bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of chromosome aberrations in recurrent abortion: A study of 269 balanced translocations
Authors: Campana Mauro , Serra Angelo , Neri Giovanni , Reynolds James F.
Published: June 2005

We have studied a sample of 5,445 couples in which the woman was ascertained to have had two or more spontaneous abortions: 396 from our Cytogenetics Unit (present series) and 5,049 from the literature (literature series). In approximately 5% of these couples one of the members was a carrier of a balanced translocation, either reciprocal (⅔ of cases) or Robertsonian (⅓). In 1% of the couples there were other chromosome anomalies, mostly gonosomal aneuploidies or mosaicisms. A pericentric inversion of the heterochromatic region of chromosome 9 was present in 3% of the couples of the present series and in 1% of the literature series. The number of female carriers exceeded significantly that of males. The probability for one member of the couple to be a carrier increased with the number of abortions at the time of ascertainment, but it does not seem modified by the concomitant presence of term pregnancies. The analysis of the cytogenetic findings in 80 cases of Robertsonian and 156 cases of reciprocal translocations suggests that some chromosomes are preferentially involved, and that in reciprocal translocations the breakpoints are not distributed at random on the chromosome arms. There is an excess of breakpoints on chromosomes 6, 7, and 22 and a dearth on chromosome 12. This distribution is significantly different from that of a sample of reciprocal translocations ascertained for a malformed child. In both samples the breakpoints seem associated with fragile sites more frequently than expected by chance. An analysis of the potential and effective chromosome imbalance suggests that in subjects with unbalanced chromosomes survival is correlated with a minimum imbalance.
Interstitial deletion of (17)(p11.2p11.2) in nine patients
Authors: Smith Ann C. M. , McGavran Loris , Robinson Jeannie , Waldstein Gail , Macfarlane Jean , Zonona Jon , Reiss Jacob , Lahr Martin , Allen Leland , Magenis Ellen , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a new and distinct syndrome involving an interstitial deletion of the short arm of choromosome 17 in nine unrelated patients (six males; three females) ranging in age from 3 months to 65 years. In eight patients, a deletion of a portion of band 17p11.2 was associated with a striking similar phenotype including brachycephaly, midface hypoplasia, prognathism, hoarse voice, and speech delay with or without hearing loss, psychomotor and growth retardation, and behavior problems. The one patient with a complete deletion of band 17p11.2 was more severely affected with facial malformations, cleft palate, and major anomalies of cardiac, skeletal, and genitourinary systems; the patient died at age 6 months. Careful cytogenetic analysis including high‐resolution techniques will be important for the further identification of patients with this previously unrecognized deletion syndrome.
Follow‐up of infants with amniotic fluid trisomy 20 mosaicism
Authors: Abuelo Dianne N. , Barsel‐Bowers Gail , Zartler Ann S. , Opitz John M. , Reynolds James F.
Published: June 2005

The finding of trisomy 20 mosaicism in amniotic fluid is a cause of considerable anxiety for both physicians and parents. Although the significance of this finding is still not clear, some reassurance can be given to prospective parents, since the outcome has been normal in all reported pregnancies carried to term. Follow‐up information on psychomotor development of these infants is needed in order to provide better genetic counseling to these families. We have followed three infants who have had normal growth and psychomotor development up to approximately 2 years.
The prenatal growth of the human body determined by the measurement of bones and organs by ultrasonography
Authors: Elejalde B. Rafael , De Elejalde Maria Mercedes , Opitz John M. , Reynolds James F. , Hall Judith G.
Published: June 2005

This paper presents the ultrasonographic analysis of the growth of two groups of human fetuses, one longitudinal and the other cross‐sectional. Measurements of all the long bones were taken, as well as measurements of the folowing diameters: Biparietal, occipitofrontal, thoracic and abdominal anterior/posterior and transverse, spinal canal width, arm, forearm, thigh and leg transverse. The bladder and the stomach were also measured. The pregnancies analyzed covered the period between the 8th and 38th week of gestation. Centiles (3rd‐97th) were calculated for each structure and week. All pregnancies known or suspected to be abnormal were removed from the study. The values obtained were tested in 102 pregnancies (test group); the expected values (from the graphs) did not deviate from the values obtained from this group of fetuses, demonstrating the reliability of the values presented in these graphs. All structures measured showed linear growth. There was no significant difference between the longitudinal and cross‐sectional groups.
Spondylocostal/spondylothoracic dysostosis: The clinical basis for prognosticating and genetic counseling
Authors: Aymé Ségolène , Preus Marilyn , Opitz John M. , Reynolds James F.
Published: June 2005

Short trunk dwarfism involving skeletal anomalies of vertebrae and ribs have been reported under various names. Both dominant and recessive and severe and mild conditions are found. We report on a patient without a severe handicap by age 3 years despite severe involvement of the thorax at birth, suggesting that a more complete classification of such anomalies is needed for counseling. We have used an objective method to classify 39 informative patients from the literature, 35 said to have a recessive disease and four a dominant one. Two patients with the costovertebral segmentation defect with mesomelia (COVESDEM) syndrome were added for comparison with our patient. The results of cluster analysis show that there are three phenotypic groups of patients. Cluster 1 contains 19 patients with a severe form of spondylothoracic dysplasia; cluster 2 includes patients with a mild autosomal recessive and a dominant type; cluster 3 groups the two sibs with the COVESDEM syndrome and our patient. One must be cautious in advising families of the prognosis for a child with severe structural chest deformity since it may not be severe from a functional point of view. More data are needed for complete discrimination between the mild autosomal recessive and dominant forms.
Animal model: The mode of inheritance of craniomandibular osteopathy in west highland white terrier dogs
Authors: Padgett George A. , Mostosky Ulreh V. , Prieur David J.
Published: June 2005

Craniomandibular osteopathy is a disease of several breeds of dogs, principally West Highland White and Scottish terriers. It is characterized by a non‐neoplastic proliferation of bone on the ramus of the mandible and/or the tympanic bulla. The disease in various respects resembles Paget's disease and infantile cortical hyperrostosis of humans. A retrospective pedigree analysis of a kindred of West Highland White terriers was performed to determine if the trait was inherited and to determine mode of inheritance. This study indicated that in West Highland White terriers, the condition is an autosomal recessive trait.
Torts of wrongful birth and wrongful life: A review
Authors: Pelias Mary Z. , Shaw Margery W.
Published: June 2005

During the past half century reproductive and prenatal technologies have become increasingly sophisticated and accessible to the public. As prospective parents have become more knowledgeable about the various reproductive options available, there has evolved a body of jurisprudence that has defined and defended the exclusive right of individuals to make their own decisions about conceiving and bearing children. This right is now protected under the constitutional umbrella of the right to privacy. If this right is violated through the negligence of one or more health care providers, the allegedly injured parents may sue for the wrongful birth of an unplanned or a defective child. Similarly, a defective child may sue for wrongful life. Both plaintiff parents and plaintiff child seek to recover monetary damages as compensation for their alleged injuries. In wrongful birth cases judicial opinions have moved from an earlier “blessings rationale” through a series of “benefits” cases toward more recent “burdens” decisions. In early suits for wrongful life the courts often held that the child had no valid cause of action and could therefore not be heard in court. More recently, however, some courts have recognized the validity of actions for wrongful life and have decided in favor of the defective children. The most recent judicial decisions suggest that courts may be following a trend to decide in favor of plaintiff parents and children at the expense of the defendant health care providers.
Midtrimester sonographic diagnosis of mandibulofacial dysostosis
Authors: Crane James P. , Beaver Heidi A. , Reynolds James F.
Published: June 2005

Two fetuses at risk for mandibulofacial dysostosis (MFD) were monitored sonographically during the midtrimester of pregnancy. Normal facial and auricular structure were identified in one fetus, and a healthy infant was subsequently delivered. Severe microtia and micrognathia were apparent in the second fetus and a diagnosis of MFD was made and confirmed at delivery. These observations indicate that midtrimester sonographic diagnosis of severe MFD is possible.
Robin sequence and oligodactyly in mother and son
Authors: Robinow M. , Johnson G. F. , Apesos J. , Reynolds James F.
Published: June 2005

A combination of the Rabin sequence with pre‐ and postaxial oligodactyly was observed in a mother and her son. This familial association has not been reported before and probably represents a previously unrecognized heritable malformation syndrome.
Molecular detection of carriers of hereditary amyloidosis in a Swedish‐American family
Authors: Wallace Margaret R. , Conneally P. Michael , Long George L. , Benson Merrill D. , Opitz John M. , Reynolds James F.
Published: June 2005

Autosomal dominant amyloidosis, also known as familial amyloidotic polyneuropathy (FAP), is a late‐onset disorder associated with variants of the protein prealbumin. In FAP Type I, the variant contains a single amino acid substitution at position 30 in the subunit. This substitution corresponds to a single base change in the gene, coincidentally creating a new site for the restriction enzyme Nsil. This change is detectable in the DNA of gene carriers with restriction fragment length polymorphism (RFLP) methods. A well‐characterized American family of Swedish origin was studied by this method using a prealbumin cDNA. The RFLP data were found to correlate with previous biochemical characterization of the prealbumin in this family, indicating that this test represents a reliable way to directly detect the DNA mutation responsible for the condition. This test can be used for preclinical diagnosis of gene carriers, including prenatal diagnosis.
Prenatal growth of the median face
Authors: Siebert Joseph R. , Opitz John M. , Reynolds James F.
Published: June 2005

The growth and development of the median facial region remain incompletely understood. Data concerning the prenatal size and growth rates of facial components are especially lacking. A group of fetuses and newborn infants with apparently normal craniofacial development and body size was therefore studied at autopsy. The interorbital distance and dimensions of the external nose, philtrum (upper lip), and mouth were determined; the growth of morphogenetically related structures—the ethmoid bone and tongue—was also studied. The slopes of linear regressions of these variables against body length indicated that growth of the median facial region proceeds slowly in the latter half of gestation. The center of the face seems to grow slower than the sides of the face. A multivariate technique, factor analysis, identified and ordered relationships among the variables. The best statistical summary of size in the median face was given by four transversely oriented variables, nose breadth, outer orbital distance, inner canthal distance, and mouth width. Within the region, a secondary cluster was dominated by sagittally oriented variables. The second best summary of median facial relationships was provided by three variables of lingual size and was followed by a group of variables representing ethmoidal size. This pattern of growth may represent the effects of a developmental hierarchy. Growth seems to be coordinated along the major axes of the body, with transverse growth controlled more rigidly than sagittal growth. The statistical independence of the three regions suggests that the controls of growth are also separate.
The meiotic segregation of human sperm chromosomes in two men with accessory marker chromosomes
Authors: Martin Renee H. , Hildebrand Kathy A. , Yamamoto Judy , Peterson Dianna , Rademaker Alfred W. , Taylor Patrick , Lin C. C. , Opitz John M.
Published: June 2005

Accessory marker chromosomes are occasionally discovered in normal individuals and they are presumed “clinically inert” since they do not appear to have any phenotypic effect. However, they do pose a theoretical risk at meiosis since they could disrupt the normal pairing and disjunction of homologous chromosomes. Sperm chromosome complements have been studied in two normal males, each of whom carry a small bisatellited accessory marker chromosome 47,XY,+mar (psps), to determine if these marker chromosomes are associated with an increased frequency of aneuploid gametes. Pronuclear chromosomes were visualized after in vitro fertilization of golden hamster eggs with human sperm.

The frequency of sperm complements containing a marker chromosome was not significantly different from 50% as theoretically expected, in either male (17/43 and 13/31 with marker chromosomes). One male had 2/43 (4.7%) aneuploid sperm, which is very close to the average frequency of aneuploid sperm seen in control donors (5%). The other male had 6/31 complements with chromosomal abnormalities. One set of sperm chromosomes had structural abnormalities, and five (16.1%) had numerical abnormalities. This frequency of aneuploidy is significantly elevated over the frequency seen in control donors (P = .0002). It is particularly interesting that all the abnormalities involved small chromosomes, as would be expected if the marker chromosome participated in distributive pairing and thereby disrupted normal disjunction of chromosomes of similar size. These preliminary results suggest that accessory marker chromosomes may increase the risk of aneuploid gametes in some individuals.
Familial growth hormone deficiency resulting from a 7.6 kb deletion within the growth hormone gene cluster
Authors: Braga Suzanne , Phillips John A. , Joss Etienne , Schwarz Hanspeter , Zuppinger Klaus , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two sibs with familial isolated growth hormone deficiency (IGHD) resulting from homozygosity for a 7.6 kb deletion within the growth hormone gene cluster. The deletion not only affects the structural gene for growth hormone (GH‐N) but also alters sequences adjacent to the chorionic somatomammotropin‐like (CS‐L) gene. In contrast to previously reported cases with IGHD type IA, our two patients responded well to growth hormone substitution and formation of blocking antibodies did not occur.
Gardner syndrome in a man with an interstitial deletion of 5q
Authors: Herrera L. , Kakati S. , Gibas L. , Pietrzak E. , Sandberg A. A. , Reynolds James F.
Published: June 2005

Chromosome analysis of blood cells from a 42‐year‐old white male with mental retardation, colon carcinoma, horseshoe kidney, absence of left lobe of the liver, agenesis of the gallbladder, and possible Gardner syndrome revealed a constitutional marker chromosome due to del(5)(ql3q15) or del(5)(q15q22). A polymorphic chromosome #22 with enlarged satellites was inherited from the father, who is phenotypically normal, and was probably unrelated to the congenital malformations. This is the first report of a Gardner syndrome patient with an interstitial deletion of 5q.
Detecting abnormal human chromosome constitutions by dual laser flow cytogenetics
Authors: Lebo Roger V. , Golbus Mitchell S. , Cheung Mei‐Chi , Opitz John M. , Reynolds James F.
Published: June 2005

Our custom dual laser chromosome sorter has been used to characterize and isolate metaphase human chromosomes rapidly for gene mapping purposes. Herein, we tested how well this system could detect unknown abnormal human chromosome constitutions. These results were compared to those of conventional cytogenetic analyses by banding and photomicrography. The sorter was used to analyze each cell line stained with two different stain pairs: DIPI‐chromomycin and Hoechst‐chromomycin. In 20 min, two histograms representing 2 × 105 chromosomes each were collected for each stain pair. A blind study of 11 samples by flow analysis demonstrated excellent concordance between the abnormal chromosomes detected and the diagnoses of Giemsa‐banded karyotypes. Aneuploidy was identified by changes in the number of chromosomes in each histogram peak, while rearrangements such as deletions and translocations caused shifts in the histogram peak positions. The direction and distance of histogram peak shifts are directly related to alterations in chromosome size and banding pattern. We conclude that dual‐laser flow analysis may provide a rapid approach to the screening and diagnosis of chromosome abnormalities.
Zimmerman‐Laband syndrome and profound mental retardation
Authors: Chodirker Bernard N. , Chudley Albert E. , Toffler Milada A. , Reed Martin H. , Opitz John M. , Reynolds James F.
Published: June 2005

A young man was diagnosed as having Zimmerman‐Laband syndrome (ZLS) on the basis of gingival fibromatosis and absence of nails on thumbs and halluces in addition to other anomalies. He also had profound mental retardation.
Lethal multiple pterygium syndrome: Report of a new case with hydranencephaly
Authors: Mbakop A. , Cox J. N. , Störmann C. , Delozier‐Blanchet C. D. , Neri Giovanni
Published: June 2005

A 28‐week male fetus with the cardinal signs of the lethal multiple pterygium syndrome (multiple pterygia, congenital joint contractures, lung hypoplasia, facial abnormalities, and hydrops) is reported here. In addition, he had hydranencephaly, an anomaly not yet reported in this group of conditions. This potentially new form of the lethal multiple pterygium was detected prenatally by ultrasound examination. In discussing the case, we consider the probable autosomal recessive inheritance pattern and raise questions about the etiology and heterogeneity of this syndrome.
A molecular approach to genetic counseling in the X‐linked muscular dystrophies
Authors: Harper P. S. , Thomas N. S. T. , Opitz John M. , Reynolds James F.
Published: June 2005

New molecular developments in our understanding of Duchenne and Becker muscular dystrophies are affecting the practical approach to genetic counseling, carrier detection, and prenatal prediction for these disorders. A plan of an investigation combining DNA and conventional techniques is outlined that is suitable for centers not actively engaged in molecular genetics research, based on the detection of molecular deletions, the most efficient use of multiple DNA polymorphisms, and the integration of this data with creatine kinase and pedigree information. Such an approach now allows accurate carrier detection for most women at risk as well as an acceptable degree of accuracy in prenatal detection for a proportion of carrier women.
Sudden death in childhood in a case of the G syndrome
Authors: Einfeld Stewart L. , Fairley Michael J. , Green Betty F. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on the unexpected death at almost 8 years of a boy with the G syndrome who had successfully survived many prior life‐threatening complications of the condition. The patient had a characteristic facial appearance, hypertelorism, second‐degree hypospadias, stridor and cough on feeding with aspiration of barium, and uncoordi‐nated esophageal swallowing mechanism, but no obvious laryngotracheobranchial defect on endoscopy (or coroner's autopsy). He had had a prior cardiac arrest and had outgrown need for a tracheostomy. Aspiration is presumed to be the cause of death.
Diagnosing human malformation patterns with a microcomputer: Evaluation of two different algorithms
Authors: Schorderet Daniel F. , Opitz John M. , Reynolds James F.
Published: June 2005

SYNDROC, a microcomputer‐aided differential diagnostic approach to human malformation patterns, is based on a pseudo‐Bayesian algorithm. This means that, for each sign, the frequency of this sign in the general population, its frequency in a particular syndrome, and the frequency of that particular syndrome have to be determined. These parameters are easy to find in common syndromes but tend to be difficult for rare or isolated cases. Thus, we implemented a new algorithm called the “descriptive algorithm,” which defines a diagnosis by a set of anomalies all having the same weight. To test this algorithm, we analyzed 100 cases representing 100 different syndromes out of the register of the Division of Medical Genetics, Children's Hospital and Medical Center, University of Washington. The descriptive algorithm was allowed to give 3 sets of diagnoses. In 91% of the cases, this algorithm proposed the correct diagnosis (54% in the first window, 28% in the second window, and 9% in the third window). The number of diagnoses proposed was 18.78 ± 16.57. The same cases were analyzed with the pseudo‐Bayesian algorithm. The concordant diagnosis was proposed in 92% of the cases (55% at the top place, 11% at the second place, and 26% at the third place or beyond). The number of diagnoses submitted was 13.5 ± 11.04. The combined algorithm gave the correct diagnosis in 96% of the cases. This study shows that the descriptive algorithm is as accurate as the pseudo‐Bayesian algorithm in diagnosing malformation patterns, but this level is accompanied by an increased number of proposed diagnoses.
Familial occurrence of esophageal atresia with and without tracheoesophagel fistula:Report of two unusual kindreds
Authors: Pletcher Beth A. , Friedes Jonathan S. , Breg W. Roy , Touloukian Robert J.
Published: June 2005

We describe 2 unique kindreds with familial occurrence of esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) and reviewed the literature on familial EA+/‐TEF. EA+/‐TEF appears to be causally heterogeneous with evidence pointing to the existence of non‐genetic developmental and multifactorial forms. The literature suggests that the parents of a single affected child should be given an empiric recurrent risk between ½ and 2%, rising to 20% if more than one sib is affected. The empiric risk of an affected child born to an affected parent is 3–4%.

Empiric risk figures are useful in counseling families at the present time; however, the 2 kindreds presented here raise the possibility of autosomal dominant transmission in certain families. A third generation of affected offspring, or additional family reports should help to clarify this issue in the future.
Phenotypic and phoniatric findings in mosaic cri du chat syndrome
Authors: Romano Corrado , Ragusa Rosa Maria , Scillato Franco , Greco Donatella , Amato Giuseppe , Barletta Cosimo
Published: June 2005

We report on mosaic 46, XY/46, XY, del(5)(p15) cri du chat syndrome. The clinical findings are compared with those compiled from a literature survey. A phoniatric evaluation was performed and compared with that of a cri du chat patient without mosaicism previously observed by the authors.
PI polymorphism in Israel: Report on six Jewish population groups
Authors: Nevo S. , Cleve H.
Published: June 2005

A total of 1148 Israeli Jews was typed for PI and divided by areas of origin in to six groups:Eastern Europe (n = 236), Central Europe (n = 156), Rumania (n = 158), Bulgaria (n = 215), North Africa (n = 229), and Middle East (n = 154). Frequencies of PI*M1 (0.74–0.77) in Jews of European countries were higher than 0.68 in Jews of N. Africa and 0.62 in Jews of the Middle East. PI*M2 frequencies were correspondingly lower in European Jews:0.11–0.14 vs 0.19 and 0.20 in non‐European Jews. PI*M3 frequency range was 0.07–0.11 in European Jews and was highest in Middle Eastern Jews (0.17). PI*Z was found in one MZ individual. PI*S was low (<0.01) except in Sephardi Jews of Bulgaria and N. Africa (0.016 and 0.015). A rare variant, PI* Elemberg, was observed in five individuals from different countries of origin. The present results are in accord with those of a previous study on some Israeli Jewish groups and on some other Middle Eastern groups.
Prenatal sonographic diagnosis of severe nonimmune hydrops in a Down syndrome fetus at 16 weeks of gestation
Authors: Sherer David M. , Miller Karen S. , Woods James R.
Published: June 2005

We have studied a fetus with the prenatal sonographic diagnosis of severe nonimmune hydrops fetalis at 16 weeks of gestration, who was later shown by amniocentesis to have Down syndrome.
Sex identification by polymerase chain reaction using X‐Y homologous primer
Authors: Nakahori Yutaka , Hamano Koichi , Iwaya Makoto , Nakagome Yasuo
Published: June 2005

A method of sex identification using the polymerase chain reaction technique is described. Using a pair of nucleotide primers from an X‐Y homologous region, both the X and the Y sequences can be amplified simultaneously, and more importantly, they result in fragments of different lengths. The success of the procedure is therefore monitored by the presence of a X‐specific band while sex is identified by the presence or absence of a Y‐specific band.
Angular homeostasis VII: Non‐monotonic correction systems
Authors: Murphy Edmond A. , Berger Kenneth R.
Published: June 2005

We extend our model of angular homeostasis to correction functions that have a single maximum at a discrepant angle less than π radians. We find that there are stable, and asymptotically stable, solutions that in general consist of self‐intersecting curves. We investigate conditions for these curves to be periodic, and describe their symmetries. One typical pattern of such a closed curve involves a finite number of loops, each having a reflection axis of symmetry, with the complete curve having a cyclic rotation group. These bear a close resemblance to patterns found in lobulated biological structures (such as the petals of a flower or the primitive fetal hand). We further discuss implications for morphogenesis.
Galactose metabolism and reproductive history in women with type 1 neurofibromatosis
Authors: Cramer Daniel W. , Korf Bruce R. , Fortier Leslie J.
Published: June 2005

To explore a possible relationship between neurofibromatosis and abnormalities of galactose metabolism, we examined the activity and characteristics of red cell galactokinase and galactose‐1‐phosphate uridyl transferase in 14 white women with type 1 neurofibromatosis and in 28 control women. Women with NF1 had a significantly lower activity of galactokinase and were more likely to have the 3‐band pattern on electrophoresis of their transferase enzyme known as the Duarte variant. In addition, we found that women with NF1 were more likely to have reproductive histories suggestive of hypogonadism, including irregular menses, infertility, ovarian cysts, and early menopause. We conclude that abnormalities of galactose metabolism may be linked to abnormalities of both germ cell and neural crest development.
Anthropometric studies in five children and their mother with a severe form multiple epiphyseal dysplasia
Authors: Villarreal Teresa , Carnevale Alessandra , Mayén Dora Gilda , Takenaga Raúl , del Castillo Victoria
Published: June 2005

We report on a form of multiple epiphyseal dysplasia with striking acromelic shortness in a woman and five of her ten children. The somatometric and metacarpo‐phalangeal pattern profile of the affected individual showed short limb dwarfism and shortness of all the tubular bones of the hand. Epiphyseal irregularities and shortness of the 4th metatarsal bones were outstanding. The disorder showed a dominant and probably autosomal pattern of inheritance with variability of expression.

The measurement of metacarpo‐phalangeal profiles allowed an objective and quantitative assessment of brachydactyly. In the family reported here, there was a clear discrepancy between the severity of shortness of hands and feet and the severity of shortness of stature. This family also illustrates the effects of a single gene in a large kindred, therefore describing the range and variability of a phenotype not otherwise available.
Nonrandom association of atrioventricular canal and del (8p) syndrome
Authors: Marino Bruno , Reale Antonino , Giannotti Aldo , Digilio Maria Cristina , Dallapiccola Bruno
Published: June 2005

We describe a patient with partial deletion of the short arm of chromosome 8 with an atrio‐ventricular canal. This type of congenital heart defect was found in 4 of the 7 previously reported del (8p) children with e congenital heart defect in which the cardiac assessment was complete. The prevalence of an atrioven‐tricular canal in this aneuploidy is high and suggests a nonrandom association of the 2 anomalies.
Constrictive amniotic bands, amniotic adhesions, and limb‐body wall complex: Discrete disruption sequences with pathogenetic overlap
Authors: Moerman Philippe , Fryns Jean‐Pierre , Vandenberghe Kamiel , Lauweryns Joseph M.
Published: June 2005

In a fetopathologic evaluation of 18 cases with amniotic bands, we discerned 3 types of lesions: (1) constrictive tissue bands, (2) amniotic adhesions, and (3) more complex anomaly patterns, designated as limb‐body wall complex (LBWC). Constrictive bands are caused by primary amnion rupture with subsequent entanglement of fetal parts (mostly limbs) by shriveled amniotic strands. Adhesive bands are the result of a broad fusion between disrupted fetal parts (mostly cephalic) and an intact amniotic membrane. Most of the craniofacial defects (encephaloceles and/or facial clefts) occurring in these fetuses are not caused by constrictive amniotic bands, but are the result of a vascular disruption sequence with or without cephalo‐amniotic adhesion. Our observations confirm the fact that amnion rupture is not aconditio sine qua nonfor the development of LBWC. However, LBWC is often complicated by rupture of the unsupported amnion with ensuing formation of constrictive bands. We think that the concept that considers the 3 lesions in question as a single pathogenetic entity is erroneous and will inevitably lead to a never‐ending debate between followers of the 2 prevailing theories. In our view, the theories of Streeter and Torpin are not mutually exclusive but rather apply to different types of lesions. The recognition of constrictive amniotic bands, amniotic adhesions, and LBWC as discrete but often combined disruption sequences with important pathogenetic overlap may resolve many dilemmas in interpretation when a fetus exhibits classical constrictive bands beside more severe defects.
Predictive testing for Huntington disease in Canada: The experience of those receiving an increased risk
Authors: Bloch Maurice , Adam Shelin , Wiggins Sandy , Huggins Marlene , Hayden Michael R.
Published: June 2005

Predictive testing for Huntington disease (HD) has been offered in some parts of Canada for nearly 5 years. Candidates who were expected to have a significant likelihood for psychological problems were those who received an increased risk for developing HD. Sixty‐six persons have now received such an increased risk result. In this manuscript we describe in detail the experiences of 4 such persons who were chosen to illustrate recurrent and common themes which have emerged during counselling, and to highlight the strategies of coping with this information. Themes include difficulties communicating about HD, defensive postures adopted in preparing for testing, ramifications of testing for the whole family, and the impact of being at high risk on the candidates' perception of the future. One candidate has had testing postponed due to active suicidal risk. Only a few candidates have expressed regret at taking the test and no person receiving an increased risk result has made a suicide attempt or required hospitalization. After receiving results, symptoms of depression and anxiety are most common in the first 2 months, but over 1 year, candidates, in general, have less depression but live with a heightened perception of the present. The potential risk of premature diagnosis of HD in an individual with an increased risk result is highlighted. The significant ramifications of testing for the relatives are shown. The importance of communication as a means of establishing a social support network, as well as the hazards of open communication, are discussed. Longitudinal evaluation will provide much needed data on the long‐term effects of living at increased risk for HD.
Incidence of neuronal ceroid‐lipofuscinoses in West Germany: Variation of a method for studying autosomal recessive disorders
Authors: Claussen Matthias , Heim Peter , Knispel Jarold , Goebel Hans H. , Kohlschütter Alfried
Published: June 2005

The incidence of neuronal ceroid‐lipofuscinoses (NCL) in West Germany was determined using a novel method which is applicable to other autosomal recessively inherited diseases. Questionnaires were sent to all pediatric departments (answer rate 189/276, 68%), schools for the blind (39/46, 85%), and neuropathological institutes (15/22,68%). Diagnoses were accepted only when based on firm clinical and/or electron microscopic criteria; 207 such identified patients were sorted according to year of birth. Plotting the cumulative number of new cases per year against the year of birth resulted in a slightly S‐shaped curve. Before the year 1962, the curve is relatively flat, probably due to inefficient case registration. Between 1968 and 1977, the slope of the curve is constant–a steep, nearly straight line. Thereafter the curve flattens out again, likely due to inefficient registration of young, still undiagnosed patients. We interpret the central segment of the curve, which is continuously straight over a period of 10 years and corresponds to 92 patients, as a period in which efficient registration of new cases occurred. The number of live births being 7,211,543 during the same period, the NCL incidence is calculated to be 1.28 per 100,000 live births (0.71 for juvenile NCL and 0.46 for late infantile NCL).
Mapping the gene for juvenile onset neuronal ceroid lipofuscinosis to chromosome 16 by linkage analysis
Authors: Gardiner R. M.
Published: June 2005

The ceroid‐lipofuscinoses are a group of inherited neurodegenerative disorders characterised by the accumulation of autofluorescent lipopigment in neurones and other cell types. The underlying biochemical defect is unknown. Juvenile onset neuronal ceroidlipofuscinosis (Batten disease; Spielmeyer‐Vogt disease) is an autosomal recessive trait. Linkage studies were undertaken to determine the location of the Batten disease (CLN3) mutation. Studies were carried out on 205 members of 42 families in which there were 76 affected individuals. Families originated from 7 North European countries and Canada.

Serum samples from 23 families, including a total of 48 affected children, were tested for a set of “classical markers.” A positive lod score was found with the haptoglobin (Hp) system. The combined male and female maximum lod score was 3.00 at θ = 0.00 and θ = 0.26, respectively. This provided an indication of localisation to the long arm of chromosome 16.

Linkage analysis was then carried out in 42 families using DNA markers for loci on human chromosome 16. The maximal lod score between Batten disease and the locus D16S148 calculated for combined sexes was 6.05. No recombinants were observed. Multilocus analysis using 5 loci indicated the most likely order to be HP–D16S151–D16S150–CLN3–D16S148–D16S147.

Work is in progress to refine the genetic and physical localisation of the Batten disease gene using additional markers in this region and a panel of somatic cell hybrids. Methods are now available which should allow the gene to be isolated and characterised.
Linkage analysis in juvenile neuronal ceroid lipofuscinosis
Authors: Haines Jonathan L. , Yan Wei‐Lang , Boustany Rose‐Mary , Jewell Ann , Julier Cecile , Breakefield Xandra O. , Gusella James F.
Published: June 2005

Neuronal ceroid lipofuscinosis (NCL, Batten disease) is an autosomal recessive disease characterized by progressive mental retardation, cortical atrophy, seizures, and retinal degeneration. Several subtypes have been delineated on the basis of age‐at‐onset and histological characteristics; the most common is the juvenile (JNCL) form. Recently, the gene for JNCL was shown to reside on chromosome 16 through linkage studies to the haptoglobin locus and anonymous DNA markers using numerous European families. We have now examined 8 families from North America with JNCL for linkage to markers in 16q21–23. Results in 3 families tend to support linkage to chromosome 16; 3 families remained uninformative, and 2 families produced negative lod scores in this region. A test of homogeneity was suggestive, but could not significantly reject the null hypothesis of homogeneity. We are continuing to collect families, particularly those with multiple living affecteds, and are identifying other probes in this region. Given close localization on chromosome 16 for JNCL, molecular strategies, including candidate gene strategies, are being explored.
Biochemical studies on the juvenile form of ceroid‐lipofuscinosis
Authors: Pullarkat Raju K. , Morris George N. , Pullarkat Premila S. , Labadie Gundula U. , Zawitosky Sandra E.
Published: June 2005

Accumulation of oligosaccharyl diphosphodolichols (oligo‐PP‐Dol) in brains of patients with various forms of ceroid‐lipofuscinoses (CL) is one of the most reproducible biochemical changes known so far. The objective of this study is to understand the biochemical basis of this observation. The biosynthesis of oligo‐PP‐Dol was studied by the incorporation of labelled glucose from UDP [14C] glucose into oligo‐PP‐Dol in cultured skin fibroblasts, and showed no changes in the level of synthesis. The level of labelled glucose incorporated into glycoproteins was also unchanged, suggesting that there is no decrease in the oligosaccharide transfer to proteins in this disorder. Since the biosynthesis and utilization of oligo‐PP‐dol are unaffected, a defect in the catabolism may be the only possibility for the storage of this compound in CL. Since terminal mannose residues are present in the accumulating oligo‐PP‐Dol, mannosidase activities at pH 4.4 and 6.0 were determined in cultured skin fibroblasts. Both mannosidase activities were unchanged in skin fibroblasts of juvenile CL. Endo‐β‐N‐acetylglucosaminidase‐1 activities were determined in cultured skin fibroblasts using dansylated Man6GlcNAcGlcNAc‐Asn as substrate. In three patients, a drastic reduction in the level of the pH 4.5 enzyme was shown, while the neutral pH enzyme activity was unaffected. A deficiency of the endo‐β‐N‐acetylglucosaminidase‐1 will not only explain the accumulation of oligo‐PP‐Dol but also the known storage of high‐mannose glycoproteins.
Stored dolichyl pyrophosphoryl oligosaccharides in Batten disease
Authors: Hall Nicholas A. , Thomas‐Oates Jane E. , Dell Anne , Haltia Matti , Lake Brian D. , Patrick A. Desmond
Published: June 2005

Each of the 3 childhood forms of Batten disease, juvenile (JB), late‐infantile (LIB), and infantile (IB), have abnormally high brain concentrations of dolichyl pyrophosphoryl oligosaccharides (Dol‐PP‐OS). In this study, the carbohydrate portions of Dol‐PP‐OS were analysed: in JB and LIB, they range in size from Man2GlcNAc2 to Glc3Man9GlcNAc2, predominant components being Man5–7GlcNAc2 and Glc3Man7GlcNAc2. In IB, they range from Man6–9GlcNAc2, no glucose containing oli‐gosacchsrides being identified. In Batten disease, the main subcellular location of Dol‐PP‐OS is within storage material, where it represents up to 7% of the dry weight. [3H]‐Mannose incorporation experiments with cultured fibroblasts show that synthesis of Dol‐PP‐OS in JB is normal. We infer that the glycosyla‐tion intermediate Glc3Man9GlcNAc2‐PP‐dol‐ichol is synthesised normally within the endo‐plasmic reticulum in Batten disease, but that catabolic derivatives accumulate within the lysosomes. It is unclear whether this process is central to the pathogenesis of the disease, though in IB a defect in the release of man‐nose residues from Dol‐PP‐OS is a distinct possibility.
English setter model and juvenile ceroid‐lipofuscinosis in man
Authors: Koppang Nils
Published: June 2005

The etiology of the juvenile type of the human ceroid‐lipofuscinosis (JCL) is unknown, in spite of the fact that the first report of this disease was given more than 160 years ago.

The necessity of good animal models for scientific progress in chronic metabolic diseases in humans is obvious. The inbred strain of English setter with ceroid‐lipofuscinosis (CCL) seems to be a perfect model for human JCL. Dogs with CCL and organs for research purposes are available from Dr. Koppang's experimental kennel in Norway.
Sheep and other animals with ceroid‐lipofuscinoses: Their relevance to Batten disease
Authors: Jolly Robert D. , Martinus Ryan D. , Palmer David N.
Published: June 2005

Distinct pathological and histopathological changes distinguish the ceroid‐lipofuscinoses from other storage diseases of humans and animals. These various disease entities likely reflect a variety of mutations of the same gene, or mutations of different genes associated with metabolism of the same or similar substrates. The disease in sheep most closely resembles the juvenile human disease. In it 50% of the lipopigment consists of subunit c of mitochondrial ATP synthase while the remaining constituents are considered normal for a lysosomal derived cytosome. The same subunit c has been shown to be also stored in affected English Setter, Border Collie, and Tibetan Terrier dogs, the Devon cow, and in the late infantile and juvenile human forms of disease but not in the infantile form. Thus it gives a chemical unity to at least some members of the group and allows a major conceptual change in regard to further directions of research.
Tibetan terrier model of canine ceroid lipofuscinosis
Authors: Riis Ronald C. , Cummings John F. , Loew Ellis R. , de Lahunta Alexander
Published: June 2005

Over a 10‐year period, we have studied the Tibetan terrier's visual electrophysiology, light and electron microscopic (EM) retinal characteristics of a slowly evolving inherited ceroid lipofuscinosis (CL). The retinal degeneration with CL inclusions (rdi) in the inner nuclear layer (bipolar cells) and nerve fiber layer (ganglion cells) has been called “rdi” to differentiate the visual abnormality from typical early retinal degeneration (erd) reported also in the Tibetan terrier. The unique “rdi” electroretinogram (ERG) gives a predominant P III wave at age 7 weeks but becomes more characteristically depressed in all phases over several years. Nyctalopia is the only functional abnormality for the first 5 to 6 year of life. Signs are remarkably few considering the pathology. Microscopic studies of the retina show accumulations, increasing with age, of autofluorescent dense inclusion particles which stain intensely by Luxol fast blue, PAS, and acid‐fast procedures. Ultrastructural studies of the retina show the dense particles to be lamellar membranes repeating every 2 to 4 nm, consistent with ceroid lipofuscin. The inner retinal layers were always the target layer to be affected first and most severely. The ganglion cells were most frequently involved. The photoreceptors eventually degenerated but relatively few particles were found in this layer.

The cytosomes in the cerebral cortex and brainstem neurons resemble lipofuscin, containing granular, lamellar, and globular components. Different pigment bodies were present in the cerebellar Purkinje cells. Neuronal loss which was moderate in the cerebellum and mild in the cerebrum was accompanied by astrogliosis and a striking presence of macrophages. The fine struture of the accumulated lipopigment varied regionally so that cytosomes in the cerebral cortical neurons differed from those in both the Purkinje cells and Bergmann glia of the cerebellum. While it was not possible to identify conclusively successive stages in a neurodegenerative progression, many remarkable cytologic changes were observed. These changes included 1) astrocyte swelling, 2) an abundance of lipopigment‐laden and vacuolated macrophages diffusely arrayed in the cerebrum but more focally concentrated in the cerebellum, and 3) distended macrophages encroaching upon abutting and distorting cerebral cortical neurons.

Personality and learning changes along with mild functional abnormalities begin to show up from 4 to 6 years. The slow progression of neuronal degeneration and the greatly delayed appearance of mild clinical signs suggest that this canine disease may be a practical model for studies on the pathogenesis of neuronal senescence and the adult human form of CL.
Amelioration of clinical disease following bone marrow transplantation in fucosidase‐deficient dogs
Authors: Taylor Rosanne M. , Farrow Brian R. H. , Stewart Graeme J.
Published: June 2005

Canine fucosidosis was studied as an animal model for the treatment of neurovisceral lysosomal storage disease. Following successful bone marrow engraftment, dogs with fucosidosis had increased levels of alpha‐L‐fucosidase enzyme activity in leukocytes, plasma, and neural and visceral tissues. This widespread increase in enzyme activity was accompanied by a rapid improvement in the peripheral nerve and visceral lesions of fucosidosis and a more gradual improvement in the central nervous system pathology. Long‐term engraftment from an early age reduced the severity and slowed the progression of clinical neurological disease. Transplantation after the onset of clinical signs was not effective. These findings suggest that the neurological damage caused by some inherited metabolic disorders, such as fucosidosis, may be preventable but emphasise the need for early diagnosis and treatment.
Monozygotic twinning and Wiedemann‐Beckwith syndrome
Authors: Clayton‐Smith Jill , Read Andrew P , Donnai Dian
Published: June 2005

Monozygotic (MZ) twinning occurs with relatively high frequency in Wiedemann‐Beckwith syndrome (WBS). Ten sets of MZ twins with WBS have been reported. Nine of these have been female and in each case the twins were discordant for the WBS phenotype. The tenth set was male. They were concordant for WBS and both had a duplication of chromosome 15 which they shared in common with their phenotypically normal mother. The WBS gene has been asigned to the locus 11p15 and there appear to be several different genetic mechanisms involving this locus which all give rise to WBS. An imprinting effect for the WBS gene has been proposed because of the transmission of the gene preferentially through the maternal line in some large pedigrees. We describe two further sets of female M7 twins with WBS. One pair is concordant and one discordant for the condition. The possible genetic mechanisms involved in the expression of WBS are discussed, with particular reference to twinning, genomic imprinting and X‐inactivation which is thought to be associated with the occurrence of MZ twinning in females.
Recurrent Wiedemann‐Beckwith syndrome with inversion of chromosome (11)(p11.2p15.5)
Authors: Norman Andrew M , Read Andrew P , Clayton‐Smith Jill , Andrews Tony , Donnai Dian
Published: June 2005

A baby with Wiedemann‐Beckwith syndrome (WBS) and her phenotypically normal mother carried the same paracentric inversion, inv(11)(p11.2 15.5), in the short arm of chromosome 11. A fetus, sib of the affected baby, had the same inversion and ultrasound scan showed exomphalos. The maternal grandmother is clinically and cytogenetically normal. The pattern of affection in this family is consistent with the suggestion that WBS can be caused by lack of a maternally imprinted gene at 11p15.5, and that in this family the inversion disrupts that gene.