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At least 1,531 records · Page 85Linked to original sources
PubMed2005

Ehlers-Danlos syndrome type VIB with characteristic facies, decreased curvatures of the spinal column, and joint contractures in two unrelated girls.

Two unrelated girls, aged 11 and 14 years, with clinical manifestations of Ehlers-Danlos syndrome (EDS) type VIB, characteristic facies, skeletal abnormalities, and other features are described. They had Marfanoid habitus with pectus excavatum; fragile, hyperextensible, and readily bruisable skin with widened, atrophic scars; recurrent hematomas; generalized joint laxity; hypotonia; scoliosis; and mild delay of gross motor development. Lysyl hydroxylase deficiency was ruled out in Patient 1. Parental consanguinity was present in Patient 2. They both had, in early childhood, down-slanting palpebral fissures, drooping lower eyelids, short nose, small mouth, and long philtrum. Facial features that persisted included thick eyebrows, hypertelorism, strabismus, blue sclerae, low-set, and slanted ears, hypoplastic columella, high-arched palate, and thin upper lip. They had tubular stenosis of the phalanges, metacarpals, and metatarsals; decreased physiological curvatures of the spinal column with tall vertebrae; and joint contractures including talipes equinovarus and progressive talipes valgus. Their hearing of high-pitched sounds was impaired. They had constipation and recurrent cystitis with an enlarged bladder. In view of these findings, we propose that these two girls represent a clinically recognizable subgroup of EDS type VIB.

Adolescent↗
PubMed2006

Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia: clinical and molecular findings in three families supporting genetic heterogeneity in Smith-McCort dysplasia.

Dyggve-Melchior-Clausen syndrome (DMC) (MIM 223800) and Smith-McCort dysplasia (SMC) (MIM 607326) are rare allelic autosomal recessive spondylo-epi-metaphyseal dysplasias (SEMDs) characterized by similar skeletal manifestations. Both phenotypes have been mapped to chromosome 18q21.1 and mutations in the DYM (dymeclin) gene were identified in 13 families with DMC and in two families with SMC. Most mutations identified in DMC predict a loss of function, while those identified in SMC are mainly missense mutations, presumably associated with residual DYM activity and a less severe phenotype. We studied three consanguineous families from Turkey, Lebanon, and Georgia, one with SMC and two with DMC and identified different homozygous DYM mutations (IVS3 194-1G > A, 938_942delTGTCT) in the DMC families. No mutation was identified in the SMC family, possibly suggesting genetic heterogeneity of this disorder.

Adolescent↗
PubMed2006

Genetic disorders among Palestinian Arabs. 4: Genetic clinics in the community.

Genetic disorders are frequent in the Arab population of Israel, mainly because of the preference for consanguineous marriages. Many of the inherited diseases are present with a high frequency only in a limited region or a single village. It is therefore not surprising that, in each of the villages, a different distribution of genetic diseases is found; thus, a detailed knowledge of the genetic disorders present in each village is of utmost importance for genetic counseling. As a direct consequence of these observations two community genetics clinics were opened as a pilot project to study their impact on the population to be served. The use of a computer database allowed for easier and more accurate genetic counseling. There were almost 1,500 visits in the 4-year period since the introduction of the services. During the years an increase in the mean number of consultations per clinic as well as a change in the type of referrals was observed. There was an increasing proportion of clinics that were made at a time in which genetic counseling allow for primary prevention. The presence of a genetic counselor in the village clinic allows for better and closer contacts with the family physician.

Arabs↗
PubMed1975

The genetic structure of a tribal population, the Yanomama Indians. XII. Biodemographic studies.

The Yyanomama Indians of Southern Venezuela and Northern Brazil are one of the largest, relatively unacculturated tribes of the tropical rain forest. Over a period of eight years data have been collected from a considerable portion of their territory on estimated age, sex ratio, fertility rates (as determined by physical examination and urine tests), and infant death rates. Although it has been impossible to collect direct data on infanticide, this subject can be approached indirectly through distortions of the sex ratio and anecdotal information. Some historical data are also available as a basis for estimating tribal expansion in the past 100 years. With this material it has been possible to construct Life Tables for the anomama,, and to explore the results of various perturbations of the input parameters. Data are also presented on patterns of mating and reproduction: number of spouses, mean and variance in number of surviving children, frequency of "extra-marital conceptions" based on the results of extensive blood group typings, and consanguinity rates as determined by observation and computer simulation. Although we do not present the Yanomama as typical, these data are seen as providing a basis for more realistic population models than have existed in the past. In addition, the data provide a basis for relatively precise estimates of such demographic measures as Fisher's Reproductive Value, Crow's Index of Total Selection, and Weiss' Index of Growth Regulation.

Adolescent↗
PubMed1985

A study of some genetic characteristics of the Fur and Baggara tribes of the Sudan.

The average inbreeding coefficients of the highly consanguineous Fur and Baggara tribes of Western Sudan were 0.04167 and 0.04450, respectively. Two hundred ninety-eight subjects from the two tribes were tested for polymorphism of hemoglobins, seven red cell enzymes, and four serum proteins. The Baggara showed a higher gene frequency of HbS and TfD and lower gene frequency of GdA and PC compared to the Fur. Both tribes showed a low gene frequency of PGM1 and high frequency of G6PD deficiency when compared to other Sudanese tribes. In spite of the high degree of inbreeding, no significant deviation from the Hardy-Weinburg equilibrium was observed in either tribe. The effects of inbreeding seem to be offset by mixing between the two tribes on Gabal Marra Plateau. The flow of the sickle gene from the Baggara into the Fur and other Sudanese tribes is discussed.

Acid Phosphatase↗
PubMed1980

Chronic Leigh Disease: a genetic and biochemical study.

The large family of a 21-year-old man who died of Leigh disease was investigated for evidence of neurological abnormalities and presence of the adenosine triphosphate-thiamine diphosphate phosphoryltransferase inhibitor factor. Of 217 persons (seven generations) included in the pedigree, 68 were examined neurologically and biochemically. Fourteen (20%), 5 of whom had abnormal neurological findings, were found to excrete the inhibitor factor. Clinical manifestations varied from severe neurological affliction to subtle deficits. A chronic relapsing course was frequently encountered, with exacerbations occurring in association with apparent metabolic stress. Parental consanguinity was identified in the propositus as well as in other family members with neurological abnormalities. Males and females were affected, and no vertical transmission of the trait was found. These multigenerational data suggest that Leigh disease in adults is inherited in an autosomal recessive manner and has variable degrees of expression with a wide spectrum of neurological manifestations.

Adult↗
PubMed1991

Hereditary branching enzyme dysfunction in adult polyglucosan body disease: a possible metabolic cause in two patients.

We describe 2 unrelated patients with adult polyglucosan body disease (APBD) diagnosed by sural nerve biopsy. Both patients were offspring of consanguineous marriages. They presented clinically with late onset pyramidal tetraparesis, micturition difficulties, peripheral neuropathy, and mild cognitive impairment. Magnetic resonance imaging of the brain revealed extensive white matter abnormalities in both. In search of a possible metabolic defect, we evaluated glycogen metabolism in these patients and their clinically unaffected children. Branching enzyme activity in the patients' polymorphonuclear leukocytes was about 15% of control values, whereas their children displayed values of 50 to 60%, suggesting a possible autosomal recessive mode of transmission. This is the first report of an inherited metabolic defect in patients with adult polyglucosan body disease. We suggest that branching enzyme dysfunction may be implicated in the pathogenesis of some patients with adult polyglucosan body disease.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1996

Leigh syndrome: clinical features and biochemical and DNA abnormalities.

We investigated the etiology of Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups, ie, 80% in the tightly defined group and 41% in the "Leigh-like" group. Eleven patients had mitochondrial DNA point mutations (nucleotide [nt] 8993 T to G, nt 8993 T to C, or nt 8344 A to G) and 1 Leigh-like patient had a heteroplasmic deletion. Twenty-nine patients had enzyme defects, ie, 13 respiratory chain complex I, 9 complex IV, and 7 pyruvate dehydrogenase complex (PDHC). Complex I deficiency is more common than recognized previously. Six PDHC-deficient patients had mutations in the X-chromosomal gene encoding the E1alpha subunit of PDHC. Parental consanguinity suggested autosomal recessive inheritance in two complex IV-deficient sibships. We found no strong correlation between the clinical features and basic defects. An assumption of autosomal recessive inheritance (frequently made in the past) would have been wrong in nearly one-half (11 of 28 tightly defined and 18 of 41 total patients) of those in whom a cause was found. A specific defect must be identified if reliable genetic counseling is to be provided.

Brain↗
PubMed1997

Allelic heterogeneity of Mediterranean myoclonus and the cystatin B gene.

Mediterranean myoclonus is a progressive myoclonus epilepsy with autosomal recessive inheritance. Another form has been described in Finland, the so-called Baltic myoclonus. Mediterranean myoclonus and Baltic myoclonus are also known as Unverricht-Lundborg disease. Linkage analyses have shown that the genes for both these forms of myoclonus are closely linked to 21q22.3 DNA markers, suggesting that they are caused by mutations at the same locus (EPM1). Recently, two heterozygous mutations were found in the cystatin B gene in patients with Unverricht-Lundborg disease. We report recombinational and linkage disequilibrium mapping of EPM1, and cystatin B gene sequencing, in 14 consanguineous pedigrees with Mediterranean myoclonus. Linkage to 21q22.3 DNA markers was observed in all these families. Haplotype analysis suggests that a common mutation segregates within these pedigrees, and that this mutation is different from the common one responsible for the Finnish form of Unverricht-Lundborg disease. No mutation was found in the exons or splice junctions of the cystatin B gene in the 14 pedigrees.

Base Sequence↗
PubMed1998

Localization of the giant axonal neuropathy gene to chromosome 16q24.

Giant axonal neuropathy (GAN) is a degenerative disorder of the peripheral nerves that is inherited as an autosomal recessive trait, presenting in early childhood and progressing to death, usually by late adolescence. Diagnosis is made by peripheral nerve biopsy, in which a striking pathological finding is seen--fibers distorted by giant axonal swellings filled with densely packed bundles of neurofilaments (the primary intermediate filament in neurons), with segregation of other axoplasmic organelles. In addition to disorganized neurofilaments in nerve, disorganization of other members of the intermediate filament family of proteins is seen in other tissues; this implies that the underlying defect is one of generalized intermediate filament organization, with neurofilaments predominantly affected. We have pursued a genomewide search for regions of homozygosity of descent in 5 consanguineous families. A 5.3-cM region of homozygosity, shared in all 5 families, was found on chromosome 16q24, and linkage was established to this locus with a LOD score of 4.18 at theta = 0.00 at the most tightly linked marker, D16S3098. Determination of this locus is the first step toward characterizing the gene responsible for a fundamental property of intermediate filament organization and may shed light on other disorders (such as amyotrophic lateral sclerosis) in which neurofilament pathology is prominent.

Axons↗
PubMed1978

Familial lupus. Family studies of HLA and serologic findings.

HLA profiles in 103 members of 4 separate kindred with multiple occurrence of SLE were compatible with the presence of a disease susceptibility factor linked to HLA or a direct effect of antigens B8, A11, and B35 on disease expression. Serum ANA was found in 52.9% of consanguineous, 56.5% of nonconsanguineous relatives of SLE probands, and 5% of controls, a finding that suggests the presence of a transmissible agent in the families. By contrast, lymphocytotoxic antibodies were not increased in relatives compared to controls.

Adolescent↗
PubMed2003

Birth prevalence and pattern of osteochondrodysplasias in an inbred high risk population.

BACKGROUND: Define the pattern and birth prevalence of the different types of osteochondrodysplasias in newborn infants in the United Arab Emirates (UAE) population, which is highly inbred and where termination of pregnancy is not accepted. METHODS: All infants with a birth weight of 500 gm and above in the three hospitals in Al Ain Medical District of the UAE were studied prospectively over a period of 5 years. For each live birth or stillbirth with suspected skeletal dysplasia, a detailed clinical and radiological examination was carried out. Pregnancy history and information regarding parental age, ethnic origin, family history, and level of consanguinity were obtained and a pedigree was constructed. RESULTS: Among the 38,048 births during the study period, 36 (9.46/10,000 births) had some type of skeletal dysplasia. Eighteen cases were attributed to autosomal recessive genes (4.7/10,000 births), 10 were due to apparent new dominant mutations (2.62/10,000), five were autosomal dominant type (1.3/10,000) and one was X-linked dominant type (0.26/10,000). In three cases, inheritance was unknown. The most common recessive type of skeletal dysplasia in our series was fibrochondrogenesis (1.05/10,000), followed by chondrodysplasia punctata (0.78/10,000). The birth prevalence rate of skeletal dysplasia doubled in the last 2 years of the 5-year observation period (6.74/10,000 in 1996 vs. 12.86/10,000 in 1999, and 13.45/10,000 in 2000). This increase involved cases caused by new dominant mutations, and occurred mainly in the first half of 1999. CONCLUSION: This prospective study has identified a high birth prevalence of skeletal dysplasia, and risk factors are postulated. These findings represent an accurate birthprevalence figure and a useful baseline for this group of birth defects in the UAE.

Adult↗
PubMed2003

The Iranian Human Mutation Gene Bank: a data and sample resource for worldwide collaborative genetics research.

As Human Genome Project exploration continues, the necessity of having a broader spectrum of genomic DNA material from different nationalities to study various aspects of hereditary disease becomes more obvious. The existence of high genetic polymorphism within and between different communities in the world makes it necessary for the gene hunters to investigate many different populations. Iran, a large country with close to 66 million people, is a land of different nationalities, tribes, and religions that offers a highly heterogeneous gene pool to the genetics researcher. The purity of many different races in this country has been highly conserved by geographical borders and by an ancient culture that has always encouraged intrafamilial marriages. All these have created a population that is remarkably heterogeneous yet high in consanguinity rate. During the last five years of investigation we have established a DNA bank, the Iranian Human Mutation Gene Bank (www.IHMGB.com), which contains all genetic diseases studied in Iran that have the Mendelian mode of inheritance. Some of the samples are assigned to common or novel mutations and others belong to patients with clinical profiles associated with particular genetic diseases but undefined mutation. This bank stores samples of DNA from the patient and his/her first-degree relatives together with a comprehensive pedigree and clinical profile for each sample. To facilitate collaboration with other scientists around the world with the same interests, we decided to present our experimental projects online. This DNA bank provides opportunities for us to collaborate with scientists outside Iran. It offers a sample resource to research scientists around the world, at no charge, for the purpose of investigating the various aspects of genetic disorders from prenatal diagnosis to gene structure and function. It is strongly stressed that no commercial benefit is involved in the establishment of this DNA bank and the DNA samples are free of charge. However, to meet our goals and to respect ethical values, DNA samples can only be used under certain conditions stated in the User Consent Form.

Consanguinity↗
PubMed2003

Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy.

Respiratory chain complex I deficiencies represent a genetically heterogeneous group of diseases resulting from mutations in either mitochondrial or nuclear DNA. Combination of denaturing high performance liquid chromatography and sequence analysis allowed us to show that a 4-bp deletion in intron 2 (IVS2+5_+8delGTAA) of the NDUFV2 gene (encoding NADH dehydrogenase ubiquinone flavoprotein 2) causes complex I deficiency and early onset hypertrophic cardiomyopathy with trunk hypotonia in three affected sibs of a consanguineous family. The homozygous mutation altering the consensus splice-donor site of exon 2 resulted in 70% decreased NDUFV2 protein and complex I deficiency. While mutation in a number of genes encoding complex I subunits essentially result in neurological symptoms, this first mutation in NDUFV2 is strikingly associated with cardiomyopathy, as previously observed in the unique case of NDFUS2 mutations.

Age of Onset↗
PubMed2001

Bruton tyrosine kinase gene mutations in Turkish patients with presumed X-linked agammaglobulinemia.

X-linked agammglobulinemia (XLA) is a ptototypical humoral immunodeficiency caused by mutations in the gene coding for Bruton tyrosine kinase (BTK). The genetic defect in XLA impairs early B cell development resulting in marked reduction of mature B cells in the blood. Studies from different countries have demonstrated that approximately 90% of males with presumed XLA bear mutations in BTK. In this study, we report for the first time the occurrence of BTK mutations in Turkey. We performed mutational analysis of the BTK gene in 16 Turkish male patients from 13 separate families with presumed XLA based on abnormally low peripheral blood B-cell numbers (lt; 1%), hypogammaglobulinemia, and recurrent bacterial infections. We found that in nine of the 13 families (69%) a Btk mutation caused XLA. Two of the mutations were previously described, but seven novel mutations were identified: two missense (Y39C, G584R), one nonsense (Q343X), and 4 deletions (1800-1821del, 1843-1847del, 1288-1292del, 291del) resulting in frameshift and premature stop codon. By contrast, no mutations in the BTK gene were identified in the other 4 families. A consanguinity in three of these families raises the possibility that mutations in other autosomal genes which affect early B cell development may contribute to their phenotype resembling XLA.

Adolescent↗
PubMed2006

Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.

In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.

Amino Acid Sequence↗
PubMed2006

A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria.

Methylmalonic aciduria (MMA-uria) is an autosomal recessive inborn error of amino acid metabolism, involving valine, threonine, isoleucine, and methionine. This organic aciduria may present in the neonatal period with life-threatening metabolic acidosis, hyperammonemia, feeding difficulties, pancytopenia, and coma. Most affected patients have mutations in the methylmalonyl-coenzyme A (methylmalonyl-CoA) mutase gene. Mildly affected patients may present in childhood with failure to thrive and recurrent attacks of metabolic acidosis. Both a higher residual activity of methylmalonyl-CoA mutase as well as the vitamin B12-responsive defects (cblA and cblB) may form the basis of the mild disorder. A few patients with moderate MMA-uria are known in whom no defect could be identified. Here we present a 16-year-old female patient with persisting moderate MMA-uria (approximately 50 mmol/mol creatinine). She was born to consanguineous Caucasian parents. Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established. Reduced incorporation of 14C-propionate into macromolecules suggested a defect in the propionate-to-succinate pathway. We found a homozygous nonsense mutation (c.139C>T) in the methylmalonyl-CoA epimerase gene (MCEE), resulting in an early terminating signal (p.R47X). Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid (MMA). This is the first report of methylmalonyl-CoA epimerase deficiency, thereby unequivocally demonstrating the biochemical role of this enzyme in human metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Long contiguous stretches of homozygosity in the human genome.

Single nucleotide polymorphisms (SNPs) are the most common sequence variation in the human genome; they have been successfully used in mapping disease genes and more recently in studying population genetics and cancer genetics. In a population-based association study using high-density oligonucleotide arrays for whole-genome SNP genotyping, we discovered that in the genomes of unrelated Han Chinese, 34 out of 515 (6.6%) individuals contained long contiguous stretches of homozygosity (LCSHs), ranging in the size from 2.94 to 26.27 Mbp (10.22+/-5.95 Mbp). Four out of four (100%) Taiwan aborigines also demonstrated this genetic characteristic. The number of LCSH regions increased markedly in the offspring of consanguineous marriages. LCSH was also detected in Caucasian samples (11/42; 26.2%) and African American samples (2/42; 4.76%). A total of 26 LCSH regions were recurrently detected among Han Chinese, Taiwan aborigines, and Caucasians. DNA copy number determination by hybridization intensity analysis and real-time quantitative PCR (qPCR) excluded deletion as the cause of LCSH. Our results suggest that LCSHs are common in the human genome of the outbred population and this genetic characteristic could have a significant impact on population genetics and disease gene studies.

Black or African American↗