bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue culture loading test with storage granules from animal models of neuronal ceroid‐lipofuscinosis (Batten disease): Testing their lysosomal degradability by normal and Batten cells
Authors: Elleder M. , Drahota Z. , Lisá V. , Mareč Vl. , Mandys V. , Müller J. , Palmer D. N.
Published: June 2005

Storage granules (SGs) from ovine and canine models of Batten disease were found to be easily phagocytosed by four cell types studied. The cell types tested were human fibroblasts and peripheral monocytes (control and from a late infantile Batten disease patient), rat C6 cell line, and neonatal cardiomyocytes. The phagocytosed SGs elicited an increase in acid phosphatase activity which was localized in the phagolysosome. After phagocytosis SGs were followed for various times ranging from 7 to 21 days and were found to be of unchanged density (phase contrast), autofluorescence, and ultrastructural appearance. These findings point to their undegradability, or very low degree of degradability, in phagolysosomes in both normal or Batten cultured cells. The Batten disease SGs are not toxic and did not cause any adverse affect on the host cells. Either the normal clearance rate from lysosomes is too slow to be measured by this technique or subunit c accumulation in lysosomes need not result from a primary lysosomal protease defect. Subunit c may aggregate, because of the lack of some normally preventive factor, resulting in a physical barrier to the degradation of this highly apolar molecule. © 1995 Wiley‐Liss, Inc.
Diagnoses of neuronal ceroid‐lipofuscinosis by immunochemical methods
Authors: Hosain Syed , Kaufmann Walter E. , Negrin Gisela , Watkins Paul A. , Siakotos Aristotle N. , Palmer David N. , Naidu SakkuBai
Published: June 2005

The neuronal ceroid‐lipofuscinoses (NCL), also known as Batten disease, are a not uncommon group of disorders affecting infants, children, and young adults. The abnormal ultrastructural profiles seen in NCL are used for standard diagnosis; however, they can be missed, and are also found in other neurodegenerative conditions. Furthermore, there is an overlap between the types of inclusion profiles among the different forms of NCL. Therefore, a more specific and biochemically‐based marker is necessary to confirm the diagnosis of NCL. Antibodies raised against the storage material from the ovine form of NCL (mitochondrial ATP synthase subunit c) were utilized to determine whether NCL could be distinguished from other metabolic‐neurodegenerative disorders. By immunoblotting and immunohistochemistry, several brain samples of well‐evaluated NCL cases confirmed increased accumulations in all NCL cases except in the brain of an infantile‐onset NCL patient. The immunoblot studies of skin fibroblasts and brain were sensitive but not highly specific to NCL, due to the recognition of this material in normal controls as well as in other neurogenetic diseases. Immunocytochemistry of skin fibroblasts clearly distinguished LINCL and JNCL cases from controls, and with further refinement has the potential for becoming a diagnostic tool. © 1995 Wiley‐Liss, Inc.
Early detection of canine ceroid‐lipofuscinosis (CCL): An ultrastructural study
Authors: Savill J. , Azzarelli B. , Siakotos A. N.
Published: June 2005

English setters from the Koppang line have been used as a model for the juvenile type of Batten disease in human patients. This disorder, canine ceroid‐lipofuscinosis (CCL), has been shown by Koppang [1973: Mech Ageing Dev 2:421–445] to be an autosomal recessive disorder. Homozygous animals show the typical storage granules by autofluorescence; however, the autofluorescence material cannot easily be detected in affected dogs before age 3–6 months. At the present time the early stages of CCL can be studied only in litters from homozygous matings. Electron microscopy was used to study the reliability of diagnosing affected animals in heterozygous‐heterozygous (HET‐HET) and heterozygous‐homozygous (HET‐HOM) litters at age 2–3 weeks. The electron micrographs of brain biopsies were examined and the number of all dense bodies (d.b.), including linear and fingerprint patterns typical of CCL, were counted per neuron. The results indicated that affected animals have higher numbers of dense bodies than nonaffected carriers. Four‐6 months later confirmatory diagnoses were made on a second contralateral biopsy taken and examined as a frozen section by autofluorescence. The diagnoses made by electron microscopy at age 2–3 weeks appeared identical to the results obtained by autofluorescence at 4–6 months of age. © 1995 Wiley‐Liss, Inc.
Abnormal degradative pathway of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid‐lipofuscinosis (Batten disease)
Authors: Ezaki Junji , Wolfe Leonhard S. , Ishidoh Kazumi , Kominami Eiki
Published: June 2005

Subunit c is normally present as an inner mitochondrial membrane component of the F0 sector of the ATP synthase complex, but in the late infantile form of neuronal ceroid‐lipofuscinosis (NCL) it was also found in lysosomes in high concentrations. The rate of degradation of subunit c as measured by pulse–chase and immunoprecipitation showed a marked delay of degradation in patients' fibroblasts with late infantile form of NCL. There were no significant differences between control cells and cells with disease in the degradation of cytochrome oxidase subunit IV, an inner membrane protein of mitochondria. Measurement of labeled subunit c in mitochondrial and lysosomal fractions showed that the accumulation of labeled subunit c in the mitochondrial fraction can be detected before lysosomal appearance of radioactive subunit c, suggesting that subunit c accumulated as a consequence of abnormal catabolism in the mitochondrion and is transferred to lysosomes through an autophagic process. The biosynthetic rate of subunit c and mRNA levels for P1 and P2 genes that code for it were almost the same in both control and patient cells. These findings suggest that a specific failure in the degradation of subunit c after its normal inclusion in mitochondria and its consequent accumulation in lysosomes. © 1995 Wiley‐Liss, Inc.
Refined localization of the Batten disease gene (CLN3) by haplotype and linkage disequilibrium mapping to D16S288‐D16S383 and exclusion from this region of a variant form of Batten disease with granular osmiophilic deposits
Authors: Mitchison H. M. , O'Rawe A. M. , Lerner T. J. , Taschner P. E. M. , Schlumpf K. , D'Arigo K. , de Vos N. , Gormally E. , Phillips H. A. , Thompson A. D. , Haines J. L. , Hart Y. M. , Andermann E. , Callen D. F. , Breuning M. H. , Gardiner R. M. , Mole S. E.
Published: June 2005

Haplotype analysis in a collaborative collection of 143 families with juvenile‐onset neuronal ceroid lipofuscinosis (JNCL) or Batten (Spielmeyer‐Vogt‐Sjögren) disease has permitted refined localization of the disease gene, CLN3, which was assigned to chromosome 16 in 1989. Recombination events in four maternal meioses delimit new flanking genetic markers for CLN3 which localize the gene to the chromosome interval 16p12.1‐11.2 between microsatellite markers D16S288 and D16S383. This narrows the position of CLN3 to a region of 2.1 cM, a significant reduction from the previous best interval. Using haplotypes, analysis of the strong linkage disequilibrium that exists between genetic markers within the D16S288‐D16S383 interval and CLN3 shows that CLN3 is in closest proximity to loci D16S299 and D16S298. Analysis of markers across the D16S288‐D16S383 region in four families with a variant form of JNCL characterized histologically by cytosomal granular osmiophilic deposits (GROD) has excluded linkage of the gene locus to the CLN3 region of chromosome 16, suggesting that JNCL with GROD is not an allelic form of JNCL. © 1995 Willy‐Liss, Inc.
Interest in genetic testing among first‐degree relatives of breast cancer patients
Authors: Lerman Caryn , Seay Janet , Balshem Andrew , Audrain Janet
Published: June 2005

The recent cloning of a breast‐ovarian cancer susceptibility gene (BRCA1), and determination of the locus of a related gene (BRCA2), offers potential for clinical genetic testing for breast cancer susceptibility. This study examined interest in and expectations about an impending genetic test among first‐degree relatives (FDRs) of breast cancer patients. One hundred five females completed two structured telephone interviews to assess demographics, breast cancer risk factors, psychological factors, and attitudes about genetic testing for breast cancer susceptibility. Overall, 91% of FDRs said that they would want to be tested, 4% said they would not, and 5% were uncertain. The most commonly cited reasons for wanting genetic testing were to learn about one's children's risk, to increase use of cancer screening tests, and to take better care of oneself. Women with less formal education were motivated by childbearing decisions and future planning to a greater degree than were women with education beyond high school. Most women anticipated a negative psychological impact of positive test results, involving increased anxiety (83%), depression (80%), and impaired quality of life (46%). In addition, 72% of women indicated that they would still worry if they tested negative. In multivariate regression analysis, level of baseline depression was the strongest predictor of an anticipated negative impact of genetic testing (Beta =.15; P,.0001). These results suggest that the demand for genetic testing for breast cancer susceptibility may be great, even among women who are not likely to have predisposing mutations. Prior to widespread availability of such testing, it will be critical to develop informed consent protocols to educate individuals about the benefits and limitations of predictive testing for this multifactorial disease. © 1995 Wiley‐Liss, Inc.
Previously apparently undescribed syndrome: Shallow orbits, ptosis, coloboma, trigonocephaly, gyral malformations, and mental and growth retardation
Authors: Ramer Jeanette C. , Lin Angela E. , Dobyns William B. , Winter Robin , Aymé Ségolène , Pallotta Rosanna , Ladda Roger L.
Published: June 2005

We describe 2 children with severe ptosis, trigonocephaly, broad nasal bridge, and major brain malformation. A total of 8 children have been reported who share most of these findings. Two of the individuals have had identical pericentric inversions involving chromosome 2p12–ql4. These cases appear to represent a unique malformation syndrome. © 1995 Wiley‐Liss, Inc.
Combined Leydig cell and Sertoli cell dysfunction in 46, XX males lacking the sex determining region Y gene
Authors: Turner Bryan , Fechner Patricia Y. , Fuqua John S. , Marcantonio Sandra M. , Periman Elizabeth J. , Vordermark Jonathan S. , Berkovitz Gary D.
Published: June 2005

We have evaluated 3 individuals with a rare form of 46, XX sex reversal. All of them had ambiguous external genitalia and mixed wolffian and mullerian structures, indicating both Leydig cell and Sertoli cell dysfunction, similar to that of patients with true hermaphroditism. However, gonadal tissue was not ovotesticular but testicular with varying degrees of dysgenesis.

SRY sequences were absent in genomic DNA from peripheral leukocytes in all 3 subjects. Y centromere sequences were also absent, indicating that testis development did not occur because of a low level mosaicism of Y bearing cells. The subjects in this report demonstrate that there is a continuum in the extent of testis determination in SRY‐negative 46, XX sex reversal, ranging from nearly normal to minimal testicular development. © 1995 Wiley‐Liss, Inc.
Splicing mutation in CYP21 associated with delayed presentation of salt‐wasting congenital adrenal hyperplasia
Authors: Kohn Brenda , Day Darren , Alemzadeh Ramin , Enerio Devi , Patel Sanjivan V. , Pelczar Joseph V. , Speiser Phyllis W.
Published: June 2005

Patients with salt‐wasting congenital adrenal hyperplasia (SW‐CAH) most commonly carry an A‐G transition at nucleotide 656 (nt 656 A→G), causing abnormal splicing of ex‐ons 2 and 3 in CYP21, the gene encoding active steroid 21‐hydroxylase. Affected infants are severely deficient in cortisol and aldo‐sterone, and usually come to medical attention during the neonatal period. We report on 2 affected boys, homozygous for the nt 656 mutation, who thrived in early infancy, but suffered salt‐wasting crises unusually late in infancy, at 3.5 and 5.5 months, respectively. Laboratory studies at presentation showed hyponatremia, hyperkalemia, dehydration, and acidosis; serum aldo‐sterone was low in spite of markedly elevated plasma renin activity. Basal 17‐hydroxyprogesterone levels were only moderately elevated, yet the stimulated levels were more typical of severe, classic CAH due to 21‐hydroxylase deficiency. Genomic DNA from the patients was analyzed. Southern blot showed no major deletions or rearrangements. CYP21 ‐specific amplification by polymerase chain reaction, coupled with allele‐specific hybridization using wild‐type and mutant probes at each of 9 sites for recognized disease‐causing mutations, revealed a single, homozygous mutation in each patient: nt 656 A→G. These results were confirmed by sequence analysis. We conclude that the common nt 656 A→G mutation is sometimes associated with delayed phenotypic expression of SW‐CAH. We speculate that variable splicing of the mutant CYP21 may modify the clinical manifestations of this disease. © 1995 Wiley‐Liss, Inc.
Oculodentodigital dysplasia with cerebral white matter abnormalities in a two‐generation family
Authors: Norton Karen K. , Carey John C. , Gutmann David H.
Published: June 2005

Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder involving eye and face abnormalities, syndactyly, and enamel hypoplasia. Some individuals with ODDD also have spastic paraparesis. Previously, we reported on a woman with sporadic ODDD and progressive neurologic dysfunction who had cerebral white matter abnormalities demonstrated by magnetic resonance imaging (MRI). We now describe a 2‐generation family with ODDD and progressive paraparesis associated with leuko‐dystrophic changes documented by MRI. This family represents one of the largest pedigrees with ODDD described so far. The presence of abnormal white matter changes in both sporadic and inherited forms of ODDD suggests that the phenotype of ODDD should be expanded to include spastic paraparesis. © 1995 Wiley‐Liss, Inc.
Analysis of variability of clinical manifestations in Waardenburg syndrome
Authors: Reynolds Jennifer E. , Meyer Joanne M. , Landa Barbara , Stevens Cathy A. , Arnos Kathleen S. , Israel Jamie , Marazita Mary L. , Bodurtha Joann , Nance Walter E. , Diehl Scott R.
Published: June 2005

Expression of clinical findings of Waardenburg syndrome type 1 (WS1) and type 2 (WS2) is extremely variable. Using our collection of 26 WS1 and 8 WS2 families, we analyzed the occurrence, severity, and symmetry of clinical manifestations associated with WS. We found significant differences between WS1 and WS2 in deafness, and in pigmentary and craniofacial anomalies. Factor analysis was used to identify manifestations which covaried, resulting in 2 orthogonal factors. Since mean factor scores were found to differ when compared between WS1 and WS2, we suggest that these factors could be useful in distinguishing WS types. We found that the WS gene was transmitted from mothers more often than from fathers. We also extensively examined the W‐Index, a continuous measure of dystopia canthorum. Our data suggest that use of the W‐Index to discriminate between affected WS1 and WS2 individuals may be problematic since 1) ranges of W‐Index scores of affected and unaffected individuals over‐lapped considerably within both WS1 and WS2, and 2) a considerable number of both affected and unaffected WS2 individuals exhibited W‐index scores consistent with dystopia canthorum. Misclassification of families may have implications for risk assessment of deafness, since WS2 families have been reported to have greater incidence of deafness, as confirmed in our study. © 1995 Wiley‐Liss, Inc.
Preliminary phenotypic map of chromosome 4p16 based on 4p deletions
Authors: Estabrooks Laurel L. , Rao Kathleen W. , Driscoll Deborah A. , Crandall Barbara F. , Dean John C. S. , Ikonen Elina , Korf Bruce , Aylsworth Arthur S.
Published: June 2005

We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf‐Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies. © 1995 Wiley‐Liss, Inc.
Gonadal dysgenesis in del(18p) syndrome
Authors: Telvi Louise , Bernheim Alain , Ion Alexandra , Fouquet Françoise , Bouc Yves Le , Chaussain Jean‐Louis
Published: June 2005

We report on a girl with syndromal gonadal dysgenesis and a de novo del(18p). Genetic factors controlling gonadal development are located not only on the X chromosome, but also on autosomes. The present case suggests that one of these genes is situated on 18p. We conclude that patients with del(18p) syndrome should be evaluated for gonadal dysgenesis. © 1995 Wiley‐Liss, Inc.
Balanced reciprocal translocation mosaicism: How frequent?
Authors: Opheim Kent E. , Brittingham Allen , Chapman Douglas , Norwood Thomas H.
Published: June 2005

We describe 2 cases of balanced reciprocal translocation (BRT) mosaicism. The frequency of this aberration in the population referred to our laboratory was determined and compared to those frequencies reported in the literature by other clinical cytogenetics laboratories. The extent of BRT mosaicism was also examined in surveys of prenatal populations, which are less likely to have a bias due to ascertainment on the basis of abnormal phenotype. The frequencies in the postnatal and prenatal populations examined in this study were calculated to be 5.7 × 10−5 (95% confidence interval is 3.2–8.2 × 10−5) and 4.1 × 10−5 (95% confidence interval is 2.0–6.2 × 10−5). However, in view of the extent of variation reported in the various studies, these estimates should be considered first approximations of the true frequency. © 1995 Wiley‐Liss, Inc.
Albright hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals
Authors: Phelan Mary C. , Rogers R. Curtis , Clarkson Kate B. , Bowyer Frank P. , Levine Michael A. , Estabrooks Laurel L. , Severson Michael C. , Dobyns William B.
Published: June 2005

Albright hereditary osteodystrophy (AHO) is a condition with characteristic physical findings (short stature, obesity, round face, brachydactyly) but variable biochemical changes (pseudohypoparathyroidism, pseudopseudohypoparathyroidism). Most patients with AHO have decreased activity of the guanine nucleotide‐binding protein (Gs protein) that stimulates adenylyl cyclase. The gene encoding the α subunit of the Gs protein (GNAS1) has been mapped to the long arm of chromosome 20. We describe 4 unrelated individuals with apparent AHO, associated with small terminal deletions of chromosome 2. All 4 patients had normal serum calcium levels consistent with pseudopseudohypoparathyroidism.

Del(2)(q37) is the first consistent karyotypic abnormality that has been documented in AHO [Phelan et al., 1993: Am J Hum Genet 53:484]. The finding of the same small terminal deletion in 4 unrelated individuals with a similar phenotype suggests that a gene locus in the 2q37 region is important in the pathogenesis of Albright syndrome. The association of Albright syndrome and the GNAS1 locus on chromosome 20 is well documented. The observation of a second potential disease locus on chromosome 2 may help explain the heterogeneity observed in this disorder. © 1995 Wiley‐Liss, Inc.
Anophthalmos‐syndactyly (Waardenburg) syndrome without oligodactyly of toes
Authors: Şayli Bekir Sitki , Akarsu A. Nurten , Altan Simay
Published: June 2005

We report on 2 brothers from a consanguineous family from a small city of southeast Turkey. Both have bilateral anophthalmia, soft tissue syndactyly of the feet, bilateral partial synostosis of metatarsals IV and V, and basal synostosis of the fourth and fifth toes on the right in the older sib only, thus differing from all previously reported cases of anophthalmos‐syndactyly syndrome. © 1995 Wiley‐Liss, Inc.
Infantile sialic acid storage disease: Biochemical studies
Authors: Berra B. , Gornati R. , Rapelli S. , Gatti R. , Mancini G. M. S. , Ciana G. , Bembi B.
Published: June 2005

Infantile free sialic acid storage disease (ISSD), is an inherited metabolic disorder characterized by hyperexcretion of free sialic acid in the urine and by its storage in the lysosomes of different tissues. In order to obtain more reliable data on the amount of total and free sialic acid, we analyzed the urine, brain, cerebellum, liver, spleen, and kidneys from a 3‐month‐old baby who died with a diagnosis of ISSD. The lysosomal nature of the disease was confirmed by an electron microscopic study of cells in culture. No significant abnormalities were found involving cholesterol, total phospholipids, glycolipids, and gangliosides in the tissues examined. However, differences in the tissue distribution of individual glycolipids and gangliosides were observed. The amount of free and total sialic acid was markedly increased, due to the storage of free sialic acid accompanied by its hyperexcretion in the urine. These results demonstrate and confirm that only acid monosaccharide transport from the lysosome compartment is involved in the pathogenesis of ISSD. © 1995 Wiley‐Liss, Inc.
Ullrich‐Turner syndrome: Neurodevelopmental changes from childhood through adolescence
Authors: Ross Judith L. , Stefanatos Gerry , Roeltgen David , Kushner Harvey , Cutler Gordon B.
Published: June 2005

Our objective was to investigate whether the previously‐described neurocognitive pattern in girls with Ullirich‐Turner syndrome is found in childhood and adolescence; we used a prospective, controlled study of neurocognitive development in girls with Ullrich‐Turner syndrome. The patients included 56 girls with Ullrich‐Turner syndrome, and 100 normal age‐ and verbal IQ‐matched female control subjects, whose ages ranged from 6–14 years. All girls with Ullrich‐Turner syndrome and the normal control girls received a battery of neurocognitive tests designed to evaluate the following domains: general cognition, memory, academic achievement, language, visualspatial/perceptual skills, visual‐motor skills, attention, and affect recognition. Our results demonstrated consistent findings in Ullrich‐Turner syndrome girls across the age range studied. In general, the Ullrich‐Turner girls resembled control subjects in terms of verbal and language abilities. We found relatively depressed performance IQ and a significant verbal IQ‐performance IQ difference. Significant differences were observed on examination of nonverbal abilities. The Ullrich‐Turner girls performed more poorly than control girls on 1) tests of visual‐motor skills including the Beery Test of Visual‐Motor Integration, the Perceptual Organization Factor, and the Rey‐Osterrieth Figures; 2) tests of visual‐spatial skills, including the Motor‐Free Visual Perception Test; 3) tests of attention, including the Freedom From Distractibility Factor; and 4) the Affective Prosody Affect Recognition Test. Ullrich‐Turner subjects showed evidence of multifocal or diffuse right cerebral dysfunction and deficits generally involving nonverbal skills that may be due to X chromosome monosomy, gonadal dysgenesis, or both. Future studies will examine the role of estrogen replacement on cognitive function in Ullrich‐Turner syndrome individuals. © 1995 Wiley‐Liss, Inc.
GAPO syndrome: A new case
Authors: Sandgren Gerd
Published: June 2005

The fifteenth known case of GAPO syndrome is presented: a probable autosomalrecessive condition of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and optic atrophy. This article contains the clinical report of a 9‐year‐old girl and a short review of the hitherto‐known cases. The syndrome could be attributed to either ectodermal dysplasia or perhaps an accumulation of extracellular connective tissue matrix. © 1995 Wiley‐Liss, Inc.
Maternal uniparental disomy of chromosome 2 in a baby with trisomy 2 mosaicism in amniotic fluid culture
Authors: Harrison Kathleen , Eisenger Katerina , Anyane‐Yeboa Kwame , Brown Stephen
Published: June 2005

We describe the first case of a baby with maternal uniparental disomy of chromosome 2. Growth failure, hypothyroidism, and hyaline membrane disease were present at birth, and the first year of life was complicated by bronchopulmonary dysplasia. At age 14 months, motor and intellectual development were normal, but growth remained below the 10th centile. The baby was investigated for uniparental disomy because trisomy 2 mosaicism had been detected in a second trimester amniocentesis. This is the first reported case in which amniotic fluid chromosome mosaicism has been associated with uniparental disomy. Implications for prenatal diagnosis are considered. © 1995 Wiley‐Liss, Inc.
Incidence and mortality rates of cystic fibrosis in Japan, 1969–1992
Authors: Imaizumi Yoko
Published: June 2005

The incidence rate and the death rate of cystic fibrosis (CF) in Japan were analyzed using Japanese Vital Statistics data for the period 1969–1992. The incidence rate was 3.1 per million live births during the period 1969–1980, where the rate was 1.5 times higher in rural than urban areas. The proportion of deaths from CF under 5 years old was 82% and under 20 years old was 94%. Overall death rates of CF per million population under 20 years of age were 0.15 for males and 0.10 for females, the difference being significant; the death rate was also significantly higher in males (2.2 per million) than females (1.3) in the first year of life. The death rate decreased from the period 1969–1973 to the period 1989–1992 for males. There were geographical variations in the incidence and the death rates among nine districts. These rates of CF were observed with the highest being in Hokkaido and the lowest in Okinawa. The death rate from CF was negatively correlated with the average temperature. The death rate was higher in rural than in urban areas during the period 1969–1985. The mean age at death from CF was 3 years for both sexes during the period 1969–1985, the value has been increased since 1979. © 1995 Wiley‐Liss, Inc.
Clinical and cytogenetic findings in seven cases of inverted duplication of 8p with evidence of a telomeric deletion using fluorescence in situ hybridization
Authors: Guo Wen‐Jun , Callif‐Daley Faith , Zapata Maria Carmen , Miller Marvin E.
Published: June 2005

We report on the clinical and cytogenetic findings in 7 cases of inverted duplication of region 8p11.2‐p23. The phenotype of inv dup (8p) compiled from this series and the literature (N = 29) consists of severe mental retardation (100%), minor facial alterations (97%), agenesis of the corpus callosum (80%), hypotonia (66%), orthopedic abnormalities (58%), scoliosis/kyphosis (40%), and congenital heart defect (26%). A telomeric deletion of region 8p23.3‐pter was confirmed in 3 of our cases studied using fluorescent in situ hybridization with a telomeric probe for 8p. Thus, these karyotypes are inv dup del(8) (qter→p23.1::p23.1→p11.2:). Our findings sugest that most cases of inv dup(8p) probably have a telomeric deletion. © 1995 Wiley‐Liss, Inc.
Growth in stature in fragile X families: A mixed longitudinal study
Authors: Loesch Danuta Z. , Huggins Richard M. , Hoang Ngoc H.
Published: June 2005

The effect of fragile X on growth in stature was estimated in individuals aged 5–20 years from 50 fragile X families. The multivariate normal model for pedigree analysis was applied to the mixed longitudinal data, which varied with regard to intervals between the measurements and their number in individual subjects, totalling 349 measurement data points from fragile X families, and 292 data points from unrelated normal subjects. The results of genetic and regression analysis showed that, in fragile X boys and girls, total pubertal height gain is impaired, whereas the rate of growth during the preadolescent period is increased, compared with the growth rate of nonfragile X subjects. Moreover, the growth parameters in fragile X males were found to be correlated with the size of CGG trinucleotide expansion. The hypothesis of premature activation of the hypothalamo‐pituitary gonadal axis is postulated as the cause of growth impairment in fragile X boys and girls, which should be verified by data on the timing of pubertal stages, hormone levels, and bone maturation. © 1995 Wiley‐Liss, Inc.
GAPO syndrome: Report on the first case in Japan
Authors: Moriya Naoki , Mitsui Tetsuo , Shibata Takanori , Yamaguchi Katsuhiro , Kanazawa Chikako , Matsunaga Akira , Hayasaka Kiyoshi
Published: June 2005

We studied a 3.5‐year‐old Japanese boy with growth retardation, alopecia, pseudoanodontia, and bilateral papilledema. He was born of nonconsanguineous parents, but his paternal grandparents were related. From his characteristic physical manifestations, we diagnosed him as the first known case of GAPO syndrome in Japan and perhaps in the Mongoloid race. Our case had prominent dilatation of scalp veins and an audible intracranial bruit. Cranial angiography documented a narrowing of the sigmoid sinuses, with no flow to either jugular vein. We discuss here the relationships between optic atrophy and intracranial vascular changes in this syndrome. © 1995 Wiley‐Liss, Inc.
Missense mutation of the β‐cardiac myosin heavy‐chain gene in hypertrophic cardiomyopathy
Authors: Arai Shoichi , Matsuoka Rumiko , Hirayama Kenji , Sakurai Hisanao , Tamura Masaharu , Ozawa Tenkou , Kimura Misa , Imamura Shin‐Ichiro , Furutani Yoshiyuki , Joh‐o Kunitaka , Kawana Masatoshi , Takao Atsuyoshi , Hosoda Saichi , Momma Kazuo
Published: June 2005

Hypertrophic cardiomyopathy occurs as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. We describe a missense mutation of the β‐cardiac myosin heavy chain (MHC) gene, a G to T transversion (741 Gly→Trp) identified by direct sequencing of exon 20 in four individuals affected with familial hypertrophic cardiomyopathy. Three individuals with sporadic hypertrophic cardiomyopathy, whose parents are clinically and genetically unaffected, had sequence variations of exon 34 of the α‐cardiac MHC gene (a C to T transversion, 1658 Asp→Asp, resulting in FokI site polymorphism), of intron 33 of the α‐cardiac MHC gene (a G to A and an A to T transversion), and also of intron 14 of the β‐cardiac MHC gene (a C to T transversion in a patient with Noonan syndrome). Including our case, 30 missense mutations of the β‐cardiac MHC gene in 49 families have been reported thus far worldwide. Almost all are located in the region of the gene coding for the globular head of the molecule, and only one mutation was found in both Caucasian and Japanese families. Missense mutations of the β‐cardiac MHC gene in hypertrophic cardiomyopathy may therefore differ according to race. © 1995 Wiley‐Liss, Inc.
Skeletal abnormalities in Rett syndrome: Increasing evidence for dysmorphogenetic defects
Authors: Leonard H. , Thomson M. , Bower C. , Fyfe S. , Constantinou J.
Published: June 2005

The presence of metatarsal and metacarpal abnormalities in some individuals has raised the possibility that Rett syndrome is, in fact, a multiple congenital abnormalities/mental retardation (MCA/MR) syndrome. We have conducted radiological examination of 17 cases of Rett syndrome in Western Australia. Short fourth and/or fifth metatarsals were identified in 65% of cases and short fourth and/or fifth metacarpals in 57%. Metatarsal (P = 0.045) and metacarpal (P = 0.006) shortness were significantly more common in girls 14 years or older. Negative ulnar variance (found in 79% of cases) appeared to be independent of age. Reduced bone density in the hands was found in 86% of cases. A nationwide study using the Australian Rett Syndrome Database is planned to follow up these findings and compare them with findings from a control group. The confirmation of these abnormalities in a high proportion of cases may provide morphologic markers to assist in the diagnosis of Rett syndrome and perhaps provide a further avenue of research into the pathogenesis of this disorder. © 1995 Wiley‐Liss, Inc.
Smith‐Magenis syndrome deletion: A case with equivocal cytogenetic findings resolved by fluorescence in situ hybridization
Authors: Juyal Ramesh C. , Greenberg Frank , Mengden Gregory A. , Lupski James R. , Trask Barbara J. , van den Engh Ger , Lindsay Elizabeth A. , Christy Heather , Chen Ken‐Shiung , Baldini Antonio , Shaffer Lisa G. , Patel Pragna I.
Published: June 2005

The availability of markers for the 17p11.2 region has enabled the diagnosis of Smith‐Magenis syndrome (SMS) by fluorescence in situ hybridization (FISH). SMS is typically associated with a discernible deletion of band 17p11.2 upon cytogenetic analysis at a resolution of 400–550 bands. We present a case that illustrates the importance of using FISH to confirm a cytogenetic diagnosis of del(17)(p11.2). Four independent cytogenetic analyses were performed with different conclusions. Results of low resolution analyses of amniocytes and peripheral blood lymphocytes were apparently normal, while high resolution analyses of peripheral blood samples in two laboratories indicated mosaicism for del(17)(p11.2). FISH clearly demonstrated a 17p deletion on one chromosome of all peripheral blood cells analyzed and ruled out mosaicism unambiguously. The deletion was undetectable by flow cytometric quantitation of chromosomal DNA content, suggesting that it is less than 2 Mb. We conclude that FISH should be used to detect the SMS deletion when routine chromosome analysis fails to detect it and to verify mosaicism. © 1995 Wiley‐Liss, Inc.
Impact of apolipoprotein E genotype variation on means, variances, and correlations of plasma lipid, lipoprotein, and apolipoprotein traits in octogenarians
Authors: Haviland Martha B. , Lussier‐Cacan Suzanne , Davignon Jean , Sing Charles F.
Published: June 2005

The impact of apoliporotein (apo) E genotype variation on means, variances and correlations between plasma lipid traits was studied in male and female octogenarians. Females had significantly higher mean levels of all 10 of the measured plasma lipid traits than males. The subset of concomitants (i.e., age, height, weight, body mass index, glucose and uric acid) that made a statistically significant contribution to interindividual variability was different in males and females for every trait considered. Gender‐specific associations between variation in apo E genotype and variation in pariticular measures of lipid metabolism, adjusted for concomitant variation, were observed: in females there were no statistically significant associations while in males the means of the three common apo E genotypes were significantly different for adjusted measures of total cholesterol, low density lipoprotein cholesterol and low density lipoprotin‐apo B. The common apo E genotypes were heterogeneous with respect to intragenotypic variance for adjusted logtransformed triglyceride levels in females only. Finally, the three common apo E genotypes were heterogeneous with respect to the correlation between traits, adjusted for concomitant variation, and gender influenced the manner in which the genotypes differed for specific correlations. This study documents that variation in the apo E gene has a significant impact on means, variances and correlations of plasma lipid traits in octogenarians, but the effects are context‐, that is, gender‐ and age‐, dependent. © 1995 Wiley‐Liss, Inc.
Juberg‐Marsidi syndrome: Report of an additional case
Authors: Tsukahara Masato , Nasu Takahito , Takihara Hiroshi , Hattori Yukio , Nakane Hiroshi , Kamata Kiyoharu , Mitsui Hiroshi , Hayashida Shigeaki
Published: June 2005

We report on a 2‐year‐old boy with Juberg‐Marsidi syndrome. He has mental retardation, short stature, micropenis, cryptorchidism, and minor facial abnormalities. His Leidig cells responded to the administration of human chorionic gonadotropin and there were positive responses of LH and FSH to the administration of LH‐RH. He showed normal weight gain and head circumference which have not been described previously. The association of Juberg‐Marsidi syndrome with HbH disease was ruled out in the propositus. © 1995 Wiley‐Liss, Inc.
Enamel hypoplasia, bilateral cataracts, and aqueductal stenosis: A new syndrome?
Authors: Seow W. Kim , Needleman H. L. , Smith Lois E. H. , Holtzman D. , Najjar S.
Published: June 2005

We report on a 12‐year‐old girl who presented with generalized enamel hypoplasia, cataracts, and enlargement of the cerebral ventricles secondary to aqueductal stenosis. Previously described syndromes of enamel defects with or without cataracts were excluded on the basis of clinical criteria and appearance of the dentition. Metabolic conditions which could have caused cataracts were excluded clinically and by biochemical tests. The combination of signs in this patient may represent a new syndrome. © 1995 Wiley‐Liss, Inc.
Risk prediction with linked markers: Pedigree analysis
Authors: Rogatko André , Rebbeck Timothy , Zacks Shelemyahu
Published: June 2005

Rogatko [1995: Am J Med Genet 59:14–23] has proposed a method for risk prediction with linked markers. The actual implementation of this method requires that the analytical forms of likelihood and risk functions be specified. It is impractical to obtain the explicit analytical form of these functions in large phase unknown pedigrees. When large phase unknown pedigrees are encountered, the compound risk can be approximated by a transformation of the discrete distribution obtained by computing the likelihood and risk functions over a grid of points. We propose a method to compute genetic risks when the functional form of the pedigree likelihood is unknown. The method was evaluated using a simple pedigree by comparing the results when functional forms were and were not known. This method was also applied to estimate genetic risks for a single pedigree with nonsyndromal X‐linked mental retardation using 3 genetic markers linked to the putative disease gene. Linkage data from an extended pedigree were combined with genome mapping data, and recurrence risk distributions were calculated for members of the pedigree. The results suggest that the proposed method provides accurate risk estimate for genetic diseases. Computer programs are available to apply this method whenever genetic markers are suspected of being linked to a disease gene. © 1995 Wiley‐Liss, Inc.
Identification of a supernumerary marker derived from chromosome 17 using FISH
Authors: Rosenberg Carla , Borovik Cleide L. , Canonaco Rosane S. , Sichero Laura C. , Queiroz Ana Paula S. , Vianna‐Morgante Angela M.
Published: June 2005

We report on a 15‐year‐old girl with mental retardation, obesity, short stature and minor anomalies. She had 47 chromosomes with a minute extra ring which was identified by FISH to be derived from chromosome 17. © 1995 Wiley‐Liss, Inc.
Prenatal diagnosis of a stable de novo centric fission: A case report
Authors: Bogart Mark H. , Fujita Nathan , Serles Lori , Hsia Y. E.
Published: June 2005

We report on the prenatal diagnosis of a baby with a de novo centromeric fission of chromosome 21. Both fission products were mitotically stable. Follow‐up chromosome analysis after birth confirmed the centromere fission. This chromosome fission appears to be without clinical significance for this patient. © 1995 Wiley‐Liss, Inc.
Interstitial deletion of the long arm of chromosome 6 associated with unusual limb anomalies: Report of two new patients and review of the literature
Authors: Pandya Arti , Braverman Nancy , Pyeritz Reed E. , Ying Kuang‐Lin , Kline A. D. , Falk Rena E.
Published: June 2005

We report on unusual manifestations in 2 unrelated children with interstitial deletion of 6q, with nearly identical breakpoints of 6q16.2q23.1 and 6q16.3q22.3. Major findings include growth retardation, profound developmental delay, microcephaly, facial anomalies, sparse hair, congenital heart defects, and striking hand malformations. Discordant anomalies were duodenal atresia and hypoplastic genitalia in 1 child. Split‐hand defect, polydactyly, gastrointestinal anomalies, and ectodermal dysplasia have not been described previously in children with 6q deletion. The presence of hand malformations in 2 children with similar deletion breakpoints strongly suggests that this is a candidate region for one or more genes involved in limb development. Comparison of the clinical findings of other patients with 6q2 deletion suggests a recognizable phenotype. © 1995 Wiley‐Liss, Inc.
Perinatal death in two sibs with infantile cortical hyperostosis (Caffey disease)
Authors: de Jong Greetje , Muller Linnie M. M.
Published: June 2005

We describe 2 sibs with lethal, prenatal‐onset cortical hyperostosis. Antenatal sonographic diagnosis of the first sib was that of short limb dwarfism and thoracic dysplasia (nonspecific), possibly osteogenesis imperfecta. The second sib had a similar appearance on ultrasonography. The thickened, irregularly echodense diaphyses were an aid to diagnosis. Although sporadic cases and autosomal dominant inheritance have been described, an autosomal recessive cause for the lethal prenatal onset cases cannot be excluded. © 1995 Wiley‐Liss, Inc.
Sternal cleft: Case report and review of a series of nine patients
Authors: Héron Delphine , Lyonnet Stanislas , Iserin Laurence , Munnich Arnold , Padovani Jean‐Paul
Published: June 2005

Cleft sternum is a rare malformation due to partial or total failure of sternal fusion at an early stage of embryonic development. Sternal clefts can be classified as superior, inferior, or complete. Here we report on a 2‐year‐old boy with inferior sternal cleft and complex cardiac malformation. We review a series of 9 children with sternal clefts, referred to us over a 10‐year period. Hypothetical mechanisms for this developmental anomaly are discussed. © 1995 Wiley‐Liss, Inc.
Physical findings in 21q22 deletion suggest critical region for 21q— phenotype in q22
Authors: Theodoropoulos Demetrios S. , Cowan Janet M. , Elias Ellen R. , Cole Cynthia
Published: June 2005

Multiple abnormalities were observed in a newborn infant with a deletion in the long arm of chromosome 21, from band 22q22.1→qter. The phenotype of this infant was similar to that previously described in infants with deletions spanning the long arm of chromosome 21, from the centromere to 21q22 [Rethoré et al., 1972, Exp Cell Res 70:455–456, 1973, Ann Genet (Paris) 16:271–275]. However, as a phenotypically normal child with normal intelligence and with deletion of 21q11.1–21q21.3 has also been identified [Korenberg et al., 1991, Hum Genet 87:112–118], this case suggests that the critical region of deletion for the 21q− phenotype lies distal to 21q21, within 21q22.1–22.2. © 1995 Wiley‐Liss, Inc.
X‐linked myotubular myopathy: Clinical observations in ten additional cases
Authors: Joseph Maries , Pai G. Shashidhar , Holden Kenton R. , Herman Gail
Published: June 2005

X‐linked myotubular myopathy (XLMTM) is a recessively inherited disorder, lethal to males in the first months of life. Since the first report in 1969, at least 90 cases have been described in the literature. Diagnosis is confirmed by muscle biopsy. Linkage studies have localized the disorder to the Xq28 region, close to the loci for X‐linked hydrocephalus and MASA syndrome. We report on 10 additional cases of XLMTM from six different families. In addition to classic clinical features of XLMTM, our patients showed interesting associated findings which included birth length >90th centile and large head circumference with or without hydrocephalus in 70%, narrow, elongated face in 80%, and slender, long digits in 60% of cases. There was concordance in the occurrence and severity of hydrocephalus in most sib pairs. These features in a “floppy” male infant serve as clues for early clinical diagnosis of XLMTM, which can then be confirmed by muscle biopsy. Development of polyhydramnios was observed in the third trimester of an at‐risk dizygotic twin gestation monitored by serial sonography with confirmation of XLMTM at birth. © 1995 Wiley‐Liss, Inc.
Duplication and loss of chromosome 21 in two children with Down syndrome and acute leukemia
Authors: Rogan Peter K. , Close Pamelyn , Blouin Jean‐Louis , Seip James R. , Gannutz Lee , Ladda Roger L. , Antonarakis Stylianos E.
Published: June 2005

Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25‐cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual. © 1995 Wiley‐Liss, Inc.
Mutation analysis of the gene encoding Bruton's tyrosine kinase in a family with a sporadic case of X‐linked agammaglobulinemia reveals three female carriers
Authors: Hagemann Tracy L. , Assa'ad Amal H. , Kwan Sau‐Ping
Published: June 2005

Bruton's tyrosine kinase (Btk) has been identified as the protein responsible for the primary immunodeficiency X‐linked agammaglobulinemia (XLA). We and others have cloned the gene for Btk and recently reported the genomic organization. Nineteen exons were positioned within the 37 kb gene. With the sequence data derived from our genomic map, we have designed a PCR based assay to directly identify mutations of the Btk gene in germline DNA of patients with XLA. In this report, the assay was used to analyze a family with a sporadic case of XLA to determine if other female relatives carry the disease. A four base‐pair deletion was found in the DNA of the affected boy and was further traced through three generations. With the direct identification of the mutations responsible for XLA, we can now diagnose conclusively the disease and identify the immunologically normal female carriers. This same technique can easily be applied to prenatal diagnosis in families where the mutation can be identified. © 1995 Wiley‐Liss, Inc.