drug-Induced↗
Phenotypic analysis of triphalangeal thumb and associated hand malformations.
Triphalangeal thumb (TPT), a long, finger-like thumb with three phalanges instead of two, is regarded as a subtype of preaxial polydactyly. It can occur as a sporadic disorder, but is more often seen as a dominant familial trait. We describe four white Dutch families in which triphalangeal thumb has variable expression and is sometimes associated with preaxial extra rays, rudimentary postaxial polydactyly, cutaneous syndactyly of the hands, and, rarely, postaxial polydactyly and syndactyly of the feet. A comparison with similar familial conditions reported during the past 10 years is provided. The potential significance of linkage and molecular genetic analysis for better insight into the pathogenesis of complex hand malformations is discussed.
Adult↗
Severe limb abnormalities: analysis of a cluster of five cases born during a period of 45 days.
We report on 5 individuals with severe limb abnormalities born in our hospital within a period of 45 days. Detailed clinical descriptions, photographs, and radiographs are presented. Etiological evaluations included genetic background, obstetric history, invasive procedures during pregnancy, maternal infectious diseases or maternal hyperthermia, drug use before and during pregnancy, and occupational or recreational exposures of both parents.
Abnormalities, Multiple↗
Adult patients with spina bifida cystica: genetic counselling, pregnancy and delivery.
With more aggressive surgical management, patients born with spina bifida may now reach adulthood and achieve pregnancies. Any female patient with spina bifida is strongly recommended to have preconceptional genetic counselling. The risk for parents with spina bifida of having affected offspring (approx. 4%) is considerably increased compared with the general population (0.1-0.3%). This risk may be lowered when periconceptional folic acid supplements are given. In pregnancy, special care is needed in the management of urological, obstetric, neurological and anaesthetic problems. Urological complications like neurogenic bladder, incontinence, chronic infection, increased chance of developing bladder carcinoma and impaired renal function are common in the spina bifida patient. In case of urinary diversion, obstruction may complicate the pregnancy. The incidence of premature labour is increased. Clinical assessment of the pelvis is necessary because of a possibly contracted pelvis. If the head engages normally, vaginal delivery should be allowed if possible. Caesarean section should be performed for obstetric reasons only. Cerebrospinal fluid shunts may give neurological problems during pregnancy. In most cases reported, symptoms improved spontaneously after delivery. In case of a shunt, vaginal delivery is preferable, pushing during second stage not contra-indicated, and in case of caesarean section, prophylactic antibiotics and thorough irrigation of the peritoneal cavity are indicated.
Adolescent↗
The 10,11-epoxide-10,11-diol pathway of carbamazepine in early pregnancy in maternal serum, urine, and amniotic fluid: effect of dose, comedication, and relation to outcome of pregnancy.
Epoxide metabolites of carbamazepine (CBZ) have been suggested to play a role in the occurrence of congenital malformations observed in infants exposed to CBZ. We have investigated the 10,11-epoxide-10,11-diol pathway of CBZ in pregnant epileptic patients receiving CBZ alone or in combination with other antiepileptic drugs in relation to the outcome of pregnancy in a prospective manner. The women were referred to our clinic before 16 weeks of gestation for prenatal diagnosis of fetal malformations, including neural tube defects, by ultrasound and amniocentesis. The availability of amniotic fluid samples enabled us to determine to what extent CBZ and its main metabolites reached the amniotic fluid. In 100 pregnancies with first trimester CBZ exposure (including 7 with malformed outcome), parent drug and metabolite concentrations in maternal serum were evaluated. CBZ-10,11-epoxide concentrations increased with increasing dose. Comedication with phenobarbital led to lower 10,11-epoxide concentrations in maternal serum and a higher percentage of the dose recovered in urine as 10,11-diol. Valproate comedication led to slightly higher 10,11-epoxide concentrations in maternal serum, in combination with lower CBZ concentrations and a lower percentage of the dose recovered in the urine as 10,11-diol. In amniotic fluid, concentrations of CBZ and its main metabolites in most patients were 2 to 2.5 times higher than the free concentrations in maternal serum. Metabolites and parent drug concentrations in amniotic fluid correlated with their free concentration in maternal serum, but stronger with each other in amniotic fluid. No significant differences in levels of CBZ and its metabolites were observed between pregnancies with normal and malformed outcome.
Abnormalities, Drug-Induced↗
Linkage to markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds.
We have performed linkage analysis with five markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds in order to find support for the claim by Hall et al. that a gene in this region, termed "BRCA1," is associated with predisposition to early-onset familial breast cancer. This work is part of a collaborative study, the results of which are published elsewhere in this issue. Best evidence for linkage was observed with the marker CMM86 (D17S74) in pedigrees with an average age at onset of < or = 47 years (LOD score = 1.77 at 1% recombination). In one breast-ovarian cancer family with a high probability of being linked to 17q, we observed one putative recombinant between D17S250 and D17S579, which suggests that BRCA1 is proximal to D17S579.
Adult↗
Mutations in mitochondrial tRNA genes: non-linkage with syndromes of Wolfram and chronic progressive external ophthalmoplegia.
We have recently identified a point mutation in the mitochondrially encoded tRNA(Leu(UUR)) gene which associates with a combination of type II diabetes mellitus and sensorineural hearing loss in a large pedigree. To extend this finding to other syndromes which exhibit a combination of diabetes mellitus and hearing loss we have sequenced all mitochondrial tRNA genes from two patients with the Wolfram syndrome, a rare congenital disease characterized by diabetes mellitus, deafness, diabetes insipidus and optic atrophy. In each patient, a single different mutation was identified. One is an A to G transition mutation at np 12,308 in tRNA(Leu(CUN)) gene in a region which is highly conserved between species during evolution. This mutation has been described by Lauber et al. (1) as associating with chronic progressive external ophthalmoplegia (CPEO). The other is a C to T transition mutation at np 15,904 in tRNA(Thr) gene. Both mutations are also present in the general population (frequency tRNA(Leu(CUN)) mutation 0.16, tRNA(Thr) mutation 0.015). These findings suggest that evolutionarily conserved regions in mitochondrial tRNA genes can exhibit a significant polymorphism in humans, and that the mutation at np 12,308 in the tRNA(Leu(CUN)) gene is unlikely to be associated with CPEO and Wolfram syndrome.
Base Sequence↗