A second locus for Rieger syndrome maps to chromosome 13q14.

Rieger syndrome is a genetically and phenotypically heterogeneous disorder typically characterized by malformations of the eyes, teeth, and umbilicus. The syndrome is inherited as an autosomal dominant trait and exhibits significant variable expressivity. One locus associated with this disorder has been mapped to 4q25. Using a large four-generation pedigree, we have identified a second locus for Rieger syndrome located on chromosome 13q14.     

Genetical and ultrastructural aspects of the immotile-cilia syndrome.

The immotile-cilia syndrome is a congenital disorder characterized by all cilia in the body being either immotile or showing an ineffective beating pattern. Most symptoms, not unexpectedly, come from the ciliated epithelia, but two further symptoms are: (1) male sterility caused by the spermatozoa being unable to swim progressively (the sperm tail has the same structure as a cilium), and (2) situs inversus in 50% of the cases possible caused by an inability of embryonic cilia to shift the heart to the left side. By electron microscopy, one can see directly which of the many ciliary components is the missing one. The molecular basis of this congenital defect can then be detected, and it has been found to be a heterogeneous disease. There are many genes that, when mutated, will cause the cilia to be dysfunctional or totally immotile. The fact that many genes may be responsible for the syndrome will also explain why it has a relatively high prevalence and why previous investigators have been unable to locate the (assumed single) gene by linkage analysis. The trait, situs inversus, is of particular interest as it occurs in only 50% of the assumed homozygotes. I conclude that the wild-type genes code for a control of the proper body asymmetry and the mutated ones for a lack of control, and, hence, to a random situs determination.     

Current management of the Wolff-Parkinson-White syndrome.

The Wolff-Parkinson-White syndrome is a multifaceted disorder that ranges from asymptomatic to life threatening. Accounting for approximately 20% of cases of paroxysmal supraventricular tachycardia and with a prevalence perhaps as high as 1 per 500, it is far from a rare disorder. Considering the potentially lethal complications following the administration of digoxin or verapamil, all physicians treating arrhythmias should know when to suspect the Wolff-Parkinson-White syndrome. A careful review of electrocardiograms helps identify cases of the disorder despite a wide range of findings that may mimic other conditions. Major advances in the efficacy of surgical procedures to cure this syndrome make this a reasonable alternative to life-long medical therapy for many patients. Unfortunately, available diagnostic tests lack the positive predictive value to reliably distinguish patients at risk of sudden death. This review is an update for general internists of the major developments in the evaluation and treatment of the disorder and provides specific examples helpful in differentiating these patients.     

Molecular heterogeneity of the fragile X syndrome.

The fragile X syndrome is an X-linked disorder which has been shown to be associated with the length variation of a DNA fragment containing a CGG trinucleotide repeat element at or close to the fragile site. Phenotypically normal carriers of the disorder generally have a smaller length variation than affected individuals. We have cloned the region in cosmids and defined the area containing the amplified sequence. We have used probes from the region to analyse the mutation in families. We show that the mutation evolves in different ways in different individuals of the same family. In addition we show that not all fragile X positive individuals show this amplification of DNA sequence even though they show expression of the fragile site at levels greater than 25%. One patient has alterations in the region adjacent to the CGG repeat elements. Three patients in fragile X families have the normal fragment with amplification in a small population of their cells. These observations indicate that there is molecular heterogeneity in the fragile X syndrome and that the DNA fragment length variation is not the only sequence responsible for the expression of the fragile site or the disease phenotype.     

Split hand and foot deformity and the syndrome of ectrodactyly,ectodermal dysplasia,and clefting (EEC)

Summary Five new cases of ectrodactyly are described. Two patients have the syndrome of ectrodactyly, extodermal dysplasia, and clefting (EEC). In one patient with the EEC syndrome, the disorder seems to represent a new mutation. One woman with isolated ectrodactyly has a daughter with the EEC syndrome. The variation in the clinical expression of this disorder among affected members of the same family makes it difficult to determine whether there may be several mutant alleles responsible for ectrodactyly and its related manifestations.     

Proteus syndrome in 7 patients: clinical and genetic considerations.

The Proteus syndrome is a congenital hamartomatous disorder delineated in 1983. Because of its polymorphic appearance, the syndrome was named after the greek god Proteus whose name means much less than the polymorphous much greater than. Major clinical findings include hemi hypertrophy, macrodactyly, exostoses, scoliosis, epidermal nevi, haemangiomas, deeply rugated soles of the feet and a variety of deep and subcutaneous masses. We report on 7 new cases of Proteus syndrome. All reported cases have been sporadic. Therefore this syndrome could be due to the action of a dominant lethal gene surviving by mosaicism.     

Mapping of a new SGBS locus to chromosome Xp22 in a family with a severe form of Simpson-Golabi-Behmel syndrome.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome with associated visceral and skeletal abnormalities. Alterations in the glypican-3 gene (GPC3), which is located on Xq26, have been implicated in the etiology of relatively milder cases of this disorder. Not all individuals with SGBS have demonstrated disruptions of the GPC3 locus, which raises the possibility that other loci on the X chromosome could be responsible for some cases of this syndrome. We have previously described a large family with a severe form of SGBS that is characterized by multiple anomalies, hydrops fetalis, and death within the first 8 wk of life. Using 25 simple tandem-repeat polymorphism markers spanning the X chromosome, we have localized the gene for this disorder to an approximately 6-Mb region of Xp22, with a maximum LOD score of 3.31 and with LOD scores <-2.0 for all of Xq. These results demonstrate that neither the GPC3 gene nor other genes on Xq26 are responsible for all cases of SGBS and that a second SGBS locus resides on Xp22.     

Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3.

Tourette syndrome is a neuropsychiatric disorder characterized by the presence of multiple, involuntary motor and vocal tics. Associated pathologies include attention deficit disorder and obsessive-compulsive disorder (OCD). Extensive linkage analysis based on an autosomal dominant mode of transmission with reduced penetrance has failed to show linkage with polymorphic markers, suggesting either locus heterogeneity or a polygenic origin for Tourette syndrome. An individual diagnosed with Tourette syndrome has been described carrying a constitutional (7;18) chromosome translocation (Comings et al. 1986). Other family members carrying the translocation exhibit features seen in Tourette syndrome including motor tics, vocal tics, and OCD. Since the disruption of specific genes by a chromosomal rearrangement can elicit a particular phenotype, we have undertaken the physical mapping of the 7;18 translocation such that genes mapping at the site of the breakpoint can be identified and evaluated for a possible involvement in Tourette syndrome. Using somatic cell hybrids retaining either the der(7) or the der(18), a more precise localization of the breakpoints on chromosomes 7 and 18 have been determined. Furthermore, physical mapping has identified two YAC clones that span the translocation breakpoint on chromosome 18 as determined by FISH. These YAC clones will be useful for the eventual identification of genes that map to chromosomes 7 and 18 at the site of the translocation.     

Progress in the search for genetic linkage with Tourette syndrome: An exclusion map covering more than 50% of the autosomal genome

Gilles de la Tourette syndrome is a neuropsychiatric disorder with an autosomal dominant mode of inheritance and reduced penetrance at a single genetic locus. Several research groups have genetic linkage studies underway to detect the chromosomal location of the gene that predisposes for this disorder. Strong and clear evidence of linkage has not yet been produced for Tourette syndrome. This paper presents an overview of the methods and progress of the groups centered at Yale University and Erasmus University in excluding linkage from a large portion of the genome. Our labs have screened 228 genetic marker loci for linkage with a gene for this disorder in a series of affected families in the United States, Canada, The Netherlands, and Norway. More than 50% (and perhaps as much as 66%) of the autosomal genome has now been excluded on the assumption that genetic heterogeneity is not an important factor in the Tourette syndrome pedigrees pooled for this summary.     

Software and database for the analysis of mutations in the human FBN1 gene.

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS and many mutations will have to be accumulated before genotype/phenotype relationships emerge. To facilitate mutational analysis of the FBN1 gene, a software package along with a computerized database (currently listing 63 entries) have been created.     

Marfan's Syndrome: The S. Family Re-visited

Marfan''s syndrome has been transmitted by a single pleiotropic autosomal gene through six generations of a Canadian family. At least 42 members of this family have been affected to date. The natural history of this inherited affliction in this family supports the hypothesis that Marfan''s syndrome is an abiotropic disorder of the connective tissues. Premature degeneration of the connective tissues is responsible for the serious ocular and cardiovascular complications of Marfan''s syndrome, for the shortened life span of affected individuals, and indirectly, for the economic distress of affected members of this family. Because no definitive treatment is available for Marfan''s syndrome, an educational approach to the restriction of child-bearing by affected individuals is proposed.     

Anti-Ri-associated paraneoplastic cerebellar degeneration. Report of a case and revision of the literature

Paraneoplastic cerebellar degeneration associated with anti-Ri antibodies mainly presents with opsoclonus-myoclonus-ataxia. We report here the case of a patient with anti-Ri-antibody paraneoplastic syndrome, who presented four years after treatment for small-cell lung cancer (SCLC) with oscillopsia and gait disorder. On neurological examination vertical nystagmus, ataxic gait and postural tremor of all four limbs was detected. He died one year after the onset of the symptoms because of a acute exacerbation of his severe chronic obstructive pulmonary disease. No SCLC relapse or new cancer has been detected during the one-year follow-up period.To our knowledge, our patient is the first case of anti-Ri associated disorder with oscillopsia and vertical nystagmus as the initially prominent clinical features. The findings of this case study support the variability of anti-Ri-antibody-associated paraneoplastic syndrome. Further studies must be directed to better characterize the mechanisms underlying this syndrome. Finally, paraneoplastic neurological syndromes should be kept in mind also when a neoplastic disease is not demonstrated.     

Measurement of activity of urea resistant neutrophil alkaline phosphatase as an antenatal screening test for Down's syndrome.

OBJECTIVE--To investigate the value of measuring maternal urea resistant neutrophil alkaline phosphatase activity as an antenatal screening test for Down''s syndrome. DESIGN--Case-control study of blood samples collected at nine to 27 weeks of pregnancy. SETTING--Antenatal clinics in London and Oxford. PATIENTS--72 Women whose fetuses had been diagnosed by amniocentesis or chorionic villus sampling as having Down''s syndrome and 156 women whose fetuses did not have the syndrome. Only singleton pregnancies were studied. MAIN OUTCOME MEASURE--Activity of urea resistant neutrophil alkaline phosphatase measured cytochemically. RESULTS--The median enzyme activity in the index patients was 1.65 times the expected median for the controls at the same duration of pregnancy (p less than 0.0001; 95% confidence interval 1.56 to 1.74). A cut off value that identified the 5% of control patients with the highest activities yielded a rate of detection of Down''s syndrome of 79% (95% confidence interval 70 to 89%). CONCLUSION--Activity of urea resistant neutrophil alkaline phosphatase is an effective maternal blood marker for Down''s syndrome. Its use in antenatal screening could lead to a substantial improvement in the detection of this disorder. Before introducing the test into routine medical practice it will have to be automated so that it can be used on a large scale and is less subjective.     

Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34

Ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome [AOA]; MIM 208920) is an autosomal recessive disorder characterized by ataxia, oculomotor apraxia, and choreoathetosis. These neurological features resemble those of ataxia-telangiectasia (AT), but in AOA there are none of the extraneurological features of AT, such as immunodeficiency, neoplasia, chromosomal instability, or sensitivity to ionizing radiation. It is unclear whether these patients have a true disorder of chromosomal instability or a primary neurodegenerative syndrome, and it has not been possible to identify the defective gene in AOA, since the families have been too small for linkage analysis. We have identified a new family with AOA, and we show that the patients have no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that AOA in this family is a true primary cerebellar ataxia. We have localized the disease gene, by linkage analysis and homozygosity mapping, to a 15.9-cM interval on chromosome 9q34. This work will ultimately allow the disease gene to be identified and its relevance to other types of autosomal recessive cerebellar ataxias to be determined.     

Are culture-bound syndromes as real as universally-occurring disorders?

This paper asks what it means to say that a disorder is a "real" disorder and then considers whether culture-bound syndromes are real disorders. Following J.L. Austin I note that when we ask whether some supposed culture-bound syndrome is a real disorder we should start by specifying what possible alternatives we have in mind. We might be asking whether the reported behaviours genuinely occur, that is, whether the culture-bound syndrome is a genuine phenomenon as opposed to a myth. We might be wondering whether the condition should rightly be considered a disorder, as opposed to some sort of non-disorder condition (for example, a non-disorder form of deviance, or a potentially valuable condition). We might want to know whether the culture-bound syndrome is really a distinct disorder, in the sense that scientific classification systems should include it as a separate category, or whether it is just a variant of a universally occurring disorder. I argue that some specific difficulties can arise with determining whether a culture-bound syndrome is a real disorder in each of these three senses. However, the frequent assumption that real disorders will necessarily occur universally, and that those that occur only in certain environments are suspicious is not generally justified.     

Targeting TGF-beta and the extracellular matrix in Marfan's syndrome

Marfan's syndrome is a genetic disorder affecting connective tissues, and it can lead to death due to aortic defects if left untreated. beta-blocker therapy has been used to slow the progression of this disease. Brooke et al. (2008) now report that combining angiotensin II receptor blockade by losartan with beta-blocker treatment is an effective treatment combination therapy for this disorder.     

The Ehlers-Danlos syndrome: the extracellular matrix scaffold in question

Ehlers-Danlos syndrome (EDS) is a heterogeneous heritable connective tissue disorder characterized by hyper-extensible skin, hypermobile joints and fragile vessels. The molecular causes of this disorder are often, although not strictly, related to collagens and to the enzymes that process these proteins. The classical form of the syndrome, which will be principally discussed in this review, can be due to mutations on collagen V, a fibrillar collagen present in small amounts in affected tissues. However, collagen I and tenascin have also been demonstrated to be involved in the same type of EDS. Moreover gene disruption of several other matrix molecules (thrombospondin, SPARC, small leucine rich proteoglycans...) in mice, lead to phenotypes that mimic EDS and these molecules have thus emerged as new players. As collagen V remains the prime candidate, we discuss, based on fundamental and clinical observations, its physiological role. We also explore its potential interactions with other matrix molecules to determine tissue properties.     

Localization of the translocation breakpoint in a female with Menkes syndrome to Xq13.2-q13.3 proximal to PGK-1.

Menkes syndrome is a rare X-linked recessive disorder characterized by an inability to metabolize copper. A female patient with both this disease and an X; autosome translocation with karyotype 46,X,t(X;2)(q13;q32.2) has previously been described. The translocation breakpoint in Xq13 coincides with a previous assignment of the Menkes gene at Xq13 by linkage data in humans and by analogy to the mottled mutations which are models for Menkes disease in the mouse. Therefore, this translocation probably interrupts the gene for Menkes syndrome in band Xq13. We describe here experiments to precisely map the translocation breakpoint within this chromosomal band. We have established a lymphoblastoid cell line from this patient and have used it to isolate the der(2) translocation chromosome (2pter----2q32::Xq13----Xqter) in human/hamster somatic cell hybrids. Southern blot analyses using a number of probes specific for chromosomes X and 2 have been studied to define precisely the location of the translocation breakpoint. Our results show that the breakpoint in this patient--and, therefore, likely the Menkes gene--maps to a small subregion of band Xq13.2-q13.3 proximal to the PGK1 locus and distal to all other Xq13 loci tested.     

Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12.

Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormalities. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this region. The presence of interstitial deletions of varying size led to the hypothesis that AGS is a contiguous gene deletion syndrome. This molecular analysis of cytogenetically normal AGS patients was performed in order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagille families led to the identification of a single submicroscopic deletion. The deletion included loci D20S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome.