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T G Nygaard

Publications and source records attributed to T G Nygaard.

At least 37 records · Page 2Linked to original sources
PubMed1997

Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32.

BACKGROUND: The pathogenesis of primary pulmonary hypertension (PPH) is unknown, although in some instances families with multiple affected members suggest a genetic etiology. METHODS AND RESULTS: We used microsatellite markers and linkage analysis in a large family with PPH to determine the chromosomal location of their disease gene. We tested a second, ethnically distinct, family for cosegregation of disease with markers from the linked region. We mapped the disease locus PPH1; GDB/HUGO designation (GDB:1381541; July 1996), approved when this work was accepted for publication in abstract form (Circulation. 1996;94[suppl I]:1-49.), in these families to a 27-cM region on chromosome 2q31-q32, with a maximum lod score of 3.87 associated with markers D2S350 and D2S364. CONCLUSIONS: Cosegregation of this region with disease in different ethnic groups suggests that we mapped an important locus in familial PPH. Careful study of additional families and sporadic cases will be required to confirm this localization of PPH1 and characterize its overall role.

Adolescent↗
PubMed1997

Genetic polymorphism and recombination in the subtelomeric region of chromosome 14q.

Subtelomeric regions of human chromosomes are the sites of increased meiotic recombination and have a male-to-female recombination ratio that is higher than elsewhere in the genome. We isolated two novel, polymorphic CA repeat markers from the distal part of the immunoglobulin heavy chain gene cluster, approximately 90 and 200 kb from the telomere of chromosome 14q. The 14q telomere was unambiguously located by physical mapping of telomeric YACs and Bal31 exonuclease digestion of genomic DNA. We then constructed haplotypes using genotype data from these markers and data from sCAW1 (D14S826) for use as a highly polymorphic genetic marker. Linkage analysis using the 40 pedigree CEPH reference panel and genotype data from these and other loci physically mapped to the terminal 1.5 Mb of chromosome 14q revealed an apparent increase in meiotic recombination within this region, relative to the average rate for the genome. Further, we found that recombination was higher in females than in males, indicating that the subtelomeric region of 14q differs from other human subtelomeric regions.

Chromosomes, Artificial, Yeast↗
PubMed1997

Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families.

The DYT1 locus on chromosome 9q34 is responsible for most childhood limb-onset idiopathic torsion dystonia (ITD). Linkage to DYT1 has been excluded in families with adult-onset, and predominantly cranial-cervical, ITD. We mapped a locus (DYT6) associated with prominent cranial-cervical ITD in two large Mennonite families to chromosome 8. An identical haplotype spanning 40-cM segregates with ITD in these families, suggesting a shared mutation from the recent past.

Adolescent↗
PubMed1996

Exclusion of the DYT1 locus in familial torticollis.

Clinical-genetic studies of idiopathic torsion dystonia (ITD) indicate that the DYT1 gene on chromosome 9q34 is responsible for most childhood limb-onset disease. The genetic basis of adult-onset ITD is less well studied. In most multiplex adult-onset ITD families, dystonia is limited to the cervical, cranial, or brachial muscles; in a few rare families, dystonia also involves the legs and trunk. Previous linkage studies have excluded the DYT1 locus in these atypical families. We studied two large non-Jewish families with adult-onset ITD limited to the cervical and brachial muscles and excluded the DYT1-containing region. This study further restricts the role of DYT1 to childhood limb-onset ITD and suggests that other genes are responsible for focal adult-onset ITD.

Adolescent↗
PubMed1996

Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity.

Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases.

Dopamine Agents↗
PubMed1995

A high-resolution genetic linkage map of the pericentromeric region of the human X chromosome.

We generated a high-resolution genetic linkage map of the pericentromeric region of the human X chromosome from approximately Xp11.4 to Xq22. This map contains 41 loci defined by 50 marker systems genotyped in the CEPH families. For this study we have generated 3 new markers (DXS1689, DXS1690, and DXS159) and 2 new primer sequences for previously described markers (PGK1P1 and AR). Using two different mapping algorithms based on genotype data alone, we developed two well-supported framework maps containing 15 and 18 markers with average interval sizes of 2.7 and 1.7 cM. The 18 marker map is [DXS426, PFC]-2.0-DXS255-1.2-DXS991-1.6-AR-1.3-DXS153-2.0-DX S106-1.5-DXS132-0.6- DXS1690-0.8-DXS453-1.4-DXS559-1.5-[PGK1, DXS56]-0.6-DXS1002-1.8-DXYS1X-2.0-DXS3-7.5-DX S458-2.8-DXS454, where the distance between adjacent loci is in centimorgans. As a third approach, we used physical mapping data to define bins for markers; this approach permitted us to place 26 markers on our framework map. Finally, we constructed a map based on the physical order of 35 markers from the fifth international workshop on human X chromosome mapping. A comparison of the physical and genetic maps indicates a relationship of 2 cM per megabase in this region, with two regions of reduced recombination. The first is around the centromere (DXZ1), and the second is in the region around PGK1 (DXS441 to DXS995). Our maps should aid in the fine-mapping of the many disease loci that localize to this region of the X chromosome.

Algorithms↗
PubMed1995

The gene for hereditary progressive dystonia with marked diurnal fluctuation maps to chromosome 14q.

Hereditary progressive dystonia with marked diurnal fluctuation (HPD) is a childhood-onset, postural dystonia that is characterized by marked diurnal fluctuation and a dramatic response to levodopa. Recently, the gene for dopa-responsive dystonia (DRD), an autosomal dominant dystonia showing similarly marked response to levodopa, has been mapped to chromosome 14q. Since HPD and DRD share many clinical characteristics, we have analyzed microsatellite polymorphisms in the region of the DRD locus and obtained a maximal lod score of 2.0 at D14S52 without obligate recombination events in the affected individuals. The results strongly suggest that HPD and DRD are to be caused by mutations in the same gene on the long arm of chromosome 14.

Chromosome Mapping↗
PubMed1995

Dopa-responsive dystonia.

The past 18 months have seen significant advances in our understanding of dopa(dihydroxyphenylalanine)-responsive dystonia. Clinical investigations have broadened the spectrum of disease with particular attention manifestations in infancy. Pathophysiological investigations have revealed features that distinguish dopa-responsive dystonia from childhood-onset parkinsonism. A pathological study has confirmed the 'developmental' nature of the disease. Finally, mutations causing the autosomal dominant form of dopa-responsive dystonia have been identified in the gene coding for GTP cyclohydrolase I. Mutations in tyrosine hydroxylase have been identified in two brothers and put forward as evidence of an autosomal recessive form of the disease.

Child, Preschool↗
PubMed1994

Biochemical and fluorodopa positron emission tomographic findings in an asymptomatic carrier of the gene for dopa-responsive dystonia.

We report cerebrospinal fluid monoamine metabolite analyses and 6-[18F]fluoro-1-dopa positron emission tomography (FD-PET) from an asymptomatic carrier of the gene for dopa-responsive dystonia. Cerebrospinal fluid homovanillic acid, tetrahydrobiopterin, and neopterin concentrations were reduced in this man and in his affected children. His FD-PET was normal, as we have previously found in dopa-responsive dystonia. Neurological function and FD-PET may be normal despite marked abnormality in dopamine metabolism.

Adolescent↗
PubMed1994

Dopa-responsive dystonia simulating cerebral palsy.

Five patients presented in infancy or early childhood with various combinations of pyramidal and extrapyramidal signs with normal cognitive function. Their perinatal courses were unremarkable. In each patient, initial impressions listed by several examiners included spastic diplegia or cerebral palsy. Later in each course, either extrapyramidal features or progression suggested dopa-responsive dystonia. In 4 of the 5 children, cerebrospinal fluid was obtained and disclosed reduced levels of biopterin, neopterin, and homovanillic acid in all 4. Levodopa therapy resulted in prompt improvement with normal function returning within 6 months. The disappearance of the "spasticity," extensor plantar responses, and extrapyramidal signs, following levodopa therapy, confirmed the diagnosis of doparesponsive dystonia in these patients. Three had apparently sporadic disease; the other 2 were siblings with an affected paternal grandmother. Three had onset in infancy with delayed sitting and walking before the appearance of overt dystonia; infantile onset is infrequent in dopa-responsive dystonia. The other 2 had normal milestones, but developed gait disorders with prominent imbalance in early childhood. The diagnosis of dopa-responsive dystonia should be considered in children with unexplained or atypical "cerebral palsy."

Adolescent↗
PubMed1994

Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex.

We studied the clinical features, pathology, and molecular genetics of a family (Mo) with an autosomal dominant disinhibition, frontal lobe dementia, parkinsonism, and amyotrophy. We examined seven affected members and gathered clinical information on another six. The mean onset was at age 45 years. Personality and behavioral changes (disinhibition, withdrawal, alcoholism, hyperphagia) were the first symptoms in twelve. There was early memory loss, anomia, and poor construction with preservation until late of orientation, speech, and calculations. All affected members examined had rigidity, bradykinesia, and postural instability. Mean duration to death was 13 years. We studied the neuropathology of six individuals, five of whom had been examined in life. There was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals, including one with fasciculations and muscle wasting, had anterior horn cell loss. There were no Lewy bodies, neurofibrillary tangles, or amyloid plaques. We call this disorder the "disinhibition-dementia-parkinsonism-amyotrophy complex" (DDPAC), based on the clinical syndrome found in this family and linkage to chromosome 17.

Adult↗
PubMed1994

A study of idiopathic torsion dystonia in a non-Jewish family: evidence for genetic heterogeneity.

A gene (DYT1) for idiopathic torsion dystonia (ITD) was mapped to chromosome 9q34 in non-Jewish and Jewish families; the dystonia in these families usually began in childhood, with the limb muscles affected first. The role of the DYT1 gene in adult-onset and cervical- or cranial-onset ITD is unknown. We examined 53 individuals from four generations of a non-Jewish North American family with adult-onset ITD. There were seven affected family members, with a mean age at onset of 28.4 years (range, 7 to 50 years). In six of the seven, the neck was affected first. All seven developed cervical dystonia, and dysarthria or dysphonia occurred in five. Linkage data excluded the region containing the DYT1 locus, indicating that DYT1 was not responsible for ITD in this family. This study provides evidence that a gene other than DYT1 is responsible for some cases of adult cervical-onset dystonia.

Adolescent↗
PubMed1994

Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22.

Disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) is defined by familial adult-onset behavioral disturbance, followed by frontal lobe dementia, parkinsonism, and amyotrophy in variable proportions. A genetic etiology of DDPAC was suspected because of the familial clustering in family Mo, despite their wide geographic distribution. We have mapped the DDPAC locus to a 12-cM (sex averaged) region between D17S800 and D17S787 on chromosome 17q21-22. The basis for the variability of the clinical findings and pathology in DDPAC is unknown but suggests that the DDPAC locus should be screened as a candidate locus in family studies of conditions with behavioral abnormalities and neurological degeneration.

Chromosome Mapping↗
PubMed1993

Positron emission tomographic studies of dopa-responsive dystonia and early-onset idiopathic parkinsonism.

There are two major syndromes presenting in the early decades of life with dystonia and parkinsonism: dopa-responsive dystonia (DRD) and early-onset idiopathic parkinsonism (EOIP). DRD presents predominantly in childhood with prominent dystonia and lesser degrees of parkinsonism. EOIP presents before age 40 with parkinsonism (often with associated dystonia). Both disorders are exquisitely sensitive to levodopa, although the long-term prognosis in each appears to be different. Some have suggested, however, that DRD is a form of EOIP. We performed positron emission tomography with 6-fluoro-dopa in 10 patients with DRD and 18 patients with EOIP to study the integrity of their nigrostriatal dopaminergic systems. In DRD, we found normal striatal FD uptake. In contrast, patients with EOIP had reduced striatal FD uptake. We conclude that the patho-physiologies of DRD and EOIP are distinct. Although both disorders presumably represent a deficiency of striatal dopamine, the results suggest that in DRD dopa uptake, decarboxylation, and storage mechanisms are intact. This may explain the sustained response of DRD to low doses of levodopa. 6-Fluoro-dopa positron emission tomography distinguishes DRD from EOIP.

Adolescent↗
PubMed1993

Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q.

Dopa-responsive dystonia (DRD) is an autosomal-dominant neurological disorder which appears to result from a genetically determined deficiency of striatal dopamine. Pathological evidence suggests that this may be due to the establishment of a reduced number of dopaminergic nerve terminals in the striatum, or to an excessive reduction (pruning) of these terminals in early development. We have mapped the DRD gene to chromosome 14 by linkage analysis in 3 families with a maximum 2-point lod score of 4.67 at 8.6 centiMorgans from D14S63; maximum multipoint lod scores > 6 were obtained for the intervals D14S47-D14S52 and D14S52-D14S63. The flanking loci D14S47 and D14S63 define a region of about 22 cM as containing the DRD gene.

Chromosome Mapping↗
PubMed1993

Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women.

Lubag (X-linked dystonia-parkinsonism) has been considered a sex-linked recessive trait and has been mapped to the pericentromeric region of the X chromosome. We studied a 54-year-old man with lubag and two of his female first cousins. Genetic typing was carried out using X chromosome markers. Fluorodopa PET was performed on the man and one of the women. The man had moderately severe parkinsonism and dystonia. A 61-year-old female first cousin had mild left-sided dystonia and her 54-year-old sister had mild generalized chorea. Genetic typing data revealed that all three inherited an X chromosome with marker alleles strongly associated with lubag. Cytologic analysis did not reveal evidence of X chromosomal deletion. Fluorodopa PET in both the man and one affected cousin revealed reduced striatal uptake rate constants consistent with nigrostriatal involvement. These observations suggest that lubag may be a codominant disorder and that it is possible for women to be affected.

Alleles↗