[Diagnosis and therapy of familial hyper- -lipoproteinemia (familial hypercholesterolemia or familial hyperlipoproteinemia of type II)].
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Adolescent↗
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[Familial SLE--6 cases in 3 families. A family with one case complicated with infantile lymphocytic leukemia].
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Adult↗
Homozygous abnormal haemoglobins in Cape Town. A study of Hb.C disease in a white family, Hb.E disease in an Asiatic family and Hb.S disease in a coloured family.
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Adult↗
Family with dominantly inherited ataxia, amyotrophy, and peripheral sensory loss. Spinopontine atrophy or Machado-Joseph Azorean disease in another non-Portuguese family?
A family of German extraction with progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscular atrophy of adult onset is described. Three members came to autopsy, and neuropathologically, the major changes included varying degrees of atrophy of the basis pontis and degeneration of the spinocerebellar tracts, Clarke's columns, anterior horn neurons, and fasciculus gracilis. The dentate nucleus was spared, and there was slight neuron loss from the substantia nigra in one patient. Clinically and neuropathologically, our family resembles that reported by Boller and Segarra as having spinopontine atrophy. However, several kindreds with similar findings have recently been described as having Azorean or Machado-Joseph disease in non-Portuguese families. Comparison of clinical and neuropathological features in spinopontine atrophy and Machado-Joseph disease, both in Portuguese and non-Portuguese families, reveals clinical and pathological similarities and differences between the two. The major differences in our patients include only minor extraocular movement abnormality and absence of protuberant eyes, and muscular rigidity clinically, and the sparing of the substantia nigra and the dentate nucleus neuropathologically. These differences suggest that spinopontine atrophy, as manifested in our family, is distinct from Machado-Joseph disease. Our family showed no linkage to the HLA locus on chromosome 6.
Adult↗
Management of familial breast cancer. I. Biostatistical-genetic aspects and their limitations as derived from a familial breast cancer resource.
Practical guidelines are given to promote decision-making logic by the physician in managing patients seeking consultation (consultands) because they may be at high familial risk for breast cancer and associated malignant neoplasms. The protocol is designed to aid in the assessment of patients who may become candidates for intensified cancer surveillance and/or prophylactic surgery. A resource comprised of 90 extended breast cancer-prone pedigrees provides the basis for these specific recommendations. The resource shows marked tumor heterogeneity among pedigrees, an approximate 50% incidence of breast cancer and associated malignancies among offspring of affected parents, and threefold higher risk for development of mammary carcinoma in the opposite breast of familial patients with unilateral disease than in sporadic patients. In utilizing this protocol, it is crucial that family history be highly accurate from the standpoint of genealogic relationships and pathologic tumor verification so that management recommendations may reflect sound risk factor assessment. Interpretation of familial risk factors should ideally be made by an informed medical-geneticist. All members of the medical team should then be appraised of familial risk and collectively engage in decision making with the consultand. We believe that this approach can foster more effective control of familial breast cancer.
Adolescent↗
Risks of cancer among members of families in the Gilda Radner Familial Ovarian Cancer Registry.
BACKGROUND: Increasing scientific and public interest in hereditary cancer syndromes has created a need for estimates of lifetime cancer risks among members of families with such syndromes. METHODS: Data from the Gilda Radner Familial Ovarian Cancer Registry were used to evaluate risk for cancers of the breast, cervix, uterus, colorectum, and prostate in members of 143 families containing three or more reported cases of ovarian cancer among first- or second-degree relatives. These risks were compared with those that were expected based on general population rates obtained from the Connecticut Tumor Registry. RESULTS: Overall, family members' risk of cancer at any nonovarian site was 1.5 times that of the general population (P < 0.001). Among female members, risk for cancer of the breast was 2.5 times that of the general population. Risk for cancer of the uterus was 5 times that of the general population and increased with increasing number of first-degree relatives with ovarian cancer. Among male family members having three or more first-degree relatives with ovarian cancer, prostate cancer risk was 4.5 times that of the general population. No excess risks were observed for cancer of the colorectum. CONCLUSIONS: These data support previous reports of coaggregation of cancer of the breast, uterus and ovary, and suggest coaggregation between cancer of the ovary and prostate. Differences in cancer risk profiles observed in these families with multiple ovarian cancer and in carriers of the gene BRCA1 suggest that hereditary ovarian cancer is genetically heterogeneous.
Female↗
Heterogeneity in the familial aggregation of fasting serum uric acid level in five North American populations: the Lipid Research Clinics Family Study.
This study represents the first formal examination for heterogeneity in the familial aggregation of fasting serum uric acid (UA) levels. Data from 5 clinics (Cincinnati, Stanford, Iowa, Minnesota, and Oklahoma) participating in the Lipid Research Clinics (LRC) family study, which included a total of 685 nuclear families (N = 2,146), were analyzed. Heterogeneity among the clinics in familial resemblance was detected. However, this heterogeneity could not be attributed to differences in distributional properties (such as means and variances) or to path model parameters representing latent genetic or cultural (environmental) components associated with UA levels. Intergenerational differences in genetic heritabilities were found, with higher offspring (h2 = 43%) than parent (h2z2 = 16%) estimates, but no generational differences were detected for cultural heritability (c2 = 0.09). Equal maternal and paternal cultural transmission was found, and effects due to extra sibling environments and to marital resemblance were both significant. These results show no clear indication as to the source of the heterogeneity observed for familial resemblance of UA levels in randomly selected data. This question should be further investigated, especially in clinical samples such as dyslipoproteinemic families.
Adult↗
Ectopic calcification among families in the Azores: clinical and radiologic manifestations in families with diffuse idiopathic skeletal hyperostosis and chondrocalcinosis.
OBJECTIVE: Twelve families that were multiply affected with diffuse idiopathic skeletal hyperostosis (DISH) and/or chondrocalcinosis, were identified on the island of Terceira, The Azores, potentially supporting the hypothesis that the 2 disorders share common etiopathogenic factors. The present study was undertaken to investigate this hypothesis. METHODS: One hundred three individuals from 12 unrelated families were assessed. Probands were identified from patients attending the Rheumatic Diseases Clinic, Hospital de Santo Espírito, in The Azores. Family members were assessed by rheumatologists and radiologists. Radiographs of all family members were obtained, including radiographs of the dorsolumbar spine, pelvis, knees, elbows, and wrists, and all cases were screened for known features of chondrocalcinosis. RESULTS: Ectopic calcifications were identified in 70 patients. The most frequent symptoms or findings were as follows: axial pain, elbow, knee and metacarpophalangeal (MCP) joint pain, swelling, and/or deformity, and radiographic enthesopathic changes. Elbow and MCP joint periarticular calcifications were observed in 35 and 5 patients, respectively, and chondrocalcinosis was identified in 12 patients. Fifteen patients had sacroiliac disease (ankylosis or sclerosis) on computed tomography scans. Fifty-two patients could be classified as having definite (17%), probable (26%), or possible (31%) DISH. Concomitant DISH and chondrocalcinosis was diagnosed in 12 patients. Pyrophosphate crystals were identified from knee effusions in 13 patients. The pattern of disease transmission was compatible with an autosomal-dominant monogenic disease. The mean age at which symptoms developed was 38 years. CONCLUSION: These families may represent a familial type of pyrophosphate arthropathy with a phenotype that includes peripheral and axial enthesopathic calcifications. The concurrence of DISH and chondrocalcinosis suggests a shared pathogenic mechanism in the 2 conditions.
Adult↗
Familial migraine: exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p.
Genetic isolates are highly useful in analyses of the molecular background of complex diseases since the enrichment of a limited number of predisposing genes can be predicted in representative families or in specific geographical regions. It has been suggested that the pathophysiology and etiology of familial hemiplegic migraine (FHM) and typical migraine with aura are most probably the same. Recent assignment of FHM locus to chromosome 19p in two French families makes it now possible to test this hypothesis. We report here linkage data on four families with multiple cases of migraine disorder originating from the genetically isolated population of Finland. We were interested to discover whether the migraine in these families would also show linkage to the markers on 19p. We could exclude a region of 50 cM, flanking the reported FHM locus, as a site of migraine locus in our four families. It seems evident that locus heterogeneity exists between different diagnostic classes of migraine spectrum of diseases and also between different ethnic groups.
Chromosome Mapping↗
No evidence for linkage of familial hypertrophic cardiomyopathy and chromosome 14q1 locus D14S26 in a Chinese family: evidence for genetic heterogeneity.
To understand the molecular basis of familial hypertrophic cardiomyopathy (FHC) in the Chinese population, a family with FHC was investigated. Nineteen family members who were 16 years of age or older were examined by M-mode or two-dimensional echocardiography. Eight members were diagnosed to be affected echocardiographically or clinically. Lymphocytes isolated from 20 family members were successfully transformed into permanent lymphoblastoid cell lines by Epstein-Barr virus. Three genomic DNA probes (CRI-L436, CRI-L329, and pSC14) that were derived from chromosome 14q1 loci and demonstrated to be linked closely to FHC were used to probe this family. Using the techniques of restriction fragment length polymorphism (RFLP) and linkage analysis, the probe CRI-L436, which recognized locus D14S26, was found informative in this family. The lod scores were -2.0 at theta = 0.025 and -1.49 at theta = 0.05. Thus, there was no evidence of linkage between the locus D14S26 and the gene for FHC in the pedigree studied. In addition, polymerase chain reaction (PCR) amplification did not indicate a mutation on exon 13 of the beta cardiac myosin heavy chain gene as previously reported. Our data suggest that FHC is a genetically heterogeneous disease.
Adult↗
A neonatal screening approach to the detection of familial hypercholesterolaemia and family-based coronary prevention.
We measured by radial immunodiffusion apolipoprotein B (ApoB) as a genetic marker for familial hypercholesterolaemia in heel prick blood spot samples on filter paper routinely collected from 5000 3- to 5-day-old neonates for current screening programmes. Dried blood spot ApoB levels were distributed continuously and were 9% higher in female neonates than in males (0.246 +/- 0.085 versus 0.225 +/- 0.079 g/L of whole blood, mean +/- SD, p less than 0.0001). Neonates of birth weight under 2.5 kg had lower levels than the population mean in both sexes but levels did not change with birth weight within this range; in those with the birth weights greater than 2.5 kg levels increased with increasing birth weight. Sex and birth weight could account for 5.7% of the variability of ApoB. Levels had largely stabilized by day 3 of life. Of parents of neonates whose ApoB levels were among the top 2%, 45 families were available for study when the infants were aged 12.3 +/- 3.3 months. In 6 of these families there was a persisting elevation of ApoB both in the infants (levels greater than 0.7 g/L of whole blood) and in one parent who also had elevated ApoB and a lipid profile of familial hypercholesterolaemia phenotype, results indicating an ascertainment rate of between 1 in 365 and 1 in 830 of the screened population. These studies have defined the variables affecting neonatal ApoB levels and establish that neonatal screening for familial hypercholesterolaemia is feasible. Primary prevention of vascular disease in young families with the gene should be possible with this approach.
Coronary Disease↗
Distribution of the salmonid Hpa 1 family in the salmonid species demonstrated by in vitro runoff transcription assay of total genomic DNA: a procedure to estimate repetitive frequency and sequence divergence of a certain repetitive family with a few known sequences.
An in vitro runoff transcription assay of total genomic DNA was developed. As an example of use of this assay, analysis of a highly repetitive sequence in the cherry salmon (Oncorhynchus masou) is described. Total genomic DNA of the cherry salmon was completely digested with Hpa 1, whose site is known to be in the tRNA-unrelated region of the cherry salmon Hpa 1 family. On transcription of the digested DNA in a HeLa cell extract, a discrete-sized RNA of about 100 nucleotides, constituting 70% of the transcripts, was produced, whereas on transcription of the undigested total DNA, only smeared RNA was obtained. In a fingerprint, the oligonucleotides of the discrete transcript from the digested total DNA were very distinct and exactly corresponded to those of a transcript from an Hpa 1 digest of a cloned DNA, but with few extra oligonucleotides. These results showed that the cherry salmon Hpa 1 family constitutes a major repetitive family in the genome of the cherry salmon. For determination of the distribution of the salmonid Hpa 1 family in other salmonid species, the same analysis was applied to DNAs from the chum salmon (Onchorhynchus keta), brown trout (Salmo trutta), Japanese common charr (Salvelinus leucomaenis pluvius), and Japanese huchen (Hucho perryi). The results showed that the salmonid Hpa 1 family is widespread in the genomes of salmonid species. A method and equations are also presented for estimating the relationship between the ratio of a given repetitive family to all the Pol III genes and its average sequence divergence by calculating the molar ratio of the runoff transcript to all the in vitro Pol III transcripts.
Animals↗
Ethnicity, social status, and families' experiences of caring for a mentally ill family member.
There is growing attention to the role of families nas caregivers of family members with serious mental illness. This paper presents presents data from a multicultural sample of 90 family caregivers from diverse ethnic backgrounds. The paper examines families' experiences with mental health services; their support networks and family burdens; and their conceptions of mental illness. The paper both provides one of the first comparative studies of family caregivers from different ethnic groups and suggests an agenda for future research in this area.
Black or African American↗
Mapping the locus for familial hypertrophic cardiomyopathy to chromosome 11 in a family with a case of apical hypertrophic cardiomyopathy of the Japanese type.
To identify the disease locus of familial hypertrophic cardiomyopathy (FHC) in a Chinese family, a genetic linkage study was performed using polymorphisms from various chromosomal regions. This family has eight affected members, including a case with typical features of apical hypertrophic cardiomyopathy of the Japanese type. The results revealed significant evidence of linkage of polymorphisms on chromosome 11p13-q13 and FHC in this family with a maximal lod score of 3.38 at theta = 0.00. Our data suggest that the locus responsible for FHC in this family maps to chromosome 11 and that the molecular basis of FHC in the case of apical hypertrophic cardiomyopathy of the Japanese type might be similar to that of other affected members in the same family. Further studies are needed to elucidate the whole spectrum of the genetic basis of apical hypertrophic cardiomyopathy of the Japanese type.
Base Sequence↗
HLA-typing in juvenile diabetics with and without positive family history and in families with one and two diabetic siblings.
HLA-typing was performed in two groups of juvenile-onset diabetics, one with (n = 58) and one without (n = 109) a family history of the disease. The association of this type of diabetes with certain HLA antigens (excess of B8 and B15, shortage of B7) was confirmed. No heterogeneities could be established between the two groups. This suggests that the aetiologic basis in single and familial cases of juvenile diabetes is the same. The hypothesis, that the B8 associated gene is more penetrant than the B15 associated gene, cannot be confirmed. Haplotypes were determined in families with one and two diabetic siblings. The findings of high haplotype concordance among diabetic siblings was confirmed: concordance of 2, 1 and 0 haplotypes in 7, 5 and 3 pairs respectively. There was a low degree of haplotype concordance between diabetics and nonaffected siblings in the families with two diabetics: 2, 1, and 0 haplotypes in 2, 8 and 6 pairs respectively. This led to the hypothesis of negative selection against these HLA-linked "diabetogenic" genes. This tendency was not, however, observed in families with only one diabetic. The report of a high recombination rate in families with juvenile diabetics could not be confirmed.
Adolescent↗
[Familial mitochondrial chronic progressive external ophthalmoplegia. Five families with differing genetics].
UNLABELLED: Chronic progressive external ophthalmoplegia (CPEO) is considered the most frequent form of mitochondrial encephalomyopathies. Most cases occur sporadically. We investigated 18 consecutive patients with CPEO. Thirteen cases were sporadic and five cases were familial. In one family with maternal inheritance the mitochondrial point mutation A3243G was identified. In index patients of three other families multiple deletions of mitochondrial DNA were found. One of these families showed autosomal recessive inheritance. In the two other pedigrees a definitive determination of the mode of inheritance was impossible. The fifth family revealed autosomal dominant or maternal inheritance. In their index patient no alteration of mitochondrial DNA could be identified (including sequencing of hot spots for mitochondrial mutations). CONCLUSIONS: CPEO was familial in 28% of our patients. There are three different modes of inheritance: (i) maternal transmission associated with mitochondrial point mutations as it is known for other mitochondrial disorders, (ii) autosomal recessive, and (iii) autosomal dominant inheritance. In contrast to sporadic cases with single mitochondrial deletions autosomal inheritance can be associated with multiple deletions of mitochondrial DNA. They are due to so far unknown nuclear mutations.
Adult↗
Detection of a single base deletion in codon 424 of the low density lipoprotein receptor gene in a Danish family with familial hypercholesterolemia.
We performed a screening of exon 9 of the low density lipoprotein receptor (LDLR) gene in 14 Danish families with familial hypercholesterolemia (FH) using the denaturing gradient gel electrophoresis (DGGE) technique. In one of the probands from these families an abnormal band pattern in the gradient gel was detected. Subsequent DGGE analysis of the family of this index patient revealed that the DGGE pattern cosegregated with the disease in this family. Sequencing of the exon showed a deletion of a C in codon 424 of the LDLR gene resulting in a frame shift with the introduction of a stop codon 5 codons further downstream. The mutation is referred to as FH-Odense. The predicted truncated receptor protein consists of the 428 amino terminal amino acids. Consequently, the cytosolic and membrane spanning parts of the mature LDL receptor, which normally secure the receptor in the plasma membrane, are missing. The FH-Odense mutation results in severe premature coronary atherosclerosis as shown by the clinical expression in 5 generations of the affected family.
Adolescent↗
Familial and non-familial mania.
We compared 34 manics with a positive family history of affective disorder (familial mania) and 84 manics with a negative family history of affective disorder (non-familial mania) for clinical, demographic and historical variables related to abnormal brain function and for cortical functioning measured by neuropsychological and electroencephalographic techniques. Proband and relative research diagnosis, neuropsychological and electroencephalographic interpretations were made blindly and independently of each other. Except for index admission severity of illness being greater in familial manics, we could find no significant differences for any of the variables studied. We conclude that differences in family illness patterns do not identify subgroups of manics and if it exists, heterogeneity, must be sought by studying other biologic correlates of psychopathology.
Adult↗