Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33-q34. In the present study, endoglin, a transforming growth factor beta (TGF-beta) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 basepair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-beta receptor complex.

A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34.

Hereditary haemorrhagic telangiectasia (HHT), or Osler-Weber-Rendu disease, is an autosomal dominant vascular dysplasia of unknown pathogenesis leading to 'widespread' dermal, mucosal and visceral telangiectases and recurrent haemorrhage. We have mapped the HHT gene, by linkage analysis, to markers on 9q33-34 in two large multi-generation families. Haplotype analysis and mapping of recombination breakpoints gives a 4 cM interval between D9S61 and D9S63 as the most likely location of the gene. The closest marker, D9S65, is estimated to be within 1 cM of the gene and shows a combined lod score of 11.41. Two potential candidate genes, COL5A1 and ZNF79, are also located within 9q33-34. These results provide a starting point for the eventual cloning of the HHT gene.

Structural and functional brain imaging in Friedreich's ataxia.

BACKGROUND: Although the major neuropathologic changes in Friedreich's ataxia (FA) affect the spinal cord and peripheral nerves, we previously found abnormally increased glucose metabolism in the cerebral hemispheres in ambulatory patients and a return toward normal metabolism in nonambulatory patients. OBJECTIVE: To determine whether brain atrophy accompanies the decline in cerebral glucose metabolism in FA and whether the degree of atrophy and the extent of decline in cerebral glucose metabolism are related to clinical severity. DESIGN: Prospective series. SETTING: University referral center. PATIENTS: Twenty-two patients with FA and 26 patients with dizziness, headache, or minor acute head trauma, serving as control subjects, who underwent computed tomographic scans that were interpreted as normal. MEASURES: In patients with FA and control subjects, regional atrophy was assessed using subjective and objective measures on computed tomographic scans. In patients with FA, local cerebral glucose metabolism was measured with positron emission tomography, and clinical severity was assessed with a clinical rating scale. RESULTS: Atrophy in the cerebral hemispheres, cerebellum, and brain stem was significantly greater in patients with FA than in control subjects, and the degree of atrophy correlated with the clinical severity. Local cerebral metabolic rate for glucose declined significantly from the initially elevated levels in the thalamus, cerebellum, and brain stem in correlation with increasing clinical severity. CONCLUSIONS: The structure and function of wide-spread brain regions including the cerebral hemispheres are abnormal in FA, and these abnormalities correlate with the clinical severity.

Neuropsychological changes in olivopontocerebellar atrophy.

We used standardized neuropsychological measures of intellectual, cognitive, psychomotor, and emotional functioning to compare 39 patients with olivopontocerebellar atrophy and 25 normal controls of similar age. The patients reflected greater depression, anxiety, and subjective emotional discomfort than did the control subjects. While 4 of the patients had below-normal IQ scores (Wechsler Adult Intelligence Scale [WAIS-R] Full-Scale IQ [FSIQ] less than 80), their clinical histories suggested lifelong functioning at such levels. As a group, the patients were not abnormal in general intellectual functioning and related cognitive abilities (WAIS-R FSIQ, mean [+/- SD], 93.46 +/- 13.19; Wechsler Memory Scale mental quotient, 108.95 +/- 17.43). These scores were lower than those of the normal controls (WAIS-R FSIQ, 113.72 +/- 12.68; mental quotient, 127.80 +/- 12.40); however, the controls were a highly educated group with intelligence levels that were higher than those of the average population. Moreover, when education and motor dysfunction were statistically covaried, no significant differences between the patients and the normal controls were apparent on the cognitive and intellectual tasks. Further analysis of specific memory performance in a subgroup of patients and controls matched for age, sex, and education yielded findings that were comparable with the overall group analysis. We conclude that motor dysfunction and depressed mood could leave patients with olivopontocerebellar atrophy appearing to be impaired in memory, even demented, when they are not.

Longitudinal neuropsychological and genetic linkage analysis of persons at risk for Huntington's disease.

OBJECTIVE: To determine (1) whether the neuropsychological profiles of healthy individuals at risk (AR) for Huntington's disease who were positive (AR/+) or negative (AR/-) for the Huntington's disease genetic marker differed from those of symptomatic patients with Huntington's disease and normal control individuals and (2) whether the neuropsychological performance of the two AR groups differed from each other on three assessments during a 4-year span. DESIGN: Case-control, double-blind study, with AR status determined by genetic linkage analysis (G8 probe), in addition to examination of trinucleotide repeats for most AR subjects. SETTING: The Neuropsychology Program in the Department of Psychiatry and the Department of Neurology at the University of Michigan Medical Center, Ann Arbor, a tertiary care center. PARTICIPANTS: Eight subjects matched as closely as possible for age, gender, and education in each of the following groups: AR/+, AR/-, normal control, and Huntington's disease. MEASURES: A battery of neuropsychological tasks, including measures of intelligence, memory, problem solving, and motor ability. RESULTS: Although both AR groups demonstrated variability on select intellectual subtests relative to normal subjects, they did not differ from each other on the three assessments during a 4-year span. Patients with Huntington's disease performed more poorly than the other groups across a range of neuropsychological measures. CONCLUSIONS: These results do not support previous evaluations concluding that AR/+ individuals demonstrate cognitive impairments as compared with AR/- individuals. Findings in earlier studies without genetic linkage analysis of lower performance of AR individuals, including children, as compared with normal controls may relate to extraneous environmental and familial issues that interfere with intellectual development.

At-risk persons' attitudes toward presymptomatic and prenatal testing of Huntington disease in Michigan.

One hundred fifty-five individuals at 50% risk of inheriting Huntington disease (HD) were given a questionnaire surveying their sociodemographic characteristics, experience with HD, and attitudes toward presymptomatic and prenatal testing in HD. About two-thirds (63.2%) of the persons indicated they would take a presymptomatic test even if no specific treatment was available. Although one-half (49%) of the respondents stated they would make use of a prenatal test, only 43% of these individuals would decide to terminate a heterozygous fetus. Presymptomatic test results indicating carrier status would influence some of the respondents' decisions about marriage and childbearing. This strong interest of at-risk persons to make use of both presymptomatic and prenatal diagnosis in HD indicates the need for well-organized testing programs. These programs must be designed to address the genetic, psychosocial, and ethical issues that may arise in the use of this type of genetic test.

Inconsistencies in pedigree symbols in human genetics publications: a need for standardization.

To determine consistency in usage of pedigree symbols by genetics professionals, we reviewed pedigrees printed in 10 human genetic and medical journals and 24 medical genetics textbooks. We found no consistent symbolization for common situations such as pregnancy, spontaneous abortion, death, or test results. Inconsistency in pedigree design can create difficulties in the interpretation of family studies and detract from the pedigree's basic strength of simple and accurate communication of medical information. We recommend the development of standard pedigree symbols, and their incorporation into genetic publications, professional genetics training programs, pedigree software programs, and genetic board examinations.

Cerebral glucose hypermetabolism in Friedreich's ataxia detected with positron emission tomography.

Local cerebral metabolic rate for glucose was studied with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET) in 22 patients with Friedreich's ataxia and 23 age-matched normal control subjects. The diagnosis of Friedreich's ataxia was established by the history and physical findings and by excluding other diseases through laboratory investigations. PET studies revealed a statistically significant widespread increase of local cerebral metabolic rate for glucose in the brains of patients with Friedreich's ataxia who were still ambulatory, in comparison with normal control subjects. Nonambulatory patients with Friedreich's ataxia, in comparison with normal control subjects, had significantly increased local cerebral metabolic rates for glucose in the caudate and lenticular nuclei, but not in the other structures studied. The rate was significantly greater in ambulatory patients with Friedreich's ataxia than in nonambulatory patients in all structures studied except the caudate and lenticular nuclei. The data suggest that early in the course of Friedreich's ataxia, the local cerebral metabolic rate for glucose is increased extensively in the central nervous system, and as the disease progresses, it decreases in a regionally specific manner.

Motor dysfunction in olivopontocerebellar atrophy is related to cerebral metabolic rate studied with positron emission tomography.

We compared the severity of motor dysfunction with local cerebral metabolic rates for glucose (lCMRGlc) and the degree of tissue atrophy in 30 patients with olivopontocerebellar atrophy (OPCA). We devised a scale to quantitate the degree of ataxia in the neurological examinations. lCMRGlc was measured with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Tissue atrophy was assessed by visual rating of computed tomographic scans. PET studies revealed marked hypometabolism in the cerebellar vermis, cerebellar hemispheres, and brainstem of OPCA patients compared with 30 control subjects. A significant correlation was found between severity of motor impairment and lCMRGlc within the cerebellar vermis, both cerebellar hemispheres, and the brainstem. A significant but weaker relationship was noted between the degree of tissue atrophy in these regions and clinical severity. Partial correlation analysis revealed that motor dysfunction in OPCA correlated more strongly with lCMRGlc than with the amount of tissue atrophy. These results suggest that the clinical manifestations of OPCA are more closely related to the metabolic state of the tissue than to the structural changes in the cerebellum.

Speech disorders in olivopontocerebellar atrophy correlate with positron emission tomography findings.

We compared the severity of ataxic and spastic dysarthria with local cerebral metabolic rates for glucose (lCMRGlc) in 30 patients with olivopontocerebellar atrophy (OPCA). Perceptual analysis was used to examine the speech disorders, and rating scales were devised to quantitate the degree of ataxia and spasticity in the speech of each patient. lCMRGlc was measured with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). PET studies revealed marked hypometabolism in the cerebellar hemispheres, cerebellar vermis, and brainstem of OPCA patients compared with 30 control subjects. With data normalized to the cerebral cortex, a significant inverse correlation was found between the severity of ataxia in speech and the lCMRGlc within the cerebellar vermis, cerebellar hemispheres, and brainstem, but not within the thalamus. No significant correlation was found between the severity of spasticity in speech and lCMRGlc in any of these structures. The findings support the view that the severity of ataxia in speech in OPCA is related to the functional activity of the cerebellum and its connections in the brainstem.

Cerebellar and brainstem hypometabolism in olivopontocerebellar atrophy detected with positron emission tomography.

We studied local cerebral metabolic rates for glucose (1CMRglc) with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET) in 30 patients with olivopontocerebellar atrophy (OPCA) and 30 age-matched control subjects without neurological disease. The diagnosis of OPCA was based on the history and physical findings and on the exclusion of other causes of cerebellar ataxia by means of laboratory investigations. Computed tomographic scans revealed some degree of atrophy of the cerebellum in most patients with OPCA, and many also had atrophy of the brainstem. PET studies in these patients revealed significant hypometabolism in the cerebellar hemispheres, cerebellar vermis, and brainstem in comparison with the normal control subjects. A significant relationship was found between the degree of atrophy and the level of 1CMRglc in the cerebellum and brainstem. Nevertheless, several patients had minimal atrophy and substantially reduced 1CMRglc, suggesting that atrophy does not fully account for the finding of hypometabolism. 1CMRglc was within normal limits for the thalamus and cerebral cortex. The data suggest that PET/1CMRglc may be useful as a diagnostic test in patients with the adult onset of cerebellar ataxia.

PET scan investigations of Huntington's disease: cerebral metabolic correlates of neurological features and functional decline.

Fifteen drug-free patients with early to midstage Huntington's disease were evaluated with quantitative neurological examinations, scales for functional capacity, computed tomographic (CT) scans, and positron emission tomographic (PET) scans of 18F-2-fluoro-2-deoxyglucose (18F-FDG) uptake. All patients had abnormal indices of caudate metabolism on PET scanning, whereas in patients with early disease indices of putamen metabolism and CT measures of caudate atrophy were normal. Indices of caudate metabolism correlated highly with the patients' overall functional capacity (r = 0.906; p less than 0.001) and bradykinesia/rigidity (r = -0.692; p less than 0.01). Indices of putamen metabolism correlated highly with motor functions: chorea (r = -0.841; p less than 0.01), oculomotor abnormalities (r = -0.849; p less than 0.01), and fine motor coordination (r = -0.866; p less than 0.01). Indices of thalamic metabolism correlated positively with dystonia (r = 0.559; p less than 0.05). The data suggest that PET scanning with 18F-FDG is a sensitive measure of brain dysfunction in Huntington's disease and that basal ganglia metabolism is highly correlated with the overall functional capacity of individual patients and with the degree of their motor abnormalities.

Genetic counseling for families with inherited susceptibility to breast and ovarian cancer.

Efforts are under way to isolate a gene (BRCA1) on chromosome 17q12-21. Mutations in this gene predispose women to breast and ovarian cancer. Women with germline mutations in BRCA1 are estimated to have an 85% lifetime risk of developing breast cancer and an increased but as yet undetermined risk of ovarian cancer. It is estimated that one in 200 to 400 American women may be carriers of BRCA1 mutations. We have identified several families that show linkage between breast and/or ovarian cancer and genetic markers that flank BRCA1. It is now possible, within these linked families, to prospectively identify family members likely to be carrying BRCA1 mutations. Because of profound and immediate clinical ramifications, we offered to provide this information to one such extended family. To provide information to this family, we developed a protocol to address the many issues that arise in the delivery of these services. Although testing for BRCA1 mutation carriers is currently limited to very rare families being analyzed for research purposes, this experience presages the complexities of the much larger scale availability of population screening for BRCA1 mutations, which is likely to become a reality in the next few years.

Positron emission tomography measures of benzodiazepine receptors in Huntington's disease.

We performed positron emission tomographic (PET) measurements of the regional distribution volume of benzodiazepine receptors and regional glucose metabolism in 6 drug-free patients with early Huntington's disease following injection of [11C]flumazenil, a nonsubtype selective central benzodiazepine receptor antagonist, and 18F-2-fluoro-2-deoxy-D-glucose, respectively. Flumazenil data were analyzed with a recently developed two-compartment, two-parameter tracer kinetic model. Benzodiazepine receptor density is related to distribution volume for flumazenil. In comparison with a group of healthy volunteers, benzodiazepine receptor density was significantly decreased in the caudate nucleus. Glucose metabolism was significantly reduced not only in the caudate nucleus but also in the putamen and thalamus. The changes in benzodiazepine receptor density observed in the caudate nucleus are commensurate with data obtained in postmortem autoradiographic studies of receptor density. Based on such postmortem studies we also anticipated changes in putamen and thalamic benzodiazepine receptor density. However, relatively little is known on receptor changes in early Huntington's disease, because the autoradiographic data available were obtained mostly in patients with advanced disease. The decreased glucose metabolism in the caudate and putamen agrees well with previously published results of PET studies, whereas metabolic impairment of the thalamus has not yet been described in Huntington's disease. The present study suggests that regional metabolism and gamma-aminobutyric acid (GABA)-benzodiazepine receptor changes in subcortical structures of patients with early Huntington's disease do not occur with the same time course: Caudate benzodiazepine receptor density is already severely impaired when other subcortical structures reveal only minor abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype.

Hereditary haemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome is an autosomal dominant vascular dysplasia characterised by recurrent haemorrhage. Our initial linkage studies found an HHT gene to be localised to 9q3 in two large kindreds. In the present study, we examine an additional five unrelated HHT families. Linkage analysis in this region resulted in a peak multipoint location score of 13.03, 10 cM proximal of D9S60. We found significant evidence for heterogeneity of HHT. Multipoint analysis supports the family specific two point studies with odds of 3,000,000:1 showing linkage and heterogeneity over linkage and homogeneity. Four of the seven families give a posterior probability of > 99% of being of the linked type, and three families appear unlinked to this region of 9q, and by multipoint analysis completely exclude the candidate region for HHT. Two new crossovers in affected persons in one of the linked families further define the proximal border of the candidate region on 9q3. A possible correlation in clinical phenotype between the 9q3 linked families and unlinked families is described. Although six of the seven families clearly meet the clinical criteria for HHT diagnosis, a significant absence of pulmonary arteriovenous malformations is seen in all three 9q3 unlinked families. Genetic heterogeneity of HHT and its potential correlation with a clinical phenotype may have a significant impact on the clinical management and treatment of HHT patients.

A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12.

Hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber (ORW) disease is an autosomal dominant vascular dysplasia. Initial linkage studies identified an ORW gene localized to 9q33-q34 but with some families clearly excluding this region. A probable correlation in clinical phenotype between the 9q3-linked families and unlinked families was described with a significantly lower incidence of pulmonary arteriovenous malformations observed in the unlinked families. In this study we examined four unrelated ORW families for which linkage to chromosome 9q33-q34 has been previously excluded. Linkage was established for all four families to markers on chromosome 12, with a combined maximum lod score of 10.77 (theta = 0.04) with D12S339. Mapping of crossovers using haplotype analysis indicated that the candidate region lies in an 11-CM interval between D12S345 and D12S339, in the pericentromeric region of chromosome 12. A map location for a second ORW locus is thus established that exhibits a significantly reduced incidence of pulmonary involvement.

A gene for familial venous malformations maps to chromosome 9p in a second large kindred.

Venous malformations are a common form of vascular anomaly that cause pain and disfigurement and can be life threatening if they involve critical organs. They occur sporadically or in a familial form, where multiple lesions are usually present. We have identified a large kindred showing autosomal dominant inheritance of venous malformations. Using this family we confirm linkage of a familial form of venous malformations to chromosome 9p. We suggest that blue rubber bleb naevus syndrome can be considered a particular manifestation of this form of familial venous malformations. The candidate region for this gene encompasses the interferon gene cluster and the MTS1 (p16) tumour suppressor gene.

Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to > 100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.

Recommendations for standardized human pedigree nomenclature.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to >100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.